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

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 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 I2 and τ2. 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 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-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 Health Technology Assessment; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Pre-eclampsia, a condition in pregnancy that results in raised blood pressure and protein in the urine, is a major cause of complications for the mother and baby. WHAT IS NEEDED?: A way of accurately identifying women at high risk of pre-eclampsia to allow clinicians to start preventative interventions such as administering aspirin or frequently monitoring women during pregnancy. WHERE ARE THE RESEARCH GAPS?: Although over 100 tools (models) have been reported worldwide to predict pre-eclampsia, to date their performance in women managed in the UK NHS is unknown. WHAT DID WE PLAN TO DO?: We planned to comprehensively identify all published models that predict the risk of pre-eclampsia occurring at any time during pregnancy and to assess if this prediction is accurate in the UK population. If the existing models did not perform satisfactorily, we aimed to develop new prediction models. WHAT DID WE FIND?: We formed the International Prediction of Pregnancy Complications network, which provided data from a large number of studies (78 studies, 25 countries, 125 researchers, 3,570,993 singleton pregnancies). We were able to assess the performance of 24 out of the 131 models published to predict pre-eclampsia in 11 UK data sets. The models did not accurately predict the risk of pre-eclampsia across all UK data sets, and their performance varied within individual data sets. We developed new prediction models that showed promising performance on average across all data sets, but their ability to correctly identify women who develop pre-eclampsia varied between populations. The models were more clinically useful when used in the care of first-time mothers pregnant with one child, compared to a strategy of treating them all as if they were at high-risk of pre-eclampsia. WHAT DOES THIS MEAN?: Before using the International Prediction of Pregnancy Complications models in various populations, they need to be adjusted for characteristics of the particular population and the setting of application.

Author Correction: Associations of social and economic and pregnancy exposures with blood pressure in UK White British and Pakistani children age 4/5.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Associations of social and economic and pregnancy exposures with blood pressure in UK White British and Pakistani children age 4/5.

South Asians have higher rates of coronary heart disease (CHD) than White European individuals. Blood pressure (BP) is one of the most important risk factors for CHD and ethnic differences in BP have been identified in childhood. Early life exposures could explain some of these differences. We examined associations of family social and economic and maternal pregnancy exposures and BP at age 4/5 in 1644 White British and 1824 Pakistani mother-offspring pairs from the Born in Bradford study. We found that systolic BP was similar but diastolic BP was higher, in Pakistani compared to White British children (adjusted mean differences were -0.170 mmHg 95% CI -0.884, 0.543 for systolic BP; 1.328 mmHg 95% CI 0.592, 2.064 for diastolic BP). Social and economic exposures were not associated with BP in either ethnic group. Maternal BMI was positively associated with BP in both groups but this association was mediated by child BMI. Only gestational hypertension was associated with child systolic and diastolic BP and this was only identified in Pakistani mother-offspring pairs. These findings suggest that Pakistani populations may have a different BP trajectory compared to White British groups and that this is already evident at age 4/5 years.

The identification and treatment of women with hyperglycaemia in pregnancy: an analysis of individual participant data, systematic reviews, meta-analyses and an economic evaluation.

