ORCID Profile
0000-0001-6031-6953
Current Organisation
University of Nottingham
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Publisher: Public Library of Science (PLoS)
Date: 06-07-2021
DOI: 10.1371/JOURNAL.PMED.1003686
Abstract: Timely interventions in women presenting with preterm labour can substantially improve health outcomes for preterm babies. However, establishing such a diagnosis is very challenging, as signs and symptoms of preterm labour are common and can be nonspecific. We aimed to develop and externally validate a risk prediction model using concentration of vaginal fluid fetal fibronectin (quantitative fFN), in combination with clinical risk factors, for the prediction of spontaneous preterm birth and assessed its cost-effectiveness. Pregnant women included in the analyses were 22 +0 to 34 +6 weeks gestation with signs and symptoms of preterm labour. The primary outcome was spontaneous preterm birth within 7 days of quantitative fFN test. The risk prediction model was developed and internally validated in an in idual participant data (IPD) meta-analysis of 5 European prospective cohort studies (2009 to 2016 1,783 women mean age 29.7 years median BMI 24.8 kg/m 2 67.6% White 11.7% smokers 51.8% nulliparous 10.4% with multiple pregnancy 139 [7.8%] with spontaneous preterm birth within 7 days). The model was then externally validated in a prospective cohort study in 26 United Kingdom centres (2016 to 2018 2,924 women mean age 28.2 years median BMI 25.4 kg/m 2 88.2% White 21% smokers 35.2% nulliparous 3.5% with multiple pregnancy 85 [2.9%] with spontaneous preterm birth within 7 days). The developed risk prediction model for spontaneous preterm birth within 7 days included quantitative fFN, current smoking, not White ethnicity, nulliparity, and multiple pregnancy. After internal validation, the optimism adjusted area under the curve was 0.89 (95% CI 0.86 to 0.92), and the optimism adjusted Nagelkerke R 2 was 35% (95% CI 33% to 37%). On external validation in the prospective UK cohort population, the area under the curve was 0.89 (95% CI 0.84 to 0.94), and Nagelkerke R 2 of 36% (95% CI: 34% to 38%). Recalibration of the model’s intercept was required to ensure overall calibration-in-the-large. A calibration curve suggested close agreement between predicted and observed risks in the range of predictions 0% to 10%, but some miscalibration (underprediction) at higher risks (slope 1.24 (95% CI 1.23 to 1.26)). Despite any miscalibration, the net benefit of the model was higher than “treat all” or “treat none” strategies for thresholds up to about 15% risk. The economic analysis found the prognostic model was cost effective, compared to using qualitative fFN, at a threshold for hospital admission and treatment of ≥2% risk of preterm birth within 7 days. Study limitations include the limited number of participants who are not White and levels of missing data for certain variables in the development dataset. In this study, we found that a risk prediction model including vaginal fFN concentration and clinical risk factors showed promising performance in the prediction of spontaneous preterm birth within 7 days of test and has potential to inform management decisions for women with threatened preterm labour. Further evaluation of the risk prediction model in clinical practice is required to determine whether the risk prediction model improves clinical outcomes if used in practice. The study was approved by the West of Scotland Research Ethics Committee (16/WS/0068). The study was registered with ISRCTN Registry ( ISRCTN 41598423 ) and NIHR Portfolio (CPMS: 31277).
Publisher: Oxford University Press (OUP)
Date: 19-02-2010
Abstract: The onset of labour is associated with inflammatory cascades in the uteroplacental unit, and these are prematurely activated in preterm labour. Infection can induce an inflammatory response, which results in premature onset of the pro-inflammatory parturient cascades and preterm delivery. We have become interested in two proteins called prokineticins and the role they may play in labour and its premature onset. Prokineticin 1 and 2 bind to two G-protein coupled receptors, called prokineticin receptor 1 and 2. Expression of the prokineticins and their receptors is elevated in the uteroplacental unit during labour and they can induce expression of a host of genes known to be important in initiating the inflammatory and contractile events of labour. Prokineticins have also been shown to directly induce contractility of smooth muscles. Analysing the promoter regions of the prokineticins and their receptors highlights their potential regulation by pathways activated by infectious agents. Hence, we propose that infection can result in premature activation of prokineticin expression and signalling in the uteroplacental unit and this initiates a premature inflammatory and contractile cascade leading to preterm birth. Antagonism of prokineticin action may provide a suitable therapy for preterm labour that targets both inflammation and contractile pathways.
