OBJECTIVE: to demonstrate the application of the atypicality index as an adjunct to first-trimester risk assessment for major trisomies by the combined test. METHODS: This was a study of 123 998 Danish women with a singleton pregnancy who underwent routine first-trimester screening, including risk assessment for major trisomies. An atypicality index, which is a measure of the degree to which a profile is atypical, was produced for measurements of fetal nuchal translucency thickness and maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein-A. The incidence of adverse pregnancy outcome, including miscarriage, intrauterine death and termination of pregnancy, was tabulated according to the screening result and atypicality index. RESULTS: in pregnancies with low risk and those with high risk for major trisomies according to the combined screening test, the incidence of adverse pregnancy outcome increased with increasing atypicality index. In pregnancies with a low risk for trisomies and atypicality index of ≥ 99%, the incidence of adverse outcome was 5.1 (95% CI, 3.4-7.6) times higher compared with that in low-risk pregnancies with a typical measurement profile, reflected by an atypicality index of

OBJECTIVE: to examine the effect of self-declared race on serum placental growth factor (PlGF) and sFlt-1/PlGF ratio and the impact on pre-eclampsia (PE) prediction. DESIGN: Prospective observational study. SETTING: Two UK maternity hospitals. POPULATION: 29 035 women with singleton pregnancies attending a routine 35+0 to 36+6 weeks' gestation hospital visit, including 654 (2.3%) who subsequently developed PE. METHODS: the predictive performance of PlGF and sFlt-1/PlGF for PE in minority racial groups (versus white) was examined. MAIN OUTCOME MEASURE: Delivery with PE. RESULTS: Compared with white women, mean PlGF was higher and sFlt-1/PlGF ratio lower in black, South Asian, East Asian and mixed race women. In white women at a PlGF concentration cut-off corresponding to a screen-positive rate (SPR) of 10%, detection rates (DRs) were 49.1% for PE at any time and 72.3% for PE within 2 weeks after screening. In black women, at the same PlGF concentration cut-off for white women, the SPR was 5.5%, and DRs 33.6% and 55.0%, respectively; the number of PE cases was too small to evaluate screening performance in other racial groups. Using a fixed cut-off in sFlt-1/PlGF ratio to identify women at risk of developing PE, similarly diagnostically disadvantaged black women. Bias was overcome by adjusting metabolite concentrations for maternal characteristics and use of the competing risks model to estimate patient-specific risks. CONCLUSION: Screening for PE with fixed cut-offs in PlGF or sFlt-1/PlGF diagnostically disadvantages black women. It is essential that measured levels of PlGF be adjusted for race as well as other maternal characteristics.

OBJECTIVE: the competing-risks model for assessment of risk for pre-eclampsia (PE) at 35-37 weeks' gestation identifies the majority of women who are at high risk of subsequent delivery with PE. We aimed to examine the incidence and relative risk of adverse pregnancy outcomes in patient groups stratified according to the estimated risk of delivery with PE. METHODS: This was a prospective non-interventional, observational study in women with a singleton pregnancy attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. The risk of delivery with PE for each patient in the study population was estimated using the competing-risks model, combining the prior distribution of gestational age at delivery with PE and the likelihood from multiples of the median values of mean arterial pressure, placental growth factor and soluble fms-like tyrosine kinase-1. The patients were assigned to one of the following five risk categories: Group A, ≥ 1 in 2; Group B, 1 in 5 to 1 in 3; Group C, 1 in 20 to 1 in 6; Group D, 1 in 50 to 1 in 21; and Group E,

BACKGROUND: Antenatal identification of pregnancies at high risk of delivering small for gestational age neonates may improve the management of the condition and reduce the associated adverse perinatal outcomes. In a series of publications, we have developed a new competing-risks model for small for gestational age prediction, and we demonstrated that the new approach has a superior performance to that of the traditional methods. The next step in shaping the appropriate management of small for gestational age is the timely assessment of these high-risk pregnancies according to an antenatal stratification plan. OBJECTIVE: This study aimed to demonstrate the stratification of pregnancy care based on individual patient risk derived from the application of the competing-risks model for small for gestational age that combines maternal factors with sonographic estimated fetal weight and uterine artery pulsatility index at midgestation. STUDY DESIGN: This was a prospective observational study of 96,678 singleton pregnancies undergoing routine ultrasound examination at 19 to 24 weeks of gestation, which included recording of estimated fetal weight and measurement of uterine artery pulsatility index. The competing-risks model for small for gestational age was used to create a patient-specific stratification curve capable to define a specific timing for a repeated ultrasound examination after 24 weeks. We examined different stratification plans with the intention of detecting approximately 80%, 85%, 90%, and 95% of small for gestational age neonates with birthweight

OBJECTIVE: to examine the predictive performance of a previously reported competing-risks model of screening for pre-eclampsia (PE) at 35-37 weeks' gestation by combinations of maternal risk factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1) in a validation dataset derived from the screened population of the STATIN study. METHODS: This was a prospective third-trimester multicenter study of screening for PE in singleton pregnancies by means of a previously reported algorithm that combines maternal risk factors and biomarkers. Women in the high-risk group were invited to participate in a trial of pravastatin vs placebo, but the trial showed no evidence of an effect of pravastatin in the prevention of PE. Patient-specific risks of delivery with PE were calculated using the competing-risks model, and the performance of screening for PE by maternal risk factors alone and by various combinations of risk factors with MAP, UtA-PI, PlGF and sFlt-1 was assessed. The predictive performance of the model was examined by, first, the ability of the model to discriminate between the PE and no-PE groups using the area under the receiver-operating-characteristics curve (AUC) and the detection rate at a fixed false-positive rate of 10%, and, second, calibration by measurements of calibration slope and calibration-in-the-large. RESULTS: the study population of 29 677 pregnancies contained 653 that developed PE. In screening for PE by a combination of maternal risk factors, MAP, PlGF and sFlt-1 (triple test), the detection rate at a 10% false-positive rate was 79% (95% CI, 76-82%) and the results were consistent with the data used for developing the algorithm. Addition of UtA-PI did not improve the prediction provided by the triple test. The AUC for the triple test was 0.923 (95% CI, 0.913-0.932), demonstrating very high discrimination between affected and unaffected pregnancies. Similarly, the calibration slope was 0.875 (95% CI, 0.831-0.919), demonstrating good agreement between the predicted risk and observed incidence of PE. CONCLUSION: the competing-risks model provides an effective and reproducible method for third-trimester prediction of term PE. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

OBJECTIVE: to compare the predictive performance for preterm-pre-eclampsia (PE) in first-trimester screening by serum placental growth factor (PlGF) versus pregnancy associated plasma protein-A (PAPP-A), in combination with maternal risk factors, mean arterial pressure (MAP) and uterine artery pulsatility index (UtA-PI), after adjustment for the effect of aspirin in women receiving this treatment. DESIGN: Non-intervention multicentre screening studies for PE in singleton pregnancies. SETTING: Maternity hospitals. POPULATION: Two independent prospective studies of 8775 and 16 451 women with singleton pregnancies attending for routine assessment at 11+0 -13+6 weeks' gestation. METHODS: the competing risks model was used to estimate patient-specific risks of delivery with PE at

BACKGROUND: Preeclampsia is associated with increased risks of life-threatening, -altering, and -ending complications. Assessment of risk for preeclampsia at 35 to 36 weeks' gestation by the Fetal Medicine Foundation 36-week competing-risk model identifies approximately 75% of women who will develop term preeclampsia, at a 10% screen-positive rate. OBJECTIVE: This study aimed to assess whether the Fetal Medicine Foundation 36-week model can provide personalized guidance to women about the probable timing of their delivery, whether or not they develop pregnancy hypertension. STUDY DESIGN: in this prospective nonintervention screening study at 2 maternity hospitals in England, women who did not have preeclampsia (American College of Obstetricians and Gynecologists definition) and were attending a routine hospital visit at 35 0/7 to 36 6/7 weeks' gestation underwent assessment of risk for preeclampsia, including maternal demographic characteristics, medical history, mean arterial pressure, and serum placental growth factor and soluble fms-like tyrosine kinase-1. Fetal Medicine Foundation 36-week model risk categories for subsequent preeclampsia were defined as: A, ≥0.500; B, 0.20 to 0.499; C, 0.05 to 0.199; D, 0.020 to 0.049; and E,

Background: There is good evidence that first-trimester assessment of the risk for preterm preeclampsia and treatment of the high-risk group with aspirin reduces the incidence of preterm preeclampsia. Furthermore, there is evidence that aspirin is associated with an increased risk of maternal and neonatal hemorrhagic complications. Against this background, there are ongoing debates whether aspirin should be recommended for all women or to a subpopulation of women predicted to be at increased risk of developing preeclampsia. Moreover, if a strategy of the prediction and prevention of preterm preeclampsia is to be used, what method should be used for the prediction, and what risk cutoff should be used to decide on who to treat? Objective: This study aimed to compare the policies of universal treatment, stratified treatment, and no treatment with aspirin. Study Design: Decisions about aspirin prophylaxis were considered from the perspective of the Bayesian decision theory. Using this approach, the treatment policies were evaluated for risks of preterm preeclampsia, effects of aspirin, and trade-offs between the harms and benefits of the treatment. Evidence on the risk of preterm preeclampsia was taken from the Screening programme for pre-eclampsia study, which was a first-trimester screening study for the prediction of preeclampsia. Evidence of the effect of aspirin was taken from the Aspirin for Evidence-Based Preeclampsia Prevention trial, which was a trial of aspirin vs placebo in the prevention of preterm preeclampsia. The trade-off between the benefits and harms of aspirin was specified by addressing the question, “What is the maximum number of women that should be treated to prevent 1 case of preterm preeclampsia?” the number can be considered as an exchange rate between the harms and benefits of using aspirin to prevent preterm PE. Given the uncertainty about the harms associated with aspirin, the treatment policies were compared across a wide range of exchange rates. Results: for exchange rates between 10 and 1000 women treated with aspirin to prevent 1 case of preterm preeclampsia, the net benefit achieved from the risk assessment and targeted treatment of women at high risk of preterm preeclampsia was higher than that from women with no treatment or women with universal treatment with aspirin. Conclusion: Universal treatment with aspirin should be avoided. Risk-based screening should be used, and the cutoff for taking aspirin should be determined from the consideration of the trade-off between the benefits and harms and detection, false-positive, and screen-positive rates.

BACKGROUND: Antenatal identification of women at high risk to deliver small-for-gestational-age neonates may improve the management of the condition. The traditional but ineffective methods for small-for-gestational-age screening are the use of risk scoring systems based on maternal demographic characteristics and medical history and the measurement of the symphysial-fundal height. Another approach is to use logistic regression models that have higher performance and provide patient-specific risks for different prespecified cutoffs of birthweight percentile and gestational age at delivery. However, such models have led to an arbitrary dichotomization of the condition; different models for different small-for-gestational-age definitions are required and adding new biomarkers or examining other cutoffs requires refitting of the whole model. An alternative approach for the prediction of small-for-gestational-age neonates is to consider small for gestational age as a spectrum disorder whose severity is continuously reflected in both the gestational age at delivery and z score in birthweight for gestational age. OBJECTIVE: This study aimed to develop a new competing risks model for the prediction of small-for-gestational-age neonates based on a combination of maternal demographic characteristics and medical history with sonographic estimated fetal weight, uterine artery pulsatility index, and mean arterial pressure at 19 to 24 weeks' gestation. STUDY DESIGN: This was a prospective observational study of 96,678 women with singleton pregnancies undergoing routine ultrasound examination at 19 to 24 weeks' gestation, which included recording of estimated fetal weight, uterine artery pulsatility index, and mean arterial pressure. The competing risks model for small for gestational age is based on a previous joint distribution of gestational age at delivery and birthweight z score, according to maternal demographic characteristics and medical history. The likelihoods of the estimated fetal weight, uterine artery pulsatility index, and mean arterial pressure were fitted conditionally to both gestational age at delivery and birthweight z score and modified the previous distribution, according to the Bayes theorem, to obtain an individualized posterior distribution for gestational age at delivery and birthweight z score and therefore patient-specific risks for any desired cutoffs for birthweight z score and gestational age at delivery. The model was internally validated by randomly dividing the data into a training data set, to obtain the parameters of the model, and a test data set, to evaluate the model. The discrimination and calibration of the model were also examined. RESULTS: the estimated fetal weight was described using a regression model with an interaction term between gestational age at delivery and birthweight z score. Folded plane regression models were fitted for uterine artery pulsatility index and mean arterial pressure. The prediction of small for gestational age by maternal factors was improved by adding biomarkers for increasing degree of prematurity, higher severity of smallness, and coexistence of preeclampsia. Screening by maternal factors with estimated fetal weight, uterine artery pulsatility index, and mean arterial pressure, predicted 41%, 56%, and 70% of small-for-gestational-age neonates with birthweights of