BACKGROUND: Gestational diabetes mellitus (GDM) is associated with a higher risk of important adverse outcomes. Practice varies and the best strategy for identifying and treating GDM is unclear. AIM: To estimate the clinical effectiveness and cost-effectiveness of strategies for identifying and treating women with GDM. METHODS: We analysed individual participant data (IPD) from birth cohorts and conducted systematic reviews to estimate the association of maternal glucose levels with adverse perinatal outcomes; GDM prevalence; maternal characteristics/risk factors for GDM; and the effectiveness and costs of treatments. The cost-effectiveness of various strategies was estimated using a decision tree model, along with a value of information analysis to assess where future research might be worthwhile. Detailed systematic searches of MEDLINE® and MEDLINE In-Process & Other Non-Indexed Citations®, EMBASE, Cumulative Index to Nursing and Allied Health Literature Plus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment database, NHS Economic Evaluation Database, Maternity and Infant Care database and the Cochrane Methodology Register were undertaken from inception up to October 2014. RESULTS: We identified 58 studies examining maternal glucose levels and outcome associations. Analyses using IPD alone and the systematic review demonstrated continuous linear associations of fasting and post-load glucose levels with adverse perinatal outcomes, with no clear threshold below which there is no increased risk. Using IPD, we estimated glucose thresholds to identify infants at high risk of being born large for gestational age or with high adiposity; for South Asian (SA) women these thresholds were fasting and post-load glucose levels of 5.2 mmol/l and 7.2 mmol/l, respectively and for white British (WB) women they were 5.4 and 7.5 mmol/l, respectively. Prevalence using IPD and published data varied from 1.2% to 24.2% (depending on criteria and population) and was consistently two to three times higher in SA women than in WB women. Lowering thresholds to identify GDM, particularly in women of SA origin, identifies more women at risk, but increases costs. Maternal characteristics did not accurately identify women with GDM; there was limited evidence that in some populations risk factors may be useful for identifying low-risk women. Dietary modification additional to routine care reduced the risk of most adverse perinatal outcomes. Metformin (Glucophage,® Teva UK Ltd, Eastbourne, UK) and insulin were more effective than glibenclamide (Aurobindo Pharma - Milpharm Ltd, South Ruislip, Middlesex, UK). For all strategies to identify and treat GDM, the costs exceeded the health benefits. A policy of no screening/testing or treatment offered the maximum expected net monetary benefit (NMB) of £1184 at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year (QALY). The NMB for the three best-performing strategies in each category (screen only, then treat; screen, test, then treat; and test all, then treat) ranged between -£1197 and -£1210. Further research to reduce uncertainty around potential longer-term benefits for the mothers and offspring, find ways of improving the accuracy of identifying women with GDM, and reduce costs of identification and treatment would be worthwhile. LIMITATIONS: We did not have access to IPD from populations in the UK outside of England. Few observational studies reported longer-term associations, and treatment trials have generally reported only perinatal outcomes. CONCLUSIONS: Using the national standard cost-effectiveness threshold of £20,000 per QALY it is not cost-effective to routinely identify pregnant women for treatment of hyperglycaemia. Further research to provide evidence on longer-term outcomes, and more cost-effective ways to detect and treat GDM, would be valuable. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013004608. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Hyperglycemia in pregnancy: prevalence, impact, and management challenges.

Gestational diabetes mellitus (GDM) is one of the most common medical conditions in pregnancy, and the prevalence is growing with increasing rates of women of advanced age becoming pregnant and the increasing prevalence of maternal obesity and inactivity. GDM is associated with an increased risk of maternal and infant short- and long-term ill-health. There is a positive linear association between increasing maternal glucose at oral glucose tolerance testing and risk of important perinatal outcomes, including cesarean section, large for gestational age, and infant adiposity. A "step-up" approach, where diet and lifestyle information is provided followed by pharmacological interventions as required to control and reduce hyperglycemia, is effective at reducing the risk of macrosomia, but treatment of GDM will increase demand on health services. There is limited evidence to suggest which identification strategy is best or what thresholds should be used to diagnose GDM or what the effects of different diagnostic strategies have on short- or long-term maternal and offspring outcomes. Trials of interventions in pregnancy aimed at preventing GDM have not demonstrated a benefit; therefore, trials are needed to evaluate interventions aimed at optimizing the health of all women of childbearing age, outside of pregnancy. A consistent, evidence-based, sustained approach to supporting women to live healthily, including the achievement of a normal body mass index before and after pregnancy, is urgently needed.

Continuous subcutaneous insulin infusion versus multiple daily injections of insulin for pregnant women with diabetes.