Publisher: Wiley
Date: 23-04-2012
DOI: 10.1111/J.1365-2265.2011.04317.X
Abstract: Circulating concentrations of the peptide kisspeptin have been proposed as a novel biomarker for early detection of pre-ecl sia. Our aims were to assess analytical and clinical performance characteristics of a commercial kisspeptin assay and to determine sensitivity and specificity of the test for pre-ecl sia. Prospective, longitudinal study in a United Kingdom tertiary referral Antenatal Metabolic Clinic. Severely obese (body mass index, BMI > 40 kg/m(2), n = 194) and lean (BMI < 25 kg/m(2), n = 78) pregnant women. A commercial kisspeptin ELISA (Phoenix Pharmaceuticals) was assessed for analytical sensitivity, specificity, precision, linearity, recovery and stability in maternal plasma s les at 16, 28 and 36 weeks gestation. Pre-ecl sia, defined using International Society for the Study of Hypertension in Pregnancy guidelines blood pressure delivery gestation birthweight. Kisspeptin concentrations were lower in early pregnancy in obese women (P < 0.001), and in women who later developed pre-ecl sia (P < 0.05), compared with women with uncomplicated pregnancies. For 16-week plasma kisspeptin in prediction of pre-ecl sia, area under the receiver-operator characteristic curve was 0.80 (P < 0.01), positive and negative likelihood ratios were 3.0 and 0.2, and test sensitivity and specificity were 85.7 and 71.4%, respectively. In regression analyses, kisspeptin (16 weeks) associated positively with delivery gestation (P < 0.05) and birthweight (P < 0.0001), and negatively with 28- and 36-week blood pressure (P < 0.0001). Kisspeptin concentration in early pregnancy is a promising biomarker for pre-ecl sia and low birthweight but cannot be recommended, in isolation, for universal screening because of inadequate test sensitivity and specificity. Large-scale studies are required to assess its potential in a panel of biomarkers.
Publisher: Oxford University Press (OUP)
Date: 11-2013
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.PSYNEUEN.2015.09.019
Abstract: The maternal hypothalamic-pituitary-adrenal-axis (HPAA) undergoes dramatic activation during pregnancy. Increased cortisol and corticotrophin-releasing-hormone (CRH) associate with low birthweight and preterm labor. In non-pregnant obesity, the HPAA is activated but circulating cortisol levels are normal or lower than in lean women. We hypothesized that maternal cortisol levels would be lower in obese pregnancy, and would associate with increased fetal size and length of gestation. Fasting serum cortisol was measured at 16, 28 and 36 weeks gestation and at 3-6 months postpartum in 276 severely obese and 135 lean women. In a subset of obese (n=20) and lean (n=20) we measured CRH, hormones that regulate bioavailable cortisol (corticosteroid-binding-globulin, estradiol, estriol, and progesterone). Urinary glucocorticoid metabolites were measured in pregnant (obese n=6, lean n=5) and non-pregnant (obese n=7, lean n=7) subjects. Maternal cortisol and HPAA hormones were lower in obese pregnancy. Total urinary glucocorticoid metabolites increased significantly in lean pregnancy, but not in obese. Lower maternal cortisol in obese tended to be associated with increased birthweight (r=-0.13, p=0.066). In obese, CRH at 28 weeks correlated inversely with gestational length (r=-0.49, p=0.04), and independently predicted gestational length after adjustment for confounding factors (mean decrease in CRH of -0.25 pmol/L (95% CI -0.45 to -0.043 pmol/L) per/day increase in gestation). In obese pregnancy, lower maternal cortisol without an increase in urinary glucocorticoid clearance may indicate a lesser activation of the HPAA than in lean pregnancy. This may offer a novel mechanism underlying increased birthweight and longer gestation in obese pregnancy.