OBJECTIVE: to develop a new competing-risks model for the prediction of a small-for-gestational-age (SGA) neonate, based on maternal factors and biophysical and biochemical markers at 11-13 weeks' gestation. METHODS: This was a prospective observational study in 60 875 women with singleton pregnancy undergoing routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation. All pregnancies had pregnancy-associated plasma protein-A and placental growth factor (PlGF) measurements, 59 001 had uterine artery pulsatility index (UtA-PI) measurements and 58 479 had mean arterial pressure measurements; 57 131 cases had complete data for all biomarkers. We used a previously developed competing-risks model for the joint distribution of gestational age (GA) at delivery and birth-weight Z-score, according to maternal demographic characteristics and medical history. The likelihoods of the biophysical markers were developed by fitting folded-plane regression models, a technique that has already been used in previous studies for the likelihoods of biochemical markers. The next step was to modify the prior distribution by the likelihood, according to Bayes' theorem, to obtain individualized distributions for GA at delivery and birth-weight Z-score. We used the 57 131 cases with complete data to assess the discrimination and calibration of the model for predicting SGA with, without or independently of pre-eclampsia, by different combinations of maternal factors and biomarkers. RESULTS: the distribution of biomarkers, conditional to both GA at delivery and birth-weight Z-score, was best described by folded-plane regression models. These continuous two-dimensional likelihoods update the joint distribution of birth-weight Z-score and GA at delivery that has resulted from a competing-risks approach; this method allows application of user-defined cut-offs. The best biophysical predictor of preterm SGA was UtA-PI and the best biochemical marker was PlGF. The prediction of SGA was consistently better for increasing degree of prematurity, greater severity of smallness, coexistence of PE and increasing number of biomarkers. The combination of maternal factors with all biomarkers predicted 34.3%, 48.6% and 59.1% of all cases of a SGA neonate with birth weight

OBJECTIVE: to develop further a new competing-risks model for the prediction of a small-for-gestational-age (SGA) neonate, by including second-trimester ultrasonographic estimated fetal weight (EFW). METHODS: This was a prospective observational study in 96 678 women with singleton pregnancy undergoing routine ultrasound examination at 19-24 weeks' gestation. All pregnancies had ultrasound biometry assessment, and EFW was calculated according to the Hadlock formula. We refitted in this large dataset a previously described competing-risks model for the joint distribution of gestational age (GA) at delivery and birth-weight Z-score, according to maternal demographic characteristics and medical history, to obtain the prior distribution. The continuous likelihood of the EFW was fitted conditionally to GA at delivery and birth-weight Z-score and modified the prior distribution, according to Bayes' theorem, to obtain individualized distributions for GA at delivery and birth-weight Z-score and therefore patient-specific risks for any cut-offs for GA at delivery and birth-weight Z-score. We assessed the discriminative ability of the model for predicting SGA with, without or independently of pre-eclampsia occurrence. A calibration study was carried out. Performance of screening was evaluated for SGA defined according to the Fetal Medicine Foundation birth-weight charts. RESULTS: the distribution of EFW, conditional to both GA at delivery and birth-weight Z-score, was best described by a regression model. For earlier gestations, the association between EFW and birth weight was steeper. The prediction of SGA by maternal factors and EFW improved for increasing degree of prematurity and greater severity of smallness but not for coexistence of pre-eclampsia. Screening by maternal factors predicted 31%, 34% and 39% of SGA neonates with birth weight

OBJECTIVES: to expand a new competing-risks model for prediction of a small-for-gestational-age (SGA) neonate, by the addition of pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF), and to evaluate and compare PAPP-A and PlGF in predicting SGA. METHODS: This was a prospective observational study of 60 875 women with singleton pregnancy undergoing routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation. We fitted a folded-plane regression model for the PAPP-A and PlGF likelihoods. A previously developed maternal history model and the likelihood models were combined, according to Bayes' theorem, to obtain individualized distributions for gestational age (GA) at delivery and birth-weight Z-score. We assessed the discrimination and calibration of the model. McNemar's test was used to compare the detection rates for SGA with, without or independently of pre-eclampsia (PE) occurrence, of different combinations of maternal history, PAPP-A and PlGF, for a fixed false-positive rate. RESULTS: the distributions of PAPP-A and PlGF depend on both GA at delivery and birth-weight Z-score, in the same continuous likelihood, according to a folded-plane regression model. The new approach offers the capability for risk computation for any desired birth-weight Z-score and GA at delivery cut-off. PlGF was consistently and significantly better than PAPP-A in predicting SGA delivered before 37 weeks, especially in cases with co-existence of PE. PAPP-A had similar performance to PlGF for the prediction of SGA without PE. At a fixed false-positive rate of 10%, the combination of maternal history, PlGF and PAPP-A predicted 33.8%, 43.8% and 48.4% of all cases of a SGA neonate with birth weight

OBJECTIVE: to examine the impact of first-trimester crown-rump length (CRL) measurement error on the interpretation of estimated fetal weight (EFW) and classification of fetuses as small-, large- or appropriate-for-gestational age on subsequent growth scans. METHODS: We examined the effects of errors of ± 2, ± 3 and ± 4 mm in the measurement of fetal CRL on percentiles of EFW at 20, 32 and 36 weeks' gestation and classification as small-, large- or appropriate-for-gestational age. Published data on CRL measurement error were used to determine variation present in practice. RESULTS: a measurement error of -2 mm in first-trimester CRL shifts an EFW on the 10th percentile at the 20-week scan to around the 20th percentile, and the effect of a CRL measurement error of + 2 mm would shift an EFW on the 10th percentile to around the 5th percentile. At 32 weeks, a first-trimester CRL measurement error would shift an EFW on the 10th percentile to the 7th (+ 2 mm) or 14th (-2 mm) percentile; at 36 weeks, the EFW would shift from the 10th percentile to the 8th (+ 2 mm) or 12th (-2 mm) percentile. Published data suggest that measurement errors of 2 mm or more are common in practice. CONCLUSION: Because of the widespread and potentially severe consequences of CRL measurement errors as small as 2 mm on clinical assessment, patient management and research results, there is a need to increase awareness of the impact of CRL measurement error and to reduce measurement error variation through standardization and quality control. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

BACKGROUND: in women with a singleton pregnancy and sonographic short cervix in midgestation, vaginal administration of progesterone reduces the risk of early preterm birth and improves neonatal outcomes without any demonstrable deleterious effects on childhood neurodevelopment. In women with twin pregnancies, the rate of spontaneous early preterm birth is 10 times higher than that in singletons, and in this respect, all twins are at an increased risk of preterm birth. However, 6 trials in unselected twin pregnancies reported that vaginal administration of progesterone from midgestation had no significant effect on the incidence of early preterm birth. Such apparent lack of effectiveness of progesterone in twins may be due to inadequate dosage or treatment that is started too late in pregnancy. OBJECTIVE: the early vaginal progesterone for the prevention of spontaneous preterm birth in twins, a randomized, placebo-controlled, double-blind trial, was designed to test the hypothesis that among women with twin pregnancies, vaginal progesterone at a dose of 600 mg per day from 11 to 14 until 34 weeks' gestation, as compared with placebo, would result in a significant reduction in the incidence of spontaneous preterm birth between 24+0 and 33+6 weeks. STUDY DESIGN: the trial was conducted at 22 hospitals in England, Spain, Bulgaria, Italy, Belgium, and France. Women were randomly assigned in a 1:1 ratio to receive either progesterone or placebo, and in the random-sequence generation, there was stratification according to the participating center. The primary outcome was spontaneous birth between 24+0 and 33+6 weeks' gestation. Statistical analyses were performed on an intention-to-treat basis. Logistic regression analysis was used to determine the significance of difference in the incidence of spontaneous birth between 24+0 and 33+6 weeks' gestation between the progesterone and placebo groups, adjusting for the effect of participating center, chorionicity, parity, and method of conception. Prespecified tests of treatment interaction effects with chorionicity, parity, method of conception, compliance, and cervical length at recruitment were performed. A post hoc analysis using mixed-effects Cox regression was used for further exploration of the effect of progesterone on preterm birth. RESULTS: We recruited 1194 women between May 2017 and April 2019; 21 withdrew consent and 4 were lost to follow-up, which left 582 in the progesterone group and 587 in the placebo group. Adherence was good, with reported intake of ≥80% of the required number of capsules in 81.4% of the participants. After excluding births before 24 weeks and indicated deliveries before 34 weeks, spontaneous birth between 24+0 and 33+6 weeks occurred in 10.4% (56/541) of participants in the progesterone group and in 8.2% (44/538) in the placebo group (odds ratio in the progesterone group, adjusting for the effect of participating center, chorionicity, parity, and method of conception, 1.35; 95% confidence interval, 0.88-2.05; P=.17). There was no evidence of interaction between the effects of treatment and chorionicity (P=.28), parity (P=.35), method of conception (P=.56), and adherence (P=.34); however, there was weak evidence of an interaction with cervical length (P=.08) suggestive of harm to those with a cervical length of ≥30 mm (odds ratio, 1.61; 95% confidence interval, 1.01-2.59) and potential benefit for those with a cervical length of

OBJECTIVE: to examine the predictive performance of the relevant guideline by the Royal College of Obstetricians and Gynaecologists (RCOG) for neonates that are small for gestational age (SGA), and to compare the performance of the RCOG guideline with that of our competing risks model for SGA. DESIGN: Prospective observational study. SETTING: Obstetric ultrasound departments in two UK maternity hospitals. POPULATION: a total of 96 678 women with singleton pregnancies attending for routine ultrasound examination at 19-24 weeks of gestation. METHODS: Risks for SGA for different thresholds were computed, according to the competing risks model using maternal history, second-trimester estimated fetal weight, uterine artery pulsatility index and mean arterial pressure. The detection rates by the RCOG guideline scoring system and the competing risks model for SGA were compared, at the screen positive rate (SPR) derived from the RCOG guideline. MAIN OUTCOME MEASURES: Small for gestational age (SGA),

BACKGROUND: Effective screening for term preeclampsia is provided by a combination of maternal factors with measurements of mean arterial pressure, serum placental growth factor, and serum soluble fms-like tyrosine kinase-1 at 35 to 37 weeks of gestation, with a detection rate of ≈75% at a screen-positive rate of 10%. However, there is no known intervention to reduce the incidence of the disease. METHODS: in this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1120 women with singleton pregnancies at high risk of term preeclampsia to receive pravastatin at a dose of 20 mg/d or placebo from 35 to 37 weeks of gestation until delivery or 41 weeks. The primary outcome was delivery with preeclampsia at any time after randomization. The analysis was performed according to intention to treat. RESULTS: a total of 29 women withdrew consent during the trial. Preeclampsia occurred in 14.6% (80 of 548) of participants in the pravastatin group and in 13.6% (74 of 543) in the placebo group. Allowing for the effect of risk at the time of screening and participating center, the mixed-effects Cox regression showed no evidence of an effect of pravastatin (hazard ratio for statin/placebo, 1.08 [95% CI, 0.78-1.49]; P=0.65). There was no evidence of interaction between the effect of pravastatin, estimated risk of preeclampsia, pregnancy history, adherence, and aspirin treatment. There was no significant between-group difference in the incidence of any secondary outcomes, including gestational hypertension, stillbirth, abruption, delivery of small for gestational age neonates, neonatal death, or neonatal morbidity. There was no significant between-group difference in the treatment effects on serum placental growth factor and soluble fms-like tyrosine kinase-1 concentrations 1 and 3 weeks after randomization. Adherence was good, with reported intake of ≥80% of the required number of tablets in 89% of participants. There were no significant between-group differences in neonatal adverse outcomes or other adverse events. CONCLUSIONS: Pravastatin in women at high risk of term preeclampsia did not reduce the incidence of delivery with preeclampsia. Registration: URL: https://www.isrctn.com; Unique identifier ISRCTN16123934.