BACKGROUND: Diabetes results in a rise in blood glucose above normal physiological levels; if untreated this may cause damage to many systems including the cardiovascular and renal systems. Pregnancy increases resistance to insulin action; for those women who have pre-gestational diabetes, this results in an increasing insulin requirement. There are several methods of administering insulin. Conventionally, insulin has been administered subcutaneously, formally referred to as intensive conventional treatment, but now more usually referred to as multiple daily injections (MDI). An alternative method of insulin administration is the continuous subcutaneous insulin infusion pump (CSII). OBJECTIVES: To compare CSII with MDI of insulin for pregnant women with pre-existing and gestational diabetes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2016) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised trials comparing CSII with MDI for pregnant women with diabetes. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed studies and two review authors extracted data. Disagreements were resolved through discussion with the third author. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We included five single-centre trials (undertaken in Italy) with 153 women and 154 pregnancies in this review.There were no clear differences in the primary outcomes reported between CSII and MDI in the included trials: caesarean section (risk ratio (RR) 1.09, 95% confidence interval (CI) 0.66 to 1.77; three trials, 71 women, evidence graded very low), large-for-gestational age (RR 4.15, 95% CI 0.49 to 34.95; three trials, 73 infants; evidence graded very low), and perinatal mortality (RR 2.33, 95% CI 0.38 to 14.32; four trials, 83 infants, evidence graded very low). Other primary outcomes were not reported in these trials (hypertensive disorders of pregnancy, development of type 2 diabetes, composite outcome of serious neonatal outcomes, and neurosensory disability).There was no clear evidence of differences in the maternal secondary outcomes: maternal weight gain during pregnancy, 24 hour mean blood glucose in each trimester, mean maternal HbA1c in each trimester, maternal hypoglycaemia, and maternal hyperglycaemia. The included studies did not report several GRADE outcomes: perineal trauma, return to pre-pregnancy weight, postnatal depression, induction of labour. Many maternal secondary outcomes were also not reported.In two trials, including a total of 61 infants, CSII was associated with an increase in mean birthweight compared with MDI (mean difference (MD) 220.56 g, 95% CI -2.09 g to 443.20 g; P = 0.05). However, the large CI including anything from a small reduction to an increase in mean birthweight and the lack of a difference in macrosomia rate (RR 3.20, CI 0.14 to 72.62; two trials, 61 infants) suggests uncertainty. Large-for-gestational age (see above), andsmall-for-gestational age also suggests uncertainty of effect. No significant differences were found in: gestation at delivery, preterm birth < 37 weeks' gestation, preterm birth < 32 weeks' gestation, neonatal hypoglycaemia (evidence graded very low), respiratory distress syndrome, neonatal hyperbilirubinaemia, and fetal anomaly. There were no data reported on many important infant outcomes, including the GRADE outcomes adiposity and diabetes. There was no follow-up of infants in childhood or adulthood, so longer-term outcomes were not reported.The only outcome reported for use of health service resources wasmaternal days hospitalised, which did not show a difference between groups in the small number of women included (MD 9.40, CI -6.04 to 24.84; one trial, 10 women).The methods used by the trials were poorly reported, for example although blinding of participants and clinicians regarding intervention allocation is impossible, it is possible to blind assessors and this along with other aspects of trial methods was not reported, which means that the trials are at an unclear or high risk of bias. We do not know if the women who participated were representative, and therefore if the results can be generalised. Most GRADE outcomes were not reported. For the GRADE outcomes that were reported, our assessment was that the evidence is very low quality (caesarean section, large-for-gestational age, perinatal mortality, andneonatal hypoglycaemia). This was due to design limitations in the included trials, small sample sizes in the trials contributing data, wide CIs crossing both the line of no effect and the line of appreciable benefit and/or harm, and often few events. We are therefore uncertain whether CSII or MDI improves outcomes for pregnant women with diabetes and their infants, and the results of further studies may differ substantially from those presented in this review. AUTHORS' CONCLUSIONS: There is no evidence to support the use of one particular form of insulin administration over another for pregnant women with diabetes. There are only a small number of trials appropriate for meta-analysis, a small number of women included and questionable generalisability of the trial population.Pump technology has progressed since these trials were undertaken. Well-designed randomised trials are required to evaluate comparisons such as patch pumps against MDI and more conventional CSII against MDI. These trials should be adequately powered to assess the effect of interventions, and report the core set of outcomes used in Cochrane reviews of diabetes in pregnancy. Trials to assess the effects of pumps on birthweight and macrosomia rates are needed. It would be beneficial for future trials to undertake longer-term follow-up of participants and their infants, assess women's preferences, and conduct an economic evaluation.

Is objective and accurate cognitive assessment across the menstrual cycle possible? A feasibility study.