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.PSYNEUEN.2015.05.004
Abstract: Maternal emotional distress symptoms, including life satisfaction, anxiety and depressed mood, are worse in Severely Obese (SO) than lean pregnancy and may alter placental genes regulating fetal glucocorticoid exposure and placental growth. We hypothesised that the associations between increased maternal distress symptoms and changes in placental gene expression including IGF2 and genes regulating fetal glucocorticoid exposure are more pronounced in SO pregnancy. We also considered whether there were sex-specific effects. Placental mRNA levels of 11β-HSDs, NR3C1-α, NR3C2, ABC transporters, mTOR and the IGF2 family were measured in term placental s les from 43 lean (BMI≤25kg/m(2)) and 50 SO (BMI≥40kg/m(2)) women, in whom distress symptoms were prospectively evaluated during pregnancy. The mRNA levels of genes with a similar role in regulating fetal glucocorticoid exposure were strongly inter-correlated. Increased maternal distress symptoms associated with increased NR3C2 and IGF2 isoform 1(IGF2-1) in both lean and SO group (p≤0.05). Increased distress was associated with higher ABCB1 and ABCG2 mRNA levels in SO but lower ABCB1 and higher 11β-HSD1 mRNA levels in lean (p≤0.05) suggesting a protective adaptive response in SO placentas. Increased maternal distress associated with reduced mRNA levels of ABCB1, ABCG2, 11β-HSD2, NR3C1-α and IGF2-1 in placentas of female but not male offspring. The observed sex differences in placental responses suggest greater vulnerability of female fetuses to maternal distress with potentially greater fetal glucocorticoid exposure and excess IGF2. Further studies are needed to replicate these findings and to test whether this translates to potentially greater negative outcomes of maternal distress in female offspring in early childhood.
Publisher: Wiley
Date: 22-01-2018
DOI: 10.1111/AJO.12762
Abstract: The National Health and Medical Research Council (NHMRC) Centre of Research Excellence in Stillbirth and the Perinatal Society of Australia and New Zealand (PSANZ) have recently partnered in updating an important clinical practice guideline, Care of pregnant women with decreased fetal movements. This guideline offers 12 recommendations and a suggested care pathway, with the aim to improve the quality of care for women reporting decreased fetal movements through an evidence-based approach. Adoption of the guideline by clinicians and maternity hospitals could result in earlier identification of higher-risk pregnancies, improved perinatal health outcomes for women and their babies, and reduced stillbirth rates.
Publisher: Wiley
Date: 13-09-2017
Publisher: Springer Science and Business Media LLC
Date: 02-11-2020
DOI: 10.1186/S12916-020-01766-9
Abstract: Pre-ecl sia 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-ecl sia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-ecl sia using in idual 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. IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-ecl sia 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-ecl sia 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. 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%. 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-ecl sia 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. PROSPERO ID: CRD42015029349 .
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.PREGHY.2014.03.028
Abstract: The hypothalamic-pituitary-adrenal (HPA) axis is important for fetal growth and timing of parturition. Maternal obesity is associated with macrosomia (birthweight ⩾4000g) and prolonged pregnancy (⩾41weeks). We aimed to characterise HPA axis hormones in obese pregnancy and to test associations with these pregnancy outcomes. Fasting cortisol was measured by radioimmunoassay in venous blood at 16, 28 and 36 weeks of gestation in 286 obese (BMI 44.05±3.98kg/m(2)) and 137 lean (BMI 22.71±1.66kg/m(2)) pregnant women. In subsets (n=20 obese, 20 lean) we measured corticosteroid binding globulin (CBG) and CRH by radioimmunoassay progesterone, estradiol (E2), estriol (E3) and sex-hormone-binding-globulin (SHBG) by ELISA and albumin by bromocresol green binding. Free cortisol levels were calculated using Coolen's equation. Cortisol, CBG, calculated free cortisol, CRH, E2, E3, progesterone and SHBG levels rose similarly during pregnancy in obese and lean, but were significantly lower in obese (p<0.05). In obese, lower free cortisol at 16 weeks was associated with higher birthweight (r=-0.46, p<0.05). Cortisol was not associated with labour onset. CRH was significantly lower at 36 weeks in women who delivered at ⩾41weeks and in women with macrosomic babies (p<0.05) and correlated negatively with gestation at delivery in obese (r=-0.557, p<0.05). Our findings suggest that decreased HPA axis activity in obese pregnancy may be a mechanism underlying macrosomia and prolonged pregnancy.