BACKGROUND: the established method of identifying a group of women at high risk of delivering a small-for-gestational-age (SGA) neonate, requiring increased surveillance, is use of risk scoring systems based on maternal demographic characteristics and medical history. Although this approach is relatively simple to perform, it does not provide patient-specific risks and has an uncertain performance in predicting SGA. Another approach to predict delivery of a SGA neonate is to use logistic regression models that combine maternal factors with first-trimester biomarkers. These models provide patient-specific risks for different prespecified cut-offs of birth-weight percentile and gestational age (GA) at delivery. OBJECTIVES: First, to develop a competing-risks model for prediction of SGA based on maternal demographic characteristics and medical history, in which GA at the time of delivery and birth-weight Z-score are treated as continuous variables. Second, to compare the predictive performance of the new model for SGA neonates to that of previous methods. METHODS: This was a prospective observational study in 124 443 women with singleton pregnancy undergoing routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation. The dataset was divided randomly into a training and a test dataset. The training dataset was used to develop a model for the joint distribution of GA at delivery and birth-weight Z-score from variables of maternal characteristics and medical history. This patient-specific joint Gaussian distribution of GA at delivery and birth-weight Z-score allows risk calculation for SGA defined in terms of different birth-weight percentiles and GA. The new model was then validated in the test dataset to assess performance of screening and we compared its predictive performance to that of logistic regression models for different SGA definitions. RESULTS: in the new model, the joint Gaussian distribution of GA at delivery and birth-weight Z-score is shifted to lower GA at delivery and birth-weight Z-score values, resulting in an increased risk for SGA, by lower maternal weight and height, black, East Asian, South Asian and mixed racial origin, medical history of chronic hypertension, diabetes mellitus and systemic lupus erythematosus and/or antiphospholipid syndrome, conception by in-vitro fertilization and smoking. In parous women, variables from the last pregnancy that increased the risk for SGA were history of pre-eclampsia or stillbirth, decreasing birth-weight Z-score and decreasing GA at delivery of the last pregnancy and interpregnancy interval

OBJECTIVES: to develop a continuous likelihood model for pregnancy-associated plasma protein-A (PAPP-A), in the context of a new competing-risks model for prediction of a small-for-gestational-age (SGA) neonate, and to compare the predictive performance of the new model for SGA to that of previous methods. METHODS: This was a prospective observational study of 60 875 women with singleton pregnancy undergoing routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation. The dataset was divided randomly into a training dataset and a test dataset. The training dataset was used for PAPP-A likelihood model development. We used Bayes' theorem to combine the previously developed prior model for the joint Gaussian distribution of gestational age (GA) at delivery and birth-weight Z-score with the PAPP-A likelihood to obtain a posterior distribution. This patient-specific posterior joint Gaussian distribution of GA at delivery and birth-weight Z-score allows risk calculation for SGA defined in terms of different birth-weight percentiles and GA. The new model was validated internally in the test dataset and we compared its predictive performance to that of the risk-scoring system of the UK National Institute for Health and Care Excellence (NICE) and that of logistic regression models for different SGA definitions. RESULTS: PAPP-A has a continuous association with both birth-weight Z-score and GA at delivery according to a folded-plane regression. The new model, with the addition of PAPP-A, was equal or superior to several logistic regression models. The new model performed well in terms of risk calibration and consistency across different GAs and birth-weight percentiles. In the test dataset, at a false-positive rate of about 30% using the criteria defined by NICE, the new model predicted 62.7%, 66.5%, 68.1% and 75.3% of cases of a SGA neonate with birth weight

OBJECTIVES: to examine multiples of the median (MoM) values of serum free beta-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) in a large series of pregnancies with a vanishing twin, determine the association of these values with the interval between embryonic death and blood sampling, and develop a model that would allow incorporation of these metabolites in first-trimester combined screening for trisomy. METHODS: This was a retrospective study comparing maternal serum free β-hCG and PAPP-A levels at 11-13 weeks' gestation in 528 dichorionic pregnancies with a vanishing twin, including 194 (36.7%) with an empty gestational sac and 334 (63.3%) with a dead embryo, with those in 5280 normal singleton pregnancies matched for method of conception and date of examination. In vanishing-twin pregnancies with a dead embryo, marker levels were examined in relation to the estimated time between embryonic death and maternal blood sampling. RESULTS: First, in pregnancies with a vanishing twin, median free β-hCG MoM was not significantly different from that in normal singleton pregnancies (1.000; 95% CI, 0.985-1.016 vs 0.995; 95% CI, 0.948-1.044; P = 0.849). Second, PAPP-A MoM was higher in vanishing-twin pregnancies than in normal singleton pregnancies (1.000; 95% CI, 0.985-1.015), both in the group with an empty gestational sac (1.165; 95% CI, 1.080-1.256; P = 0.0001) and in that with a dead embryo (1.175; 95% CI, 1.105-1.249; P < 0.0001). Third, in vanishing-twin pregnancies with a dead embryo, PAPP-A MoM was related inversely to the interval between estimated gestational age at embryonic demise and blood sampling (P < 0.0001). Fourth, in first-trimester screening for trisomy 21 in singleton pregnancies, the estimated detection rate, at a 5% false-positive rate, was 82% in screening by a combination of maternal age and fetal nuchal translucency thickness, and this increased to 86% with the addition of serum free β-hCG and to 91% with the addition of serum PAPP-A. Fifth, similar performance of screening can be achieved in pregnancies with a vanishing twin, provided the appropriate adjustments are made to the level of PAPP-A for the interval between estimated gestational age at embryonic demise and blood sampling. CONCLUSIONS: First-trimester screening for trisomy in pregnancies with a vanishing twin should rely on a combination of maternal age, fetal nuchal translucency thickness and serum free β-hCG, as in singleton pregnancy, without the use of serum PAPP-A. Alternatively, PAPP-A can be included but only after appropriate adjustment for the interval between estimated gestational age at fetal demise and blood sampling. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVES: First, to obtain measurement-error models for biometric measurements of fetal abdominal circumference (AC), head circumference (HC) and femur length (FL), and, second, to examine the impact of biometric measurement error on sonographic estimated fetal weight (EFW) and its effect on the prediction of small- (SGA) and large- (LGA) for-gestational-age fetuses with EFW  90th percentile, respectively. METHODS: Measurement error standard deviations for fetal AC, HC and FL were obtained from a previous large study on fetal biometry utilizing a standardized measurement protocol and both qualitative and quantitative quality-control monitoring. Typical combinations of AC, HC and FL that gave EFW on the 10th and 90th percentiles were determined. A Monte-Carlo simulation study was carried out to examine the effect of measurement error on the classification of fetuses as having EFW above or below the 10th and 90th percentiles. RESULTS: Errors were assumed to follow a Gaussian distribution with a mean of 0 mm and SDs, obtained from a previous well-conducted study, of 6.93 mm for AC, 5.15 mm for HC and 1.38 mm for FL. Assuming errors according to such distributions, when the 10th and 90th percentiles are used to screen for SGA and LGA fetuses, respectively, the detection rates would be 78.0% at false-positive rates of 4.7%. If the cut-offs were relaxed to the 30th and 70th percentiles, the detection rates would increase to 98.2%, but at false-positive rates of 24.2%. Assuming half of the spread in the error distribution, using the 10th and 90th percentiles to screen for SGA and LGA fetuses, respectively, the detection rates would be 86.6% at false-positive rates of 2.3%. If the cut-offs were relaxed to the 15th and 85th percentiles, respectively, the detection rates would increase to 97.0% and the false-positive rates would increase to 6.3%. CONCLUSIONS: Measurement error in fetal biometry causes substantial error in EFW, resulting in misclassification of SGA and LGA fetuses. The extent to which improvement can be achieved through effective quality assurance remains to be seen but, as a first step, it is important for practitioners to understand how biometric measurement error impacts the prediction of SGA and LGA fetuses. © 2019 the Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

OBJECTIVE: the traditional definition of pre-eclampsia (PE) is based on the development of hypertension and proteinuria. This has been revised recently to include cases without proteinuria but with evidence of renal, hepatic or hematological dysfunction. The aim of this study was to examine the impact of new definitions of PE on, first, the incidence and severity of the disease and, second, the performance of the competing-risks model for first-trimester assessment of risk for PE. METHODS: This was a retrospective study of 66 964 singleton pregnancies that were classified as having PE, gestational hypertension (GH) or no PE or GH, according to the traditional criteria of the International Society for the Study of Hypertension in Pregnancy (ISSHP-old), which defines PE as the presence of both hypertension and proteinuria. We reviewed the records of pregnancies with GH, and those cases with high creatinine or liver enzymes or low platelet count were reclassified as having PE, according to the new criteria of ISSHP (ISSHP-new) and the new criteria of the American College of Obstetricians and Gynecologists (ACOG). The groups of PE according to the traditional and new criteria were compared for, first, gestational age at delivery, birth-weight percentile and incidence of a small-for-gestational-age (SGA) neonate with birth weight

The established method of the assessment of the risk for development of preeclampsia is to identify risk factors from maternal demographic characteristics and medical history; in the presence of such factors, the patient is classified as high risk and in their absence as low risk. Although this approach is simple to perform, it has poor performance of the prediction of preeclampsia and does not provide patient-specific risks. This review describes a new approach that allows the estimation of patient-specific risks of delivery with preeclampsia before any specified gestational age by maternal demographic characteristics and medical history with biomarkers obtained either individually or in combination at any stage in pregnancy. In the competing risks approach, every woman has a personalized distribution of gestational age at delivery with preeclampsia; whether she experiences preeclampsia or not before a specified gestational age depends on competition between delivery before or after the development of preeclampsia. The personalized distribution comes from the application of Bayes theorem to combine a previous distribution, which is determined from maternal factors, with likelihoods from biomarkers. As new data become available, what were posterior probabilities take the role as the previous probability, and data collected at different stages are combined by repeating the application of Bayes theorem to form a new posterior at each stage, which allows for dynamic prediction of preeclampsia. The competing risk model can be used for precision medicine and risk stratification at different stages of pregnancy. In the first trimester, the model has been applied to identify a high-risk group that would benefit from preventative therapeutic interventions. In the second trimester, the model has been used to stratify the population into high-, intermediate-, and low-risk groups in need of different intensities of subsequent monitoring, thereby minimizing unexpected adverse perinatal events. The competing risks model can also be used in surveillance of women presenting to specialist clinics with signs or symptoms of hypertensive disorders; combination of maternal factors and biomarkers provide patient-specific risks for preeclampsia that lead to personalized stratification of the intensity of monitoring, with risks updated on each visit on the basis of biomarker measurements.

BACKGROUND: in the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention trial, risks of preterm preeclampsia were obtained from the competing risk model. Consenting women with risks of greater than 1 in 100 were randomized to treatment with aspirin or placebo. The trial showed strong evidence of an effect (odds ratio, 0.38, 95% confidence interval, 0.20-0.74) on the incidence of preterm preeclampsia, which was the primary outcome of Aspirin for Evidence-Based Preeclampsia Prevention. There was a small and insignificant effect on the incidence of term preeclampsia, which was a secondary outcomes (odds ratio, 0.95, 95% confidence interval, 0.64-1.39). These differential effects on term and preterm preeclampsia could reflect a mechanism in which the action of aspirin is to delay the delivery with preeclampsia, thereby converting what would be, without treatment, preterm preeclampsia to term preeclampsia. OBJECTIVE: the objective of the study was to examine the hypothesis that the effect of aspirin is to delay the time of delivery in women who have preeclampsia. STUDY DESIGN: This was an unplanned exploratory analysis of data from the Aspirin for Evidence-Based Preeclampsia Prevention trial. The delay hypothesis predicts that in groups for which preterm preeclampsia, without aspirin, were infrequent relative to term preeclampsia, a reduction in term preeclampsia would be expected because few cases of preterm preeclampsia would be converted to term preeclampsia. In contrast, in groups for which preterm preeclampsia were frequent relative to term preeclampsia, the conversion of preterm preeclampsia to term preeclampsia by aspirin would reduce or even reverse any effect on the incidence term preeclampsia. This is examined using the Aspirin for Evidence-Based Preeclampsia Prevention trial data by analysis of the effect of aspirin on the incidence of term preeclampsia stratified according to the risk of preterm preeclampsia at randomization. Given that women were included in Aspirin for Evidence-Based Preeclampsia Prevention with risks of preterm preeclampsia >1 in 100, a risk cutoff if 1 in 50 was used to define higher risk and lower risk strata. A statistical model in which the effect of aspirin is to delay the gestational age at delivery was fitted to the Aspirin for Evidence-Based Preeclampsia Prevention trial data and the consistency of the predictions from this model with the observed incidence was demonstrated. RESULTS: in the lower-risk group (