OBJECTIVES: Variation in plasma hormone levels influences the neurobiology of brain regions involved in cognition and emotion processing. Fluctuations in hormone levels across the menstrual cycle could therefore alter cognitive performance and wellbeing; reports have provided conflicting results, however. The aim of this study was to assess whether objective assessment of cognitive performance and self-reported wellbeing during the follicular and luteal phases of the menstrual cycle is feasible and investigate the possible reasons for variation in effects previously reported. METHODS: The Cambridge Neuropsychological Test Automated Battery and Edinburgh Postnatal Depression Scale were used to assess the cognitive performance and wellbeing of 12 women. Data were analysed by self-reported and hormone-estimated phases of the menstrual cycle. RESULTS: Recruitment to the study and assessment of cognition and wellbeing was without issue. Plasma hormone and peptide estimation showed substantial individual variation and suggests inaccuracy in self-reported menstrual phase estimation. CONCLUSION: Objective assessment of cognitive performance and self-assessed wellbeing across the menstrual cycle is feasible. Grouping data by hormonal profile rather by self-reported phase estimation may influence phase-mediated results. Future studies should use plasma hormone and peptide profiles to estimate cycle phase and group data for analyses.

Assessment of cognitive function across pregnancy using CANTAB: a longitudinal study.

Significant changes in endogenous plasma hormone levels are required to sustain pregnancy which provides a unique opportunity to study their effect on cognitive function. Four carefully selected tests from the Cambridge Neuropsychological Automated Test Battery (CANTAB) were administered to assess the cognitive function of a group of 23 women during each trimester of pregnancy and at three months following birth. Test scores were compared with a control group of 24 non-pregnant women. The Edinburgh Postnatal Depression Scale was administered to assess anxiety and risk of depression. The National Adult Reading Test (NART) was used as a measure of verbal intelligence. Plasma hormone levels were measured at each time-point. The pregnant group scored significantly lower than the control group on the Spatial Recognition Memory (SRM) test at the second trimester and postpartum assessments (p⩽0.004). A significant pregnant group-time interaction (p=0.005) for SRM performance was demonstrated. Compared to their first trimester assessment, the pregnant group scored on average 11.7% less on each subsequent SRM test. The pregnant group reported more symptoms of anxiety and depression compared to the control group (EPDS-4 point increase in mean score at each assessment, p=0.002). There were no plasma hormone levels and test score associations identified. These data suggest SRM performance is adversely affected by pregnancy. Other aspects of executive function seem to be unaffected. Although the pregnant group reported more symptoms of anxiety and depression compared to the control group, analysis indicates that this confounder is not responsible for the SRM differences.

Care during the third stage of labour: a postal survey of UK midwives and obstetricians.

BACKGROUND: There are two approaches to care during the third stage of labour: Active management includes three components: administration of a prophylactic uterotonic drug, cord clamping and controlled cord traction. For physiological care, intervention occurs only if there is clinical need. Evidence to guide care during the third stage is limited and there is variation in recommendations which may contribute to differences in practice. This paper describes current UK practice during the third stage of labour. METHODS: A postal survey of 2230 fellows and members of the Royal College of Obstetricians and Gynaecologists (RCOG) and 2400 members of the Royal College of Midwives was undertaken. Respondents were asked about care during the third stage of labour, for vaginal and caesarean births and their views on the need for more evidence to guide care in the third stage. The data were analysed in Excel and presented as descriptive statistics. RESULTS: 1189 (53%) fellows and members of the RCOG and 1702 (71%) midwives responded, of whom 926 (78%) and 1297 (76%) respectively had conducted or supervised births in the last year. 93% (863/926) of obstetricians and 73% (942/1297) of midwives report 'always or usually' using active management. 66% (611/926) of obstetricians and 33% (430/1297) of midwives give the uterotonic drug with delivery of the anterior shoulder; this was intramuscular Syntometrine(R) for 79% (728/926) and 86% (1118/1293) respectively. For term births, 74% (682/926) of obstetricians and 41% (526/1297) of midwives clamp the cord within 20 seconds, as do 57% (523/926) and 55% (707/1297) for preterm births. Controlled cord traction was used by 94% of both obstetricians and midwives. For caesarean births, intravenous oxytocin was the uterotonic used by 90% (837/926) of obstetricians; 79% (726/926) clamp the cord within 20 seconds for term births as do 63% (576/926) for preterm births.Physiological management was used 'always or usually' by 2% (21/926) of obstetricians and 9% (121/1297) of midwives. 81% (747/926) of obstetricians and 89% (1151/1297) of midwives thought more evidence from randomised trials was needed; the most popular question was when is best to clamp the cord. CONCLUSIONS: Active management of the third stage of labour is widely used by both obstetricians and midwives in the UK. Syntometrine(R) is usually used for vaginal births and oxytocin for caesarean births; when this is given and when the cord is clamped varies.