Publisher: Springer Science and Business Media LLC
Date: 2008
Abstract: At term, amniotic fluid contents may mediate the onset of labor through the activation of amniotic fluid macrophages and their migration into the myometrium. To test this concept, the authors examine the histological changes that occur in myometrial biopsies at term prior to (n = 53) and during (n = 15) labor. Biopsies were stained with an antimacrophage antibody, anti-CD34 (endothelial cells), and anti-caspase 3 (apoptotic cells). The s les showed a variable inflammatory infiltrate of neutrophils and macrophages, with a greater infiltrate in the s les obtained during labor (P < .001, Fisher exact test). Prior to labor, there were prominent changes in the myometrial fibers that reflected shearing, shrinkage, edema, and particularly apoptosis endothelial cells of thin-walled vessels prominent in the biopsies displayed marked nuclear biotinylation, and the vascular lumen contained fibrin and platelet thrombi, microparticles, desquamated endothelial cells, amniotic squamous cells, and mucoid material. These changes were also present in s les obtained during labor. In an additional 10 patients in labor with male fetuses, myometrial s les were examined for the presence of macrophages carrying a Y chromosome indicative of a fetal origin, but none were observed. These findings suggest that endothelial cell damage and amniotic fluid embolism are very common at term prior to clinical labor and provide a mechanism by which surfactant protein A and phospholipids present in the amniotic fluid may access myometrial cells and provoke the inflammatory response that occurs during parturition. The authors' studies give no support to the suggestion that fetal macrophages might invade the human myometrium at term.
Publisher: Public Library of Science (PLoS)
Date: 09-03-2017
Publisher: BMJ
Date: 07-2013
Publisher: National Institute for Health and Care Research
Date: 09-2021
DOI: 10.3310/HTA25520
Abstract: The diagnosis of preterm labour is challenging. False-positive diagnoses are common and result in unnecessary, potentially harmful treatments (e.g. tocolytics, antenatal corticosteroids and magnesium sulphate) and costly hospital admissions. Measurement of fetal fibronectin in vaginal fluid is a biochemical test that can indicate impending preterm birth. To develop an externally validated prognostic model using quantitative fetal fibronectin concentration, in combination with clinical risk factors, for the prediction of spontaneous preterm birth and to assess its cost-effectiveness. The study comprised (1) a qualitative study to establish the decisional needs of pregnant women and their caregivers, (2) an in idual participant data meta-analysis of existing studies to develop a prognostic model for spontaneous preterm birth within 7 days in women with symptoms of preterm labour based on quantitative fetal fibronectin and clinical risk factors, (3) external validation of the prognostic model in a prospective cohort study across 26 UK centres, (4) a model-based economic evaluation comparing the prognostic model with qualitative fetal fibronectin, and quantitative fetal fibronectin with cervical length measurement, in terms of cost per QALY gained and (5) a qualitative assessment of the acceptability of quantitative fetal fibronectin. The model was developed using data from five European prospective cohort studies of quantitative fetal fibronectin. The UK prospective cohort study was carried out across 26 UK centres. Pregnant women at 22 +0 –34 +6 weeks’ gestation with signs and symptoms of preterm labour. Quantitative fetal fibronectin. Spontaneous preterm birth within 7 days. The in idual participant data meta-analysis included 1783 women and 139 events of spontaneous preterm birth within 7 days (event rate 7.8%). The prognostic model that was developed included quantitative fetal fibronectin, smoking, ethnicity, nulliparity and multiple pregnancy. The model was externally validated in a cohort of 2837 women, with 83 events of spontaneous preterm birth within 7 days (event rate 2.93%), an area under the curve of 0.89 (95% confidence interval 0.84 to 0.93), a calibration slope of 1.22 and a Nagelkerke R 2 of 0.34. The economic analysis found that the prognostic model was cost-effective compared with using qualitative fetal fibronectin at a threshold for hospital admission and treatment of ≥ 2% risk of preterm birth within 7 days. The outcome proportion (spontaneous preterm birth within 7 days of test) was 2.9% in the validation study. This is in line with other studies, but having slightly fewer than 100 events is a limitation in model validation. A prognostic model that included quantitative fetal fibronectin and clinical risk factors showed excellent performance in the prediction of spontaneous preterm birth within 7 days of test, was cost-effective and can be used to inform a decision support tool to help guide management decisions for women with threatened preterm labour. The prognostic model will be embedded in electronic maternity records and a mobile telephone application, enabling ongoing data collection for further refinement and validation of the model. This study is registered as PROSPERO CRD42015027590 and Current Controlled Trials ISRCTN41598423. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment Vol. 25, No. 52. See the NIHR Journals Library website for further project information.