OBJECTIVES: to develop gestational age-based reference ranges for the pulsatility index in the umbilical artery (UA-PI) and fetal middle cerebral artery (MCA-PI) and the cerebroplacental ratio (MCA-PI/UA-PI), and to examine the maternal characteristics and medical history that affect these measurements. METHODS: This was a cross-sectional study of 72 387 pregnancies undergoing routine ultrasound examination at 20 + 0 to 22 + 6 weeks' gestation (n = 3712), 31 + 0 to 33 + 6 weeks (n = 29 035), 35 + 0 to 36 + 6 weeks (n = 37 252) or 41 + 0 to 41 + 6 weeks (n = 2388). For the purpose of this study, we included data for only one of the second- or third-trimester visits. The inclusion criteria were singleton pregnancy, dating by fetal crown-rump length at 11 + 0 to 13 + 6 weeks' gestation, live birth of a morphologically normal neonate and ultrasonographic measurements by sonographers who had received the Fetal Medicine Foundation Certificate of Competence in Doppler ultrasound. Since the objectives of the study were to establish reference ranges, rather than normal ranges, and to examine factors from maternal characteristics and medical history that affect these measurements, we included all pregnancies having routine ultrasound examinations, irrespective of whether the mother had a pre-existing medical condition, such as diabetes mellitus, or a pregnancy complication, such as pre-eclampsia or suspected fetal growth restriction. Median and SD models were fitted between UA-PI, MCA-PI and CPR and gestational age. Assessment of goodness of fit of the models was by inspection of quantile-to-quantile (Q-Q) plots of Z-scores calculated using the mean and SD models. The distributions of MCA-PI, UA-PI and CPR Z-scores were examined in relation to maternal characteristics and medical history. RESULTS: the relationship between the median and gestational age was linear for UA-PI and cubic for MCA-PI and CPR and the SD was log quadratic for all three. MCA-PI and CPR increased with gestational age from 20 weeks' gestation to reach a peak at around 32 and 34 weeks, respectively, and decreased thereafter, whereas UA-PI decreased linearly with gestational age from 20 to 42 weeks. Compared to the general population, significant deviations in multiples of the median values of UA-PI, MCA-PI and CPR were observed in subgroups of maternal age, body mass index, racial origin, method of conception and parity. CONCLUSION: This study established new reference ranges for UA-PI, MCA-PI and CPR, according to gestational age, and reports maternal characteristics and medical history that affect these measurements. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

BACKGROUND: in the weeks preceding the clinical onset of preeclampsia, the maternal serum level of the angiogenic placental growth factor is decreased and that of the antiangiogenic factor soluble fms-like tyrosine kinase-1 is increased. Women presenting at specialist clinics with signs or symptoms of hypertensive disorders have been stratified according to concentrations of placental growth factor or the ratio of concentrations of soluble fms-like tyrosine kinase-1 and placental growth factor to determine clinical management for the subsequent 1-4 weeks. An alternative approach for the prediction of preeclampsia is use of the competing risks model, a Bayes' theorem based method, to derive patient-specific risk for preeclampsia by various combinations of maternal characteristics and medical history with multiples of the median values of biomarkers. OBJECTIVE: the purpose of this study was to compare the performance of screening for delivery with preeclampsia at ≤2 and ≤4 weeks after assessment at 35+0-36+6 weeks gestation between the use of percentile cut-offs in placental growth factor alone or the soluble fms-like tyrosine kinase-1/placental growth factor ratio and the competing risks model. STUDY DESIGN: This was a prospective observational study in women who attended a routine hospital visit at 35+0-36+6 weeks gestation in 2 maternity hospitals in England. The visits included the recording of maternal demographic characteristics and medical history and the measurement of serum placental growth factor and soluble fms-like tyrosine kinase-1 and mean arterial pressure. The areas under the receiver operating characteristics curves were used to compare the predictive performance for preeclampsia with delivery at ≤2 and ≤4 weeks from assessment of screening by placental growth factor alone and the soluble fms-like tyrosine kinase-1/placental growth factor ratio with that of a previously developed competing risks model with a combination of maternal factors, placental growth factor, soluble fms-like tyrosine kinase-1, and mean arterial pressure (triple test). RESULTS: First, the study population of 15,247 pregnancies included 326 pregnancies (2.1%) that subsequently experienced preeclampsia. Second, in the screening for delivery with preeclampsia at ≤2 and ≤4 weeks from assessment, the performance of the triple test was superior to that of placental growth factor alone or the soluble fms-like tyrosine kinase-1/placental growth factor ratio. The area under the receiver operating characteristics curves for preeclampsia at ≤2 weeks in screening by the triple test (0.975; 95% confidence interval, 0.964-0.985) was higher than that of placental growth factor alone (0.900; 95% confidence interval, 0.866-0.935; P

BACKGROUND: the established method of screening for preeclampsia is to identify risk factors from maternal demographic characteristics and medical history; in the presence of such factors the patient is classified as high risk and in their absence as low risk. However, the performance of such an approach is poor. We developed a competing risks model, which allows combination of maternal factors (age, weight, height, race, parity, personal and family history of preeclampsia, chronic hypertension, diabetes mellitus, systemic lupus erythematosus or antiphospholipid syndrome, method of conception and interpregnancy interval), with biomarkers to estimate the individual patient-specific risks of preeclampsia requiring delivery before any specified gestation. The performance of this approach is by far superior to that of the risk scoring systems. OBJECTIVE: the objective of the study was to examine the predictive performance of the competing risks model in screening for preeclampsia by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor, referred to as the triple test, in a training data set for the development of the model and 2 validation studies. STUDY DESIGN: the data for this study were derived from 3 previously reported prospective, nonintervention, multicenter screening studies for preeclampsia in singleton pregnancies at 11+0 to 13+6 weeks' gestation. In all 3 studies, there was recording of maternal factors and biomarkers and ascertainment of outcome by appropriately trained personnel. The first study of 35,948 women, which was carried out between February 2010 and July 2014, was used to develop the competing risks model for prediction of preeclampsia and is therefore considered to be the training set. The 2 validation studies were comprised of 8775 and 16,451 women, respectively, and they were carried out between February and September 2015 and between April and December 2016, respectively. Patient-specific risks of delivery with preeclampsia at

BACKGROUND: We have proposed previously that the competing-risks model for prediction of pre-eclampsia (PE) based on maternal characteristics and medical history (prior model), developed in singleton pregnancies, can be extended to risk assessment for twins; in dichorionic (DC) and monochorionic (MC) twin pregnancies with the same characteristics as in singleton pregnancies, the distribution of gestational age at delivery with PE was shifted to the left by 8 and 10 weeks, respectively. However, in a subsequent validation study, we found that, in both the training and validation datasets, the observed incidence of PE was lower than the predicted one and such overestimation of risk was particularly marked for early PE. OBJECTIVES: First, to develop a new extension of the competing-risks prior model in screening for PE by maternal demographic characteristics and medical history in twin pregnancies in a training dataset. Second, to examine the predictive performance of this model in screening for PE with delivery

BACKGROUND: Screening for preeclampsia at 11-13 weeks' gestation by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor (triple test) can predict about 90% of preeclampsia, with delivery at

OBJECTIVE: to examine the predictive performance of the competing-risks model in screening for pre-eclampsia (PE) by maternal demographic characteristics and medical history in twin pregnancy, in a training dataset used for development of the model and a validation dataset. METHODS: the data for this study were derived from two prospective non-intervention multicenter screening studies for PE in twin pregnancies at 11 + 0 to 13 + 6 weeks' gestation. The first study of 2219 women, which was reported previously, was used to develop the competing-risks model for prediction of PE and is therefore considered to be the training set. The validation study comprised 2999 women. Patient-specific risks of delivery with PE at

OBJECTIVE: to report the incidence of preterm pre-eclampsia (PE) in women who are screen positive according to the criteria of the National Institute for Health and Care Excellence (NICE) and the American College of Obstetricians and Gynecologists (ACOG), and compare the incidence with that in those who are screen positive or screen negative by the Fetal Medicine Foundation (FMF) algorithm. METHODS: This was a secondary analysis of data from the ASPRE study. The study population consisted of women with singleton pregnancy who underwent prospective screening for preterm PE by means of the FMF algorithm, which combines maternal factors and biomarkers at 11-13 weeks' gestation. The incidence of preterm PE in women fulfilling the NICE and ACOG criteria was estimated; in these patients the incidence of preterm PE was then calculated in those who were screen negative relative to those who were screen positive by the FMF algorithm. RESULTS: a total of 34 573 women with singleton pregnancy delivering at ≥ 24 weeks' gestation underwent prospective screening for preterm PE, of which 239 (0.7%) cases developed preterm PE. At least one of the ACOG criteria was fulfilled in 22 287 (64.5%) pregnancies and the incidence of preterm PE was 0.97% (95% CI, 0.85-1.11%); in the subgroup that was screen positive by the FMF algorithm the incidence of preterm PE was 4.80% (95% CI, 4.14-5.55%), and in those that were screen negative it was 0.25% (95% CI, 0.18-0.33%), with a relative incidence in FMF screen negative to FMF screen positive of 0.051 (95% CI, 0.037-0.071). In 1392 (4.0%) pregnancies, at least one of the NICE high-risk criteria was fulfilled, and in this group the incidence of preterm PE was 5.17% (95% CI, 4.13-6.46%); in the subgroups of screen positive and screen negative by the FMF algorithm, the incidence of preterm PE was 8.71% (95% CI, 6.93-10.89%) and 0.65% (95% CI, 0.25-1.67%), respectively, and the relative incidence was 0.075 (95% CI, 0.028-0.205). In 2360 (6.8%) pregnancies fulfilling at least two of the NICE moderate-risk criteria, the incidence of preterm PE was 1.74% (95% CI, 1.28-2.35%); in the subgroups of screen positive and screen negative by the FMF algorithm the incidence was 4.91% (95% CI, 3.54-6.79%) and 0.42% (95% CI, 0.20-0.86%), respectively, and the relative incidence was 0.085 (95% CI, 0.038-0.192). CONCLUSION: in women who are screen positive for preterm PE by the ACOG or NICE criteria but screen negative by the FMF algorithm, the risk of preterm PE is reduced to within or below background levels. The results provide further evidence to support the personalized risk-based screening method that combines maternal factors and biomarkers. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

BACKGROUND: Preeclampsia is a major pregnancy complication with adverse short- and long-term implications for both the mother and baby. Screening for preeclampsia at 11-13 weeks' gestation by a combination of maternal demographic characteristics and medical history with measurements of biomarkers can identify about 75% of women who develop preterm preeclampsia with delivery at

OBJECTIVE: to test the hypothesis that the performance of first-trimester screening for pre-eclampsia (PE) by a method that uses Bayes' theorem to combine maternal factors with biomarkers is superior to that defined by current National Institute for Health and Care Excellence (NICE) guidelines. METHODS: This was a prospective multicenter study (screening program for pre-eclampsia (SPREE)) in seven National Health Service maternity hospitals in England, of women recruited between April and December 2016. Singleton pregnancies at 11-13 weeks' gestation had recording of maternal characteristics and medical history and measurements of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum pregnancy-associated plasma protein-A (PAPP-A). The performance of screening for PE by the Bayes' theorem-based method was compared with that of the NICE method. Primary comparison was detection rate (DR) using NICE method vs mini-combined test (maternal factors, MAP and PAPP-A) in the prediction of PE at any gestational age (all-PE) for the same screen-positive rate determined by the NICE method. Key secondary comparisons were DR of screening recommended by the NICE guidelines vs three Bayes' theorem-based methods (maternal factors, MAP and PAPP-A; maternal factors, MAP and PlGF; and maternal factors, MAP, UtA-PI and PlGF) in the prediction of preterm PE, defined as that requiring delivery < 37 weeks. RESULTS: All-PE developed in 473 (2.8%) of the 16 747 pregnancies and preterm PE developed in 142 (0.8%). The screen-positive rate by the NICE method was 10.3% and the DR for all-PE was 30.4% and for preterm PE it was 40.8%. Compliance with the NICE recommendation that women at high risk for PE should be treated with aspirin from the first trimester to the end of pregnancy was only 23%. The DR of the mini-combined test for all-PE was 42.5%, which was superior to that of the NICE method by 12.1% (95% CI, 7.9-16.2%). In screening for preterm PE by a combination of maternal factors, MAP and PlGF, the DR was 69.0%, which was superior to that of the NICE method by 28.2% (95% CI, 19.4-37.0%) and with the addition of UtA-PI the DR was 82.4%, which was higher than that of the NICE method by 41.6% (95% CI, 33.2-49.9%). CONCLUSIONS: the performance of screening for PE as currently recommended by NICE guidelines is poor and compliance with these guidelines is low. The performance of screening is substantially improved by a method combining maternal factors with biomarkers. © 2018 Crown copyright. Ultrasound in Obstetrics & Gynecology © 2018 ISUOG.

OBJECTIVE: to develop fetal and neonatal population weight charts. The rationale was that, while reference ranges of estimated fetal weight (EFW) are representative of the whole population, the traditional approach of deriving birth-weight (BW) charts is misleading, because a large proportion of babies born preterm arise from pathological pregnancy. We propose that the reference population for BW charts, as in the case of EFW charts, should comprise all babies at a given gestational age, including those still in utero. METHODS: Two sources of data were used for this study. For both, the inclusion criteria were singleton pregnancy, dating by fetal crown-rump length at 11 + 0 to 13 + 6 weeks' gestation, availability of ultrasonographic measurements of fetal head circumference (HC), abdominal circumference (AC) and femur length (FL) and live birth of phenotypically normal neonate. Dataset 1 comprised a sample of 5163 paired measurements of EFW and BW; ultrasound examinations were carried out at 22-43 weeks' gestation and birth occurred within 2 days of the ultrasound examination. EFW was derived from the HC, AC and FL measurements using the formula reported by Hadlock et al. in 1985. Dataset 2 comprised a sample of 95 579 pregnancies with EFW obtained by routine ultrasonographic fetal biometry at 20 + 0 to 23 + 6 weeks' gestation (n = 45 034), 31 + 0 to 33 + 6 weeks (n = 19 224) or 35 + 0 to 36 + 6 weeks (n = 31 321); for the purpose of this study we included data for only one of the three visits per pregnancy. In the development of reference ranges of EFW and BW according to gestational age, the following assumptions were made: first, that EFW and BW have a common median, dependent on gestational age; and second, that deviations from the median occur in both EFW and BW and these deviations are correlated with different levels of spread for EFW and BW, dependent on gestational age. We adopted a Bayesian approach to inference, combining information from the two datasets using Markov Chain Monte-Carlo sampling. The fitted model assumed that the mean log transformed measurements of EFW and BW are related to gestational age according to a cubic equation and that deviations about the mean follow a bivariate Gaussian distribution. RESULTS: in the case of EFW in Dataset 2, there was a good distribution of values. 90th , > 95th and > 97th percentiles of the reference range of EFW according to gestational age throughout the gestational age range of 20 + 0 to 36 + 6 weeks. In the case of BW, there was a good distribution of values only for the cases delivered > 39 weeks' gestation. For preterm births, particularly at 27-36 weeks, BW was below the 3rd , 5th and 10th percentiles in a very high proportion of cases, particularly in cases of iatrogenic birth. The incidence of small-for-gestational-age fetuses and neonates in the respective EFW and BW charts was higher in women of black than those of white racial origin. CONCLUSION: We established a BW chart for all babies at a given gestational age, including those still in utero, thereby overcoming the problem of underestimation of growth restriction in preterm birth. BW and EFW charts have a common median but differ in the levels of spread from the median. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVE: to estimate the patient-specific risk of pre-eclampsia (PE) at 19-24 weeks' gestation by maternal factors and combinations of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1). On the basis of the risk of PE, the women would be stratified into high-, intermediate- and low-risk management groups. The high-risk group would require close monitoring for high blood pressure and proteinuria at 24-31 weeks. The intermediate-risk group, together with the undelivered pregnancies from the high-risk group, would have reassessment of risk for PE at 32 weeks to identify those who would require close monitoring for high blood pressure and proteinuria at 32-35 weeks. All pregnancies would have reassessment of risk for PE at 36 weeks to define the plan for further monitoring and delivery. METHODS: This was a prospective observational study of women attending for an ultrasound scan at 19-24 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE at

OBJECTIVES: to examine the effect of first-trimester screening for pre-eclampsia (PE) on the prediction of delivering a small-for-gestational-age (SGA) neonate and the effect of prophylactic use of aspirin on the prevention of SGA. METHODS: the data for this study were derived from two multicenter studies. In SPREE, we investigated the performance of screening for PE by a combination of maternal characteristics and biomarkers at 11-13 weeks' gestation. In ASPRE, women with a singleton pregnancy identified by combined screening as being at high risk for preterm PE (> 1 in 100) participated in a trial of aspirin (150 mg/day from 11-14 until 36 weeks' gestation) compared to placebo. In this study, we used the data from the ASPRE trial to estimate the effect of aspirin on the incidence of SGA with birth weight

OBJECTIVES: to evaluate the performance of a combination of angiogenic and vasoactive biomarkers to predict the development of severe pre-eclampsia (PE)/HELLP syndrome in the third trimester. METHODS: Included were 215 women referred in the third trimester to an obstetric outpatient clinic with suspected PE (mean gestational age, 35 + 4 weeks), and 94 with normal pregnancy attending a midwife clinic. Cases were categorized as having subclinical PE, essential hypertension, gestational hypertension, moderate PE, and severe PE/HELLP syndrome. Blood samples were analyzed by immunoassay and groups were compared with respect to potential clinical and biochemical biomarkers, with the primary outcome being development of severe PE/HELLP syndrome within 1 week and within 2 weeks of analysis. The most promising markers were also assessed in combination. RESULTS: in the patients presenting with mild to moderate symptoms of PE, the individual markers which performed best for the prediction of progression to severe PE/HELLP syndrome within 1 week and within 2 weeks of biomarker evaluation were C-terminal pro-endothelin-1 (CT-pro-ET-1) (area under the receiver-operating characteristics curve (AUC), 0.82 and 0.78, respectively), soluble fms-like tyrosine kinase-1 (sFlt-1) (AUC, 0.81 and 0.76), systolic blood pressure (AUC, 0.80 and 0.68) and midregional pro-atrial natriuretic peptide (AUC, 0.79 and 0.77). The combination of biomarkers with the best performance was CT-pro-ET-1, sFlt-1 and systolic blood pressure, achieving an AUC of 0.94 for prediction of development of severe PE/HELLP syndrome within 1 week and an AUC of 0.83 for prediction of their development within 2 weeks of biomarker evaluation. CONCLUSIONS: the performance of CT-pro-ET-1 for prediction of the development of PE/HELLP syndrome in the third trimester was promising, especially in combination with sFlt-1 and systolic blood pressure. This was an exploratory study and our findings should be confirmed in further studies. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVE: to examine the performance of screening for pre-eclampsia (PE) at 35-37 weeks' gestation by maternal factors and combinations of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1). METHODS: This was a prospective observational study in women with singleton pregnancy attending for an ultrasound scan at 35 + 0 to 36 + 6 weeks as part of routine pregnancy care. Bayes' theorem was used to combine the prior distribution of gestational age at delivery with PE, obtained from maternal characteristics and medical history, with various combinations of biomarker multiples of the median (MoM) values to derive the patient-specific risks of delivery with PE. The performance of such screening was estimated. RESULTS: the study population of 13 350 pregnancies included 272 (2.0%) that subsequently developed PE. In pregnancies that developed PE, the MoM values of MAP, UtA-PI and sFlt-1 were increased and PlGF MoM was decreased. At a risk cut-off of 1 in 20, the proportion of the population stratified into high risk was about 10% of the total, and the proportion of cases of PE contained within this high-risk group was 28% with screening by maternal factors alone; the detection rate increased to 53% with the addition of MAP, 67% with the addition of MAP and PlGF and 70% with the addition of MAP, PlGF and sFlt-1. The performance of screening was not improved by the addition of UtA-PI. The performance of screening depended on the racial origin of the women; in screening by a combination of maternal factors, MAP, PlGF and sFlt-1 and use of the risk cut-off of 1 in 20, the detection rate and screen-positive rate were 66% and 9.5%, respectively, for Caucasian women and 88% and 18% for those of Afro-Caribbean racial origin. CONCLUSION: Screening by maternal factors and biomarkers at 35-37 weeks' gestation can identify a high proportion of pregnancies that develop late PE. The performance of screening depends on the racial origin of the women. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVE: to examine the performance of screening for early, preterm and term pre-eclampsia (PE) at 11-13 weeks' gestation by maternal factors and combinations of mean arterial pressure (MAP), uterine artery (UtA) pulsatility index (PI), serum placental growth factor (PlGF) and serum pregnancy-associated plasma protein-A (PAPP-A). METHODS: the data for this study were derived from three previously reported prospective non-intervention screening studies at 11 + 0 to 13 + 6 weeks' gestation in a combined total of 61 174 singleton pregnancies, including 1770 (2.9%) that developed PE. Bayes' theorem was used to combine the prior distribution of gestational age at delivery with PE, obtained from maternal characteristics, with various combinations of biomarker multiples of the median (MoM) values to derive patient-specific risks of delivery with PE at

OBJECTIVE: to examine the performance of screening for preterm and term pre-eclampsia (PE) in the study population participating in the ASPRE (Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention) trial. METHODS: This was a prospective first-trimester multicenter study on screening for preterm PE in 26 941 singleton pregnancies by means of an algorithm that combines maternal factors, mean arterial pressure, uterine artery pulsatility index and maternal serum pregnancy-associated plasma protein-A and placental growth factor at 11-13 weeks' gestation. Eligible women with an estimated risk for preterm PE of > 1 in 100 were invited to participate in a double-blind trial of aspirin (150 mg per day) vs placebo from 11-14 until 36 weeks' gestation, which showed that, in the aspirin group, the incidence of preterm PE was reduced by 62%. In the screened population, the detection rates (DRs) and false-positive rates (FPRs) for delivery with PE 

OBJECTIVE: to examine the diagnostic accuracy of a previously developed model for prediction of pre-eclampsia (PE) by a combination of maternal factors and biomarkers at 11-13 weeks' gestation. METHODS: This was a prospective first-trimester multicenter study of screening for PE in 8775 singleton pregnancies. A previously published algorithm was used for the calculation of patient-specific risk of PE in each individual. The detection rates (DRs) and false-positive rates (FPRs) for delivery with PE

OBJECTIVE: to examine the diagnostic accuracy of a previously developed model for the first-trimester combined test in screening for trisomies 21, 18 and 13. METHODS: This was a prospective validation study of screening for trisomies 21, 18 and 13 by assessment of a combination of maternal age, fetal nuchal translucency, fetal heart rate and serum free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11 + 0 to 13 + 6 weeks' gestation in 108 982 singleton pregnancies undergoing routine care in three maternity hospitals. A previously published algorithm was used to calculate patient-specific risks for trisomy 21, 18 and 13 in each patient. The detection rate (DR) and false-positive rate (FPR) at estimated risk cut-offs from 1 in 2 to 1 in 1000 were determined. The proportions of trisomies detected were compared to their expected values in different risk groups. RESULTS: in the study population, there were 108 112 (99.2%) cases with normal fetal karyotype or birth of a phenotypically normal neonate and 870 (0.8%) cases with abnormal karyotype, including trisomy 21 (n = 432), trisomy 18 (n = 166), trisomy 13 (n = 56), monosomy X (n = 63), triploidy (n = 35) or other aneuploidy (n = 118). The screen-positive rates, standardized according to the maternal age distribution in England and Wales in 2011, of fetuses with abnormal or normal karyotype were compatible with those predicted from the previous model; at a risk cut-off of 1 in 100, the FPR was about 4% and the DRs for trisomies 21, 18 and 13 were 90%, 97% and 92%, respectively. There was evidence that the algorithm overestimated risk. This could, to some degree, reflect under-ascertainment in pregnancies ending in miscarriage or stillbirth. CONCLUSION: in a prospective validation study, the first-trimester combined test detected 90%, 97% and 92% of trisomies 21, 18 and 13, respectively, as well as > 95% of cases of monosomy X and triploidies and > 50% of other chromosomal abnormalities, at a FPR of 4%. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

BACKGROUND: the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention trial demonstrated that in women who were at high risk for preterm preeclampsia with delivery at

BACKGROUND: the Aspirin for Evidence-Based Preeclampsia Prevention trial was a multicenter study in women with singleton pregnancies. Screening was carried out at 11-13 weeks' gestation with an algorithm that combines maternal factors and biomarkers (mean arterial pressure, uterine artery pulsatility index, and maternal serum pregnancy-associated plasma protein a and placental growth factor). Those with an estimated risk for preterm preeclampsia of >1 in 100 were invited to participate in a double-blind trial of aspirin (150 mg/d) vs placebo from 11-14 until 36 weeks' gestation. Preterm preeclampsia with delivery at