Publisher: Elsevier BV
Date: 09-2013
DOI: 10.1016/J.PLEFA.2013.07.001
Abstract: To investigate the effect of omega-3 PUFAs, eicosapentanoic acid (EPA) and docosohexanoic acid (DHA) on inflammatory cytokine production in the amnion. Amnion explants were obtained at elective caesarean sections and cultured in vitro with EPA and DHA. IL-8 and IL-6 secretion was determined by ELISA, the role of PPARγ was investigated using specific agonists and antagonists and activity of MMP assessed by gelatin zymography. A combination of EPA and DHA significantly reduced the concentration of IL-8 and IL-6 released into the supernatant compared to untreated controls (p<0.001). Stimulation of PPARγ with troglitazone reduced IL-8 production, and the PPARγ antagonist GW9662 partially reversed this effect. The activity of MMP-9 was also significantly reduced by treatment with EPA and DHA in combination compared to untreated control (p<0.05). The omega-3 PUFAs EPA and DHA decrease the inflammatory response of the amnion, and this may be partially mediated through PPARγ.
Publisher: Springer Science and Business Media LLC
Date: 21-11-2019
DOI: 10.1186/S12884-019-2575-1
Abstract: Stillbirth is a devastating pregnancy outcome that has a profound and lasting impact on women and families. Globally, there are over 2.6 million stillbirths annually and progress in reducing these deaths has been slow. Maternal perception of decreased fetal movements (DFM) is strongly associated with stillbirth. However, maternal awareness of DFM and clinical management of women reporting DFM is often suboptimal. The My Baby’s Movements trial aims to evaluate an intervention package for maternity services including a mobile phone application for women and clinician education (MBM intervention) in reducing late gestation stillbirth rates. This is a stepped wedge cluster randomised controlled trial with sequential introduction of the MBM intervention to 8 groups of 3–5 hospitals at four-monthly intervals over 3 years. The target population is women with a singleton pregnancy, without lethal fetal abnormality, attending for antenatal care and clinicians providing maternity care at 26 maternity services in Australia and New Zealand. The primary outcome is stillbirth from 28 weeks’ gestation. Secondary outcomes address: a) neonatal morbidity and mortality b) maternal psychosocial outcomes and health-seeking behaviour c) health services utilisation d) women’s and clinicians’ knowledge of fetal movements and e) cost. 256,700 births (average of 3170 per hospital) will detect a 30% reduction in stillbirth rates from 3/1000 births to 2/1000 births, assuming a significance level of 5%. Analysis will utilise generalised linear mixed models. Maternal perception of DFM is a marker of an at-risk pregnancy and commonly precedes a stillbirth. MBM offers a simple, inexpensive resource to reduce the number of stillborn babies, and families suffering the distressing consequences of such a loss. This large pragmatic trial will provide evidence on benefits and potential harms of raising awareness of DFM using a mobile phone app. ACTRN12614000291684 . Registered 19 March 2014. Protocol Version 6.1, February 2018.
Publisher: Wiley
Date: 02-12-2015
Abstract: Decreased fetal movement is associated with adverse pregnancy and birth outcomes timely reporting and appropriate management may prevent stillbirth. Determine effects of interventions to enhance maternal awareness of decreased fetal movement. Cinahl, The Cochrane Library, EMBASE, MEDLINE, PsycINFO and SCOPUS databases without limitation on language or publication year. Randomised or non-randomised studies evaluating interventions to enhance maternal awareness of decreased fetal movement. Two authors independently extracted data and assessed quality. We included 23 publications from 16 studies of fair to poor quality. We were unable to pool results due to substantial heterogeneity between studies. Three randomised controlled trials (RCTs) and five non-randomised studies (NRSs), involving 72 888 and 115 435 pregnancies, respectively, assessed effects of interventions on stillbirth and perinatal death. One large cluster RCT (n = 68 654) reported no stillbirth reduction, one RCT (n = 3111) reported significant stillbirth reduction, and one RCT (n = 1123) was small with no deaths. All NRSs favoured intervention over standard care three studies (n = 31 131) reported significant reduction, whereas two studies (n = 84 304) reported non-significant reductions in stillbirth or perinatal deaths. Promising results from NRSs warrant further research. We found no evidence of increased maternal concern following interventions. No cost-effectiveness data were available. We found no clear evidence of benefit or harm indirect evidence suggests improved pregnancy and birth outcomes. The optimal approach to support women in monitoring their pregnancies needs to be established. Meanwhile, women need to be informed about the importance of fetal movement for fetal health. The benefits and risks of interventions to increase pregnant women's awareness of fetal movement are unclear.