OBJECTIVE: to estimate the patient-specific risk of pre-eclampsia (PE) at 31-34 weeks' gestation by a combination of maternal characteristics and medical history with multiples of the median (MoM) values of serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1) and to compare the performance of screening to that achieved by the sFlt-1/PlGF ratio. METHODS: This was a prospective observational study in women attending a third-trimester ultrasound scan at 31-34 weeks as part of routine pregnancy care. We estimated the performance of screening for PE with delivery within 4 weeks of assessment and PE with delivery from 4 weeks after assessment up to 40 weeks' gestation by the sFlt-1/PlGF ratio and by a method utilizing Bayes' theorem that combines maternal factors and MoM values of sFlt-1 and PlGF. The significance of the difference in screening performance between the two methods was assessed by comparison of the areas under the receiver-operating characteristics curves (AUC). RESULTS: the study population of 8063 singleton pregnancies included 231 (2.9%) that subsequently developed PE. In the prediction of delivery with PE at 

OBJECTIVE: to develop a model for screening for pre-eclampsia (PE) in twin pregnancies based on maternal demographic characteristics and medical history and biomarkers at 11-13 weeks' gestation. METHODS: This was a screening study in twin pregnancies at 11-13 weeks' gestation. Bayes theorem was used to combine the a-priori risk from maternal factors with various combinations of uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP), serum pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) multiples of the median (MoM) values. The performance of screening for PE requiring delivery at

OBJECTIVE: a survival-time regression model for gestational age at delivery with pre-eclampsia (PE) in singleton pregnancy, using maternal demographic characteristics and medical history, was reported previously. The objective of this study was to extend this model to dichorionic (DC) and monochorionic (MC) twin pregnancy. METHODS: the study population included 1789 DC and 430 MC twin pregnancies and 93 297 singleton pregnancies. A survival-time model for gestational age at delivery with PE was developed from variables of maternal characteristics and medical history. The risk of PE with delivery

OBJECTIVE: to compare the performance of screening by soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) ratio > 38 for the prediction of delivery with pre-eclampsia (PE) at 

OBJECTIVES: to examine the gestational age at delivery in dichorionic (DC) and monochorionic (MC) twin pregnancies, with and without pre-eclampsia (PE), and to determine the relative risk of total and preterm PE compared with that in singleton pregnancies. METHODS: This was a screening study for PE in twin pregnancies undergoing first-trimester combined screening for aneuploidy and subsequently delivering two phenotypically normal live or stillborn babies at ≥ 24 weeks' gestation. The distribution of gestational age at delivery in DC and MC twins was determined and compared with that in singleton pregnancies from the same population. The relative risk for total and preterm PE in twins compared with singleton pregnancies was determined. Kaplan-Meier estimates of the cumulative incidence of PE in twin and singleton pregnancies, assuming no other cause for delivery, were determined and hazard ratios for twins relative to singletons were obtained from a Cox proportional hazards regression model. RESULTS: the incidence of PE in singletons was 2.3% (2162/93 297), in DC twin pregnancies was 8.1% (145/1789) and in MC twin pregnancies was 6.0% (26/430). Compared with singletons, the relative risk of total PE was 3.5 for DC twins and 2.6 for MC twins. Delivery

OBJECTIVE: to compare the performance of screening for pre-eclampsia (PE) based on risk factors from medical history, as recommended by NICE and ACOG, with the method proposed by the Fetal Medicine Foundation (FMF), which uses Bayes' theorem to combine the a-priori risk from maternal factors, derived by a multivariable logistic model, with the results of various combinations of biophysical and biochemical measurements. METHODS: This was a prospective multicenter study of screening for PE in 8775 singleton pregnancies at 11-13 weeks' gestation. A previously published FMF algorithm was used for the calculation of patient-specific risk of PE in each individual. The detection rates (DRs) and false-positive rates (FPRs) for delivery with PE

OBJECTIVE: to estimate the patient-specific risk of pre-eclampsia (PE) at 19-24 weeks' gestation by a combination of maternal characteristics and medical history with multiples of the median (MoM) values of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), and stratify women into high-, intermediate- and low-risk management groups. METHODS: This was a prospective observational study in women attending a second-trimester ultrasound scan at 19-24 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE < 32 weeks and < 36 weeks' gestation were calculated using the competing-risks model to combine the prior risk from maternal characteristics and medical history with MoM values of MAP, UtA-PI, PlGF and sFlt-1. On the basis of these risks, the population was stratified into high-, intermediate- and low-risk groups. Different risk cut-offs were used to vary the proportion of the population stratified into each risk category and the performance of screening for delivery with PE at < 32 weeks' gestation, at 32-35 weeks and at ≥ 36 weeks was estimated. In addition to empirical performance, we also derived model-based performance because the number of cases of PE delivering < 32 weeks was low. RESULTS: the study population of 7748 singleton pregnancies included 268 (3.5%) that subsequently developed PE. Using a risk cut-off of 1 in 100 for PE delivering < 32 weeks' gestation and a risk cut-off of 1 in 300 for PE delivering < 36 weeks, the proportion of the population stratified into high-, intermediate- and low-risk was 0.9%, 17.2% and 81.9%, respectively. The high-risk group contained 97% of pregnancies with PE < 32 weeks and 45% of those with PE at 32-35 weeks. The intermediate-risk group contained a further 46% of women with PE at 32-35 weeks. The low-risk group contained only 0.03% of pregnancies with PE < 32 weeks and 9% of those with PE at 32-35 weeks. CONCLUSION: Risk stratification of PE by the combined test at 19-24 weeks' gestation can identify, first, a group which constitutes < 1% of the total population and contains > 95% of those that will develop PE < 32 weeks and are in need of intensive monitoring at 24-31 weeks and, second, a group which constitutes < 20% of the total and contains > 90% of those that will develop PE at 32-35 weeks and are in need of reassessment at 32 weeks. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVE: to estimate the patient-specific risk of pre-eclampsia (PE) at 30-34 weeks' gestation by a combination of maternal characteristics and medical history with multiples of the median (MoM) values of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), and stratify women into high-, intermediate- and low-risk management groups. METHODS: This was a prospective observational study in women attending a third-trimester ultrasound scan at 30-34 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE at 

OBJECTIVE: to estimate the patient-specific risk of pre-eclampsia (PE) at 35-37 weeks' gestation by a combination of maternal characteristics and medical history with multiples of the median (MoM) values of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), and stratify women into high-, intermediate- and low-risk management groups. METHODS: This was a prospective observational study in women attending a third-trimester ultrasound scan at 35-37 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE at < 4 weeks from assessment and PE at < 42 weeks' gestation were calculated using the competing-risks model to combine the prior risk from maternal characteristics and medical history with MoM values of MAP, UtA-PI, PlGF and sFlt-1. On the basis of these risks, the population was stratified into high-, intermediate- and low-risk groups. Different risk cut-offs were used to vary the proportion of the population stratified into each risk category and the performance of screening for delivery with PE at < 40 and ≥ 40 weeks' gestation was estimated. RESULTS: the study population of 3703 singleton pregnancies included 38 (1.0%) with PE < 40 weeks' gestation and 22 (0.6%) with PE ≥ 40 weeks. Using a risk cut-off of 1 in 50 for PE delivering at < 4 weeks after assessment to define the high-risk group and a risk cut-off of < 1 in 100 for PE delivering at < 42 weeks' gestation to define the low-risk group, the proportion of the population stratified into high, intermediate and low risk was 12.7%, 28.8% and 58.5%, respectively. The high-risk group contained 92% of pregnancies with PE at < 40 weeks' gestation and 73% of those with PE at ≥ 40 weeks. The intermediate-risk group contained a further 27% of women with PE at ≥ 40 weeks. In the low-risk group, none of the women developed PE at < 40 or ≥ 40 weeks' gestation. CONCLUSION: the study presents risk stratification of PE by the combined test at 35-37 weeks, aiming to identify a high-risk group in need of intensive monitoring from the time of the initial assessment and up to 40 weeks' gestation, an intermediate-risk group in need of reassessment at 40 weeks' gestation and a low-risk group that can be reassured that they are unlikely to develop PE. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Pre-eclampsia (PE), which affects about 2% of pregnancies, is a major cause of maternal and perinatal morbidity and mortality. Early detection of PE can improve pregnancy outcome by providing timely intervention and closer monitoring. The current guideline from the UK National Institute for Health and Care Excellence (NICE) recommends that, at the booking visit, women identified with one major risk factor or more than one moderate risk factor for PE should be advised to take low-dose aspirin daily from 12 weeks until delivery. However, performance of the current method of screening is poor and identifies only about 35% of PE. Extensive studies in the last decade have established that the best performance for early prediction of PE can be achieved by using a novel Bayes' theorem-based method that combines maternal characteristics and medical history together with measurements of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and pregnancy-associated plasma protein-A (PAPP-A) at 11-13 weeks' gestation. This forms the 'combined test', which could be simplified to the 'mini combined test' when only maternal factors, MAP and PAPP-A are taken into consideration. We present the protocol (version 3.1, 14 November 2016) for the 'Screening programme for pre-eclampsia' (SPREE) study, a prospective multicenter cohort study that will be carried out in seven National Health Service maternity hospitals in England. Eligible pregnant women attending their routine scan at 11-13 weeks' gestation will be invited to participate in this study. Maternal characteristics and history and measurements of MAP, UtA-PI, serum PAPP-A and PlGF will be recorded according to standardized protocols. The patient-specific risk for PE will be calculated and data on pregnancy outcomes collected. We hypothesize that the first-trimester mini combined test and combined test for PE screening, using the Bayes' theorem-based method, are likely to be superior to the current method recommended by NICE that is based on maternal demographics and history alone. Enrollment for the study commenced in April 2016. The study is registered on the International Standard Randomised Controlled Trial Number (ISRCTN) registry. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVE: to investigate the potential value of repeat measurements of uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP) and serum placental growth factor (PlGF) at 12, 22 and 32 weeks' gestation in the prediction of pre-eclampsia (PE) developing after 32 weeks. METHODS: Data were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit at 11-13, 19-24 and/or 30-34 weeks' gestation in two maternity hospitals in England. UtA-PI, MAP and PlGF were measured. Bayes' theorem was used to combine the a-priori risk from maternal factors with UtA-PI, MAP and PlGF multiples of the median values. The performance of screening for PE developing after the 30-34-week visit by UtA-PI, MAP and PlGF measured at 11-13, 19-24 and 30-34 weeks and their combinations was examined. RESULTS: Screening at 30-34 weeks by UtA-PI, MAP and PlGF detected, at a 10% false-positive rate, 79%, 86% and 92% of preterm PE and 42%, 50% and 56% of term PE. The addition of biomarker values at 11-13 and/or 19-24 weeks was not associated with any improvement in the detection rate of preterm PE; in the case of term PE, there was a marginal (< 2%) improvement in detection for UtA-PI and MAP and a modest improvement of about 5% for PlGF. CONCLUSION: Measurements of UtA-PI, MAP and PlGF in the first and/or second trimester have a small or no effect on improving the prediction of PE provided by screening in the early third trimester. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

BACKGROUND: Preeclampsia affects approximately 3% of all pregnancies and is a major cause of maternal and perinatal morbidity and death. In the last decade, extensive research has been devoted to early screening for preeclampsia with the aim of reducing the prevalence of the disease through pharmacologic intervention in the high-risk group starting from the first trimester of pregnancy. OBJECTIVE: the purpose of this study was to develop a model for preeclampsia based on maternal demographic characteristics and medical history (maternal factors) and biomarkers. STUDY DESIGN: the data for this study were derived from prospective screening for adverse obstetric outcomes in women who attended for their routine first hospital visit at 11-13 weeks gestation in 2 maternity hospitals in England. We screened 35,948 singleton pregnancies that included 1058 pregnancies (2.9%) that experienced preeclampsia. Bayes theorem was used to combine the a priori risk from maternal factors with various combinations of uterine artery pulsatility index, mean arterial pressure, serum pregnancy-associated plasma protein-A, and placental growth factor multiple of the median values. Five-fold cross validation was used to assess the performance of screening for preeclampsia that delivered at