Publisher: Wiley
Date: 25-02-2015
DOI: 10.1016/J.IJGO.2015.02.008
Abstract: While we believe that pre-ecl sia matters-because it remains a leading cause of maternal and perinatal morbidity and mortality worldwide-we are convinced that the time has come to look beyond single clinical entities (e.g. pre-ecl sia, postpartum hemorrhage, obstetric sepsis) and to look for an integrated approach that will provide evidence-based personalized care to women wherever they encounter the health system. Accurate outcome prediction models are a powerful way to identify in iduals at incrementally increased (and decreased) risks associated with a given condition. Integrating models with decision algorithms into mobile health (mHealth) applications could support community and first level facility healthcare providers to identify those women, fetuses, and newborns most at need of facility-based care, and to initiate lifesaving interventions in their communities prior to transportation. In our opinion, this offers the greatest opportunity to provide distributed in idualized care at scale, and soon.
Publisher: National Institute for Health and Care Research
Date: 12-2020
DOI: 10.3310/HTA24720
Abstract: Pre-ecl sia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management. To assess the performance of existing pre-ecl sia prediction models and to develop and validate models for pre-ecl sia using in idual participant data meta-analysis. We also estimated the prognostic value of in idual markers. This was an in idual participant data meta-analysis of cohort studies. Source data from secondary and tertiary care. We identified predictors from systematic reviews, and prioritised for importance in an international survey. Early-onset (delivery at 34 weeks’ gestation), late-onset (delivery at ≥ 34 weeks’ gestation) and any-onset pre-ecl sia. 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 C -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 I 2 and τ 2 . A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of in idual predictors for pre-ecl sia as odds ratios with 95% confidence and prediction intervals. The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-ecl sia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C -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-ecl sia, and lowest for the first-trimester clinical characteristics models to predict any pre-ecl sia. 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-ecl sia, 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-ecl sia. 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 in idual participant data. 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. 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. This study is registered as PROSPERO CRD42015029349. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment Vol. 24, No. 72. See the NIHR Journals Library website for further project information.
Publisher: Bioscientifica
Date: 12-2013
DOI: 10.1530/REP-13-0295
Abstract: The mechanisms that regulate the induction of term or preterm delivery (PTD) are not fully understood. Infection is known to play a role in the induction of pro-inflammatory cascades in uteroplacental tissues associated with preterm pathological parturition. Similar but not identical cascades are evident in term labour. In the current study, we used a mouse model to evaluate the role of prokineticins in term and preterm parturition. Prokineticins are multi-functioning secreted proteins that signal through G-protein-coupled receptors to induce gene expression, including genes important in inflammatory responses. Expression of prokineticins ( Prok1 and Prok2 ) was quantified in murine uteroplacental tissues by QPCR in the days preceding labour (days 16–19). Prok1 mRNA expression increased significantly on D18 in fetal membranes (compared with D16) but not in uterus or placenta. Intrauterine injection of PROK1 on D17 induced fetal membrane mRNA expression of the pro-inflammatory mediators Il6 , Il1b , Tnf , Cxcl2 and Cxcl5 , which are not normally up-regulated until D19 of pregnancy. However, intrauterine injection of PROK1 did not result in PTD. As expected, injection of lipopolysaccharide (LPS) induced PTD, but this was not associated with changes in expression of Prok1 or its receptor ( Prokr1 ) in fetal membranes. These results suggest that although Prok1 exhibits dynamic mRNA regulation in fetal membranes preceding labour and induces a pro-inflammatory response when injected into the uterus on D17, it is insufficient to induce PTD. Additionally, prokineticin up-regulation appears not to be part of the LPS-induced inflammatory response in mouse fetal membranes.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.PLACENTA.2015.11.015
Abstract: Gestational diabetes mellitus is defined by new-onset glucose intolerance during pregnancy. About 2-5% of all pregnant women develop gestational diabetes during their pregnancies and the prevalence has increased considerably during the last decade. This metabolic condition is manifested when pancreatic β-cells lose their ability to compensate for increased insulin resistance during pregnancy, however, the pathogenesis of the disease remains largely unknown. Gestational diabetes is strongly associated with adverse pregnancy outcome as well as with long-term adverse effects on the offspring which likely occurs due to epigenetic modifications of the fetal genome. In the current review we address gestational diabetes and the short and long term complications for both mothers and offspring focusing on the importance of fetal programming in conferring risk of developing diseases in adulthood.
Publisher: Wiley
Date: 10-07-2009
DOI: 10.1111/J.1471-0528.2009.02236.X
Abstract: To assess the cost-effectiveness of outpatient (at home) cervical ripening with isosorbide mononitrate (IMN) prior to induction of labour. Economic evaluation was conducted alongside a randomised placebo controlled trial (the IMOP trial). Large UK maternity hospital. A total of 350 nulliparous women with a singleton pregnancy, cephalic presentation > or = 37 weeks gestation, requiring cervical ripening prior to induction of labour. Isosorbide mononitrate (n = 177) or placebo (n = 173) self-administered vaginally at home at 48, 32 and 16 hours prior to the scheduled time of admission for induction. Mean health service costs between the period of randomisation and discharge for mother and infant were 1254.86 pound sterling in the IMN group and 1242.88 pound sterling in the placebo group, generating a mean cost difference of 11.98 pound sterling (bootstrap mean cost difference 12.86 pound sterling 95%CI: -106.79 pound sterling, 129.39 pound sterling) that was not statistically significant (P = 0.842). The incremental cost per hour prevented from hospital admission to delivery was 7.53 pound sterling. At the notional willingness to pay threshold of 100 pound sterling per hour prevented from hospital admission to delivery, the probability that IMN is cost-effective was estimated at 0.67. This translated into a mean net monetary benefit of 98.13 pound sterling for each woman given IMN. Although the probability that IMN is cost-effective approaches 0.7 at seemingly low willingness to pay thresholds for an hour prevented from hospital admission to delivery, our results should be viewed in the light of the clinical findings from the IMOP trial.
Publisher: BMJ
Date: 05-2020
DOI: 10.1136/BMJOPEN-2020-036981
Abstract: Gestational diabetes mellitus (GDM) is a common disorder of pregnancy and contributes to adverse pregnancy outcomes. Metformin is often used for the prevention and management of GDM however, its use in pregnancy continues to be debated. The Metformin in Pregnancy Study aims to use in idual patient data (IPD) meta-analysis to clarify the efficacy and safety of metformin use in pregnancy and to identify relevant knowledge gaps. MEDLINE, EMBASE and all Evidence-Based Medicine will be systematically searched for randomised controlled trials (RCT) testing the efficacy of metformin compared with placebo, usual care or other interventions in pregnant women. Two independent reviewers will assess eligibility using prespecified criteria and will conduct data extraction and quality appraisal of eligible studies. Authors of included trials will be contacted and asked to contribute IPD. Primary outcomes include maternal glycaemic parameters and GDM, as well as neonatal hypoglycaemia, anthropometry and gestational age at delivery. Other adverse maternal, birth and neonatal outcomes will be assessed as secondary outcomes. IPD from these RCTs will be harmonised and a two-step meta-analytic approach will be used to determine the efficacy and safety of metformin in pregnancy, with a priori adjustment for covariates and subgroups to examine effect moderators of treatment outcomes. Sensitivity analyses will assess heterogeneity, risk of bias and the impact of trials which have not provided IPD. All IPD will be deidentified and studies contributing IPD will have ethical approval from their respective local ethics committees. This study will provide robust evidence regarding the efficacy and safety of metformin use in pregnancy, and may identify subgroups of patients who may benefit most from this treatment modality. Findings will be published in peer-reviewed journals and disseminated at scientific meetings, providing much needed evidence to inform clinical and public health actions in this area.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Jane Norman.