BACKGROUND: Preeclampsia (PE) affects 2-3% of all pregnancies and is a major cause of maternal and perinatal morbidity and mortality. The traditional approach to screening for PE is to use a risk-scoring system based on maternal demographic characteristics and medical history (maternal factors), but the performance of such an approach is very poor. OBJECTIVE: to develop a model for PE based on a combination of maternal factors with second-trimester biomarkers. STUDY DESIGN: the data for this study were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit at 19-24 weeks' gestation in 3 maternity hospitals in England between January 2006 and July 2014. We had data from maternal factors, uterine artery pulsatility index (UTPI), mean arterial pressure (MAP), serum placental growth factor (PLGF), and serum soluble fms-like tyrosine kinase-1 (SFLT) from 123,406, 67,605, 31,120, 10,828, and 8079 pregnancies, respectively. Bayes' theorem was used to combine the a priori risk from maternal factors with various combinations of biomarker multiple of the median (MoM) values. The modeled performance of screening for PE requiring delivery at

BACKGROUND: Preeclampsia (PE) affects 2-3% of all pregnancies and is a major cause of maternal and perinatal morbidity and mortality. We have proposed a 2-stage strategy for the identification of pregnancies at high risk of developing PE. The objective of the first stage, at 11-13 weeks' gestation, is a reduction in the prevalence of the disease through pharmacological intervention in the high-risk group. The objective of the second stage, during the second and/or third trimesters, is to improve perinatal outcome through close monitoring of the high-risk group for earlier diagnosis of the clinical signs of the disease and selection of the appropriate, time, place, and method of delivery. OBJECTIVE: the objective of the study was to examine the performance of screening for PE by a combination of maternal factors with early third-trimester biomarkers. STUDY DESIGN: This was a cohort study and data were derived from consecutive women with singleton pregnancies attending for their routine hospital visit at 30-34 weeks' gestation in 3 maternity hospitals in England between March 2011 and December 2014. In the first phase of the study, only uterine artery pulsatility index (UTPI) was measured and then measurement of mean arterial pressure (MAP) was added, and in the final phase, the serum concentration of placental growth factor (PLGF) was measured and then soluble fms-like tyrosine kinase-1 (SFLT) was added. We had data on UTPI, MAP, PLGF, and SFLT from 30,935, 29,042, 10,123, and 8,264 pregnancies, respectively. The Bayes theorem was used to combine the a priori risk from maternal factors with various combinations of biomarker multiple of the median values. Ten-fold cross-validation was used to estimate the performance of screening for PE requiring delivery at < 37 weeks' gestation (preterm-PE) and those delivering at ≥ 37 weeks (term-PE). The empirical performance was compared with model predictions. RESULTS: in pregnancies that developed PE, the values of MAP, UTPI, and SFLT were increased and PLGF was decreased. For all biomarkers the deviation from normal was greater for preterm-PE than term-PE, and therefore, the performance of screening was inversely related to the gestational age at which delivery become necessary for maternal and/or fetal indications. Combined screening by maternal factors, MAP, UTPI, PLGF, and SFLT predicted 98% (95% confidence interval, 88-100%) of preterm-PE and 49% (95% confidence interval, 42-57%) of term-PE, at a false-positive rate of 5%. These empirical detection rates are compatible with the respective model-based rates of 98% and 54%, but the latter were optimistically biased. CONCLUSION: Combination of maternal factors and biomarkers in the early third trimester could predict nearly all cases of preterm-PE and half of those with term-PE, at 5% false-positive rate.

OBJECTIVE: to develop a model for prediction of term pre-eclampsia (PE) based on a combination of maternal factors and late third-trimester biomarkers. METHODS: Data were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit at 35-37 weeks' gestation in two maternity hospitals in the UK. Uterine artery pulsatility index (UtA-PI) was measured in 5362 pregnancies, mean arterial pressure (MAP) in 5386 and serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1) in 3920. Bayes' theorem was used to combine the a-priori risk of PE from maternal factors with various combinations of biomarkers, expressed as multiples of the median (MoM). Five-fold cross-validation was used to estimate the performance of screening for PE, requiring delivery at some stage after assessment. The empirical performance of screening was compared to model predictions. RESULTS: in pregnancies that developed PE, the values of MAP, UtA-PI and sFlt-1 were increased and PlGF was decreased compared to unaffected pregnancies. For all biomarkers evaluated, the deviation from normal was inversely related to the gestational age at which delivery became necessary for maternal or fetal indications. Screening by maternal factors and by a combination of maternal factors with all biomarkers predicted 35% and 84% of PE, respectively, at a 10% false-positive rate. CONCLUSION: a combination of maternal factors and biomarkers at 35-37 weeks' gestation can provide effective screening for term PE. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVE: Effective screening for pre-eclampsia resulting in delivery < 37 weeks' gestation (preterm PE) is provided by assessment of a combination of maternal factors, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF) at 11-13 or 19-24 weeks' gestation. This study explores the possibility of carrying out routine screening for preterm PE by maternal factors and MAP in all pregnancies and reserving measurements of UtA-PI and PlGF for a subgroup of the population, selected on the basis of the risk derived from screening by maternal factors and MAP alone. METHODS: Study data were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit at 11-13 and/or 19-24 weeks' gestation. Bayes' theorem was used to derive the a-priori risk for preterm PE from maternal factors and MAP. The posterior risk was obtained by the addition of UtA-PI and PlGF. We estimated the detection rate (DR) of preterm PE, at an overall false-positive rate (FPR) of 10%, from a policy in which first-stage screening by a combination of maternal factors and MAP defines screen-positive, screen-negative and intermediate-risk groups, with the latter undergoing second-stage screening by UtA-PI and PlGF. RESULTS: at 11-13 weeks' gestation, the model-based DR of preterm PE, at a 10% FPR, when screening the whole population by maternal factors, MAP, UtA-PI and PlGF was 74%. A similar DR was achieved by two-stage screening, with screening by maternal factors and MAP in the first stage and reserving measurement of UtA-PI and PlGF for the second stage and for only 50% of the population. If second-stage screening was offered to 30% of the population, there would be only a small reduction in DR from 74% to 71%. At 19-24 weeks, the model-based DR of preterm PE, at a 10% FPR, when screening the whole population by maternal factors, MAP, UtA-PI and PlGF was 84%. A similar DR was achieved by two-stage screening with measurements of UtA-PI and PlGF in only 70% of the population; if second-stage screening was offered to 40% of the population, the DR would be reduced from 84% to 81%. CONCLUSIONS: High DR of preterm PE can be achieved by two-stage screening in the first and second trimesters with maternal factors and MAP in the whole population and measurements of UtA-PI and PlGF in only some of the pregnancies. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVE: to examine the distribution of maternal serum pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG) at 12, 22 and 32 weeks' gestation in singleton pregnancies which develop pre-eclampsia (PE) and examine the performance of these biomarkers in screening for PE. METHODS: Serum PAPP-A and free β-hCG were measured in 94 989 cases at 11-13 weeks, 7597 at 19-24 weeks and 8088 at 30-34 weeks' gestation. Bayes' theorem was used to combine the a-priori risk from maternal characteristics and medical history with PAPP-A and free β-hCG. The empirical and model-based performance of screening for preterm PE requiring delivery < 37 weeks' gestation and term PE with delivery ≥ 37 weeks was estimated. RESULTS: Combined screening with maternal factors and serum PAPP-A at 11-13 and 30-34 weeks and with maternal factors and serum free β-hCG at 19-24 and 30-34 weeks improved the prediction provided by maternal factors alone for preterm PE. The detection rate, at a 10% false-positive rate, for preterm PE by screening with maternal factors was about 45% which improved to 51% and 53% by combined screening with PAPP-A at 11-13 weeks and 30-34 weeks, respectively, and 55% and 54% by combined screening with free β-hCG at 19-24 weeks and 30-34 weeks, respectively. Measurement of serum PAPP-A and free β-hCG was not useful in the prediction of term PE. CONCLUSIONS: Measurement of serum PAPP-A and free β-hCG could improve the prediction of preterm PE provided by maternal characteristics and medical history alone. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVE: to examine the distribution of maternal serum alpha-fetoprotein (AFP) at 12, 22 and 32 weeks' gestation in singleton pregnancies which develop pre-eclampsia (PE) and examine the performance of this biomarker in screening for PE. METHODS: Serum AFP was measured in 17 071 cases at 11-13 weeks, in 8583 cases at 19-24 weeks and 8609 cases at 30-34 weeks' gestation. Bayes' theorem was used to combine the a-priori risk from maternal characteristics and medical history with AFP. The performance of screening for PE requiring delivery < 32, at 32 + 0 to 36 + 6, < 37 and ≥ 37 weeks' gestation was estimated. RESULTS: in pregnancies that developed PE, serum AFP multiples of the median (MoM) was increased at 11-13 and 19-24 weeks' gestation, but not at 30-34 weeks, and the values were inversely related to gestational age at delivery. Combined screening with maternal factors and serum AFP improved the prediction provided by maternal factors alone for PE delivering < 37 weeks, but not for PE delivering ≥ 37 weeks. The performance of screening for preterm PE was better at 19-24 weeks than at 11-13 weeks and the detection rate (DR) for a given false-positive rate (FPR) was higher for PE delivering < 32 weeks than for PE delivering at 32 + 0 to 36 + 6 weeks. The DRs, at 10% FPR, of combined screening at 11-13 weeks for PE delivering < 32 and at 32 + 0 to 36 + 6 weeks were 54% and 45%, respectively, and these improved to 72% and 53% with screening at 19-24 weeks. CONCLUSIONS: Measurement of serum AFP at 11-13 and 19-24 weeks' gestation improves the prediction of preterm PE provided by maternal factors alone. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVE: to examine the distribution of maternal serum placental growth factor (PlGF) at 12, 22, 32 and 36 weeks' gestation in singleton pregnancies which develop pre-eclampsia (PE) and examine the performance of this biomarker in screening for PE. METHODS: Serum PlGF was measured in 40 212 cases at 11-13 weeks, in 10 282 cases at 19-24 weeks, in 10 400 at 30-34 weeks and 4043 at 35-37 weeks. Bayes' theorem was used to combine the a-priori risk from maternal characteristics and medical history with serum PlGF. The performance of screening for PE requiring delivery < 32, at 32 + 0 to 36 + 6 and ≥ 37 weeks' gestation was estimated. RESULTS: in pregnancies that developed PE, serum PlGF was decreased and the separation in multiples of the median (MoM) values from normal was greater with earlier, compared to later, gestational age at which delivery for PE became necessary. Additionally, the slope of the regression lines of PlGF MoM with gestational age at delivery in pregnancies that developed PE increased with advancing gestational age at screening. The detection rates (DRs), at a false-positive rate (FPR) of 10%, for PE delivering < 32 weeks were 79% and 97% with screening at 12 and 22 weeks, respectively. The DRs for PE delivering at 32 + 0 to 36 + 6 weeks were 57%, 65% and 90% with screening at 12, 22 and 32 weeks. The DRs for PE delivering ≥ 37 weeks were 40%, 37%, 54% and 64% with screening at 12, 22, 32 and 36 weeks, respectively. CONCLUSIONS: the performance of combined screening with maternal factors, medical history and PlGF is superior in screening for early, compared to late, PE and improves with advancing gestational age at screening. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVE: to examine the distribution of maternal serum soluble fms-like tyrosine kinase-1 (sFlt-1) at 12, 22, 32 and 36 weeks' gestation in singleton pregnancies that develop pre-eclampsia (PE) and examine the performance of this biomarker in screening for PE. METHODS: Serum sFlt-1 was measured in 7066 cases at 11-13 weeks, 8079 cases at 19-24 weeks, 8472 at 30-34 weeks and 4043 at 35-37 weeks. Bayes' theorem was used to combine the a-priori risk from maternal characteristics and medical history with serum levels of sFlt-1. The performance of screening for PE in women requiring delivery < 32, between 32 + 0 and 36 + 6 and ≥ 37 weeks' gestation was estimated. RESULTS: in pregnancies that developed PE, serum sFlt-1 was increased and the separation in multiples of the median (MoM) values from normal was greater with earlier, compared to later, gestational age at which delivery for PE became necessary. In pregnancies that developed PE, the slope of the regression lines of sFlt-1 MoM with gestational age at delivery increased with advancing gestational age at screening. Measurement of sFlt-1 at 11-13 weeks did not improve the prediction of PE achieved by maternal factors alone, sFlt-1 at 19-24 weeks improved the prediction of PE delivering < 37 weeks but not for PE delivering ≥ 37 weeks, sFlt-1 at 30-34 weeks improved the prediction of PE delivering < 37 and PE delivering ≥ 37 weeks and sFlt-1 at 35-37 weeks improved the prediction of PE delivering ≥ 37 weeks. The detection rates (DRs), at a false-positive rate (FPR) of 10%, of PE delivering < 32 weeks were 52% and 65% with screening at 12 and 22 weeks, respectively. The DRs for PE delivering between 32 + 0 and 36 + 6 weeks were 44%, 44% and 93% with screening at 12, 22 and 32 weeks. The DR for PE delivering ≥ 37 weeks were 37%, 37%, 52% and 69% with screening at 12, 22, 32 and 36 weeks, respectively. CONCLUSIONS: the performance of combined screening with maternal factors, medical history and serum sFlt-1 is superior for detection of early, compared to late, PE and improves with advancing gestational age at screening. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVE: to investigate the potential value of repeat measurements of maternal serum concentration of soluble fms-like tyrosine kinase-1 (sFlt-1) at 22 and 32 weeks' gestation in the prediction of pre-eclampsia (PE) in women delivering after 32 weeks. METHODS: the data were derived from prospective screening for adverse obstetric outcomes in women attending their routine hospital visit at 19-24 and/or 30-34 weeks' gestation in one of two maternity hospitals in England. Serum sFlt-1 was measured in 7565 and 8264 singleton pregnancies at 19-24 and 30-34 weeks, respectively. Bayes' theorem was used to combine the a-priori risk from maternal factors with sFlt-1 multiples of the median (MoM) values. The performance of screening for PE developing after the 30-34-week visit by sFlt-1, measured at 19-24, 30-34 and at both 19-24 and 30-34 weeks was examined. RESULTS: in pregnancies with PE, sFlt-1 in both the second and third trimesters was increased and the deviation from normal was inversely related to the gestational age at which delivery became necessary for maternal or fetal indications. Serum sFlt-1 at 19-24 weeks was not useful in predicting PE beyond the 30-34-week visit, but the addition of sFlt-1 at 19-24 weeks improved the prediction of PE provided by sFlt-1 at 30-34 weeks. Screening by maternal factors and sFlt-1 at 30-34 weeks predicted 94% of preterm PE and 54% of term PE, at a false-positive rate of 10%; this was improved to 99% and 64%, respectively, by the additional measurement of sFlt-1 at 19-24 weeks. CONCLUSIONS: Measurement of sFlt-1 in the second trimester improves the prediction of PE provided by screening in the early third-trimester. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVE: to examine the distribution of mean arterial pressure (MAP) at 12, 22, 32 and 36 weeks' gestation in singleton pregnancies which develop pre-eclampsia (PE) and examine the performance of this biomarker in screening for PE. METHODS: MAP was measured in 77 343 cases at 11-13 weeks, in 31 120 cases at 19-24 weeks, in 29 802 at 30-34 weeks and 5543 at 35-37 weeks. Bayes' theorem was used to combine the a-priori risk from maternal characteristics and medical history with MAP. The performance of screening for PE requiring delivery < 32, at 32 + 0 to 36 + 6 and ≥ 37 weeks' gestation was estimated. RESULTS: in pregnancies that developed PE, MAP was increased and the separation in multiples of the median (MoM) values from normal was greater with an earlier, compared to later, gestational age at which delivery for PE became necessary. Additionally, the slope of the regression lines of MAP MoM with gestational age at delivery in pregnancies that developed PE increased with advancing gestational age at screening. The detection rate (DR), at a false-positive rate of 10%, for PE delivering < 32 weeks was 66% and 72% with screening at 12 and 22 weeks, respectively. The DR for PE delivering at 32 + 0 to 36 + 6 weeks was 54%, 56% and 81% with screening at 12, 22 and 32 weeks. The DR for PE delivering ≥ 37 weeks was 45%, 43%, 49% and 59% with screening at 12, 22, 32 and 36 weeks, respectively. CONCLUSIONS: the performance of combined screening with maternal factors and MAP is superior in screening for early, compared to late, PE and, to a certain extent, improves with advancing gestational age at screening. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

INTRODUCTION: Pre-eclampsia (PE) affects 2-3% of all pregnancies and is a major cause of maternal and perinatal morbidity and mortality. Prophylactic use of low-dose aspirin in women at risk for PE may substantially reduce the prevalence of the disease. Effective screening for PE requiring delivery before 37�
weeks (preterm PE) can be provided by a combination of maternal factors, uterine artery Doppler, mean arterial pressure, maternal serum pregnancy-associated plasma protein a and placental growth factor at 11-13�
weeks' gestation, with a detection rate of 75% at a false-positive rate of 10%. We present a protocol (V.6, date 25 January 2016) for the ASpirin for evidence-based PREeclampsia prevention (ASPRE) trial, which is a double-blinded, placebo-controlled, randomised controlled trial (RCT) that uses an effective PE screening programme to determine whether low-dose aspirin given to women from 11 to 13�
weeks' gestation will reduce the incidence of preterm PE. METHODS AND ANALYSIS: all eligible women attending for their first trimester scan will be invited to participate in the screening study for preterm PE. Those found to be at high risk of developing preterm PE will be invited to participate in the RCT. Further scans will be conducted for assessment of fetal growth and biomarkers. Pregnancy and neonatal outcomes will be collected and analysed. The first enrolment for the pilot study was in April 2014. As of April 2016, 26 670 women have been screened and 1760 recruited to the RCT. The study is registered on the International Standard Randomised Controlled Trial Number (ISRCTN) registry. TRIAL REGISTRATION NUMBER: ISRCTN13633058.

OBJECTIVE:  To investigate the benefits and costs of implementing non-invasive prenatal testing (NIPT) for Down's syndrome into the NHS maternity care pathway. DESIGN:  Prospective cohort study. SETTING:  Eight maternity units across the United Kingdom between 1 November 2013 and 28 February 2015. PARTICIPANTS:  All pregnant women with a current Down's syndrome risk on screening of at least 1/1000. MAIN OUTCOME MEASURES:  Outcomes were uptake of NIPT, number of cases of Down's syndrome detected, invasive tests performed, and miscarriages avoided. Pregnancy outcomes and costs associated with implementation of NIPT, compared with current screening, were determined using study data on NIPT uptake and invasive testing in combination with national datasets. RESULTS:  NIPT was prospectively offered to 3175 pregnant women. In 934 women with a Down's syndrome risk greater than 1/150, 695 (74.4%) chose NIPT, 166 (17.8%) chose invasive testing, and 73 (7.8%) declined further testing. of 2241 women with risks between 1/151 and 1/1000, 1799 (80.3%) chose NIPT. of 71 pregnancies with a confirmed diagnosis of Down's syndrome, 13/42 (31%) with the diagnosis after NIPT and 2/29 (7%) after direct invasive testing continued, resulting in 12 live births. In an annual screening population of 698 500, offering NIPT as a contingent test to women with a Down's syndrome screening risk of at least 1/150 would increase detection by 195 (95% uncertainty interval -34 to 480) cases with 3368 (2279 to 4027) fewer invasive tests and 17 (7 to 30) fewer procedure related miscarriages, for a non-significant difference in total costs (£-46 000, £-1 802 000 to £2 661 000). The marginal cost of NIPT testing strategies versus current screening is very sensitive to NIPT costs; at a screening threshold of 1/150, NIPT would be cheaper than current screening if it cost less than £256. Lowering the risk threshold increases the number of Down's syndrome cases detected and overall costs, while maintaining the reduction in invasive tests and procedure related miscarriages. CONCLUSIONS:  Implementation of NIPT as a contingent test within a public sector Down's syndrome screening programme can improve quality of care, choices for women, and overall performance within the current budget. As some women use NIPT for information only, the Down's syndrome live birth rate may not change significantly. Future research should consider NIPT uptake and informed decision making outside of a research setting.

OBJECTIVE: to examine the distribution of uterine artery pulsatility index (UtA-PI) at 12, 22, 32 and 36 weeks' gestation in singleton pregnancies which develop pre-eclampsia (PE) and examine the performance of this biomarker in screening for PE. METHODS: UtA-PI was measured in 92 712 singleton pregnancies at 11-13 weeks, in 67 605 cases at 19-24 weeks, in 31 741 at 30-34 weeks and in 5523 at 35-37 weeks. Bayes' theorem was used to combine the a-priori risk from maternal characteristics and medical history with UtA-PI. The performance of screening for PE requiring delivery < 32, at 32 + 0 to 36 + 6, < 37 and ≥ 37 weeks' gestation was estimated. The results of combined screening were compared to those of screening by UtA-PI and by maternal factors alone. RESULTS: in pregnancies that developed PE, UtA-PI was increased and the separation in multiples of the median (MoM) values from normal was greater with earlier, compared to later, gestational age at which delivery for PE became necessary. Additionally, the slope of regression lines of UtA-PI MoM with gestational age at delivery in pregnancies that developed PE increased with increasing gestational age at screening. The detection rate (DR), at a 10% false-positive rate (FPR), for PE delivering < 32 weeks was 71% and 88% with combined screening at 11-13 and 19-24 weeks, respectively, and the DR for PE delivering at 32 + 0 to 36 + 6 weeks was 52%, 63% and 71% with screening at 11-13, 19-24 and 30-34 weeks, respectively. However, the DR of PE delivering ≥ 37 weeks was only about 40%, irrespective of the gestational age at screening. The performance of screening by the approach utilizing Bayes' theorem was superior to that of using a percentile cut-off of UtA-PI for gestational age. CONCLUSIONS: the performance of combined screening with maternal factors and UtA-PI is superior for detection of early, compared to late, PE and, to a certain extent, improves with advancing gestational age at screening. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVE: the purpose of this study was to develop a model for preeclampsia based on maternal demographic characteristics and medical history. STUDY DESIGN: This was a screening study of 120,492 singleton pregnancies at 11-13 weeks' gestation, including 2704 pregnancies (2.2%) that experienced preeclampsia. A survival-time model for the gestational age at delivery with preeclampsia was developed from variables of maternal characteristics and history. This approach assumes that, if the pregnancy was to continue indefinitely, all women would experience preeclampsia and that whether they do so or not before a specified gestational age depends on competition between delivery before or after development of preeclampsia. A 5-fold cross validation study was conducted to compare the performance of the new model with the National Institute for Health and Clinical Excellence (NICE) guidelines. RESULTS: in the new model, increased risk for preeclampsia, with a consequent shift in the Gaussian distribution of the gestational age at delivery with preeclampsia to the left, is provided by advancing maternal age, increasing weight, Afro-Caribbean and South Asian racial origin, medical history of chronic hypertension, diabetes mellitus and systemic lupus erythematosus or antiphospholipid syndrome, family history and personal history of preeclampsia, and conception by in vitro fertilization. The risk for preeclampsia decreases with increasing maternal height and in parous women with no previous preeclampsia; in the latter, the protective effect, which is related inversely to the interpregnancy interval, persists beyond 15 years. At a screen-positive rate of 11%, as defined by NICE, the new model predicted 40%, 48%, and 54% of cases of total preeclampsia and preeclampsia requiring delivery at

OBJECTIVE: to define the contribution of maternal variables that influence the measured mean arterial pressure (MAP) in screening for pregnancy complications. METHODS: Maternal characteristics and medical history were recorded, and MAP was measured, in women with a singleton pregnancy attending for three routine hospital visits at 11 + 0 to 13 + 6 weeks, 19 + 0 to 24 + 6 weeks and 30 + 0 to 34 + 6 weeks or 35 + 0 to 37 + 6 weeks' gestation. For pregnancies delivering phenotypically normal live births or stillbirths at ≥ 24 weeks' gestation, variables from maternal demographic characteristics and medical history that are important in the prediction of MAP were determined from linear mixed-effects multiple regression analysis. RESULTS: MAP was measured in 75 841 cases in the first trimester, 30 447 in the second trimester and 31 673 in the third trimester. Significant independent contributions to MAP were provided by gestational age, maternal age, weight, height, Afro-Caribbean racial origin, cigarette smoking, family history of pre-eclampsia (PE), history of PE in the previous pregnancy, interpregnancy interval, chronic hypertension and diabetes mellitus. The effects of some variables were similar, and for others differed, in the three different trimesters. Random-effects multiple regression analysis was used to define the contribution of maternal variables that influence the measured MAP and express the values as multiples of the median (MoMs). The model was shown to provide an adequate fit of MoM values for all covariates, both in pregnancies that developed PE and in those without this complication. CONCLUSIONS: a model was fitted to express the measured MAP as MoMs after adjustment for variables from maternal characteristics and medical history that affect this measurement.

OBJECTIVE: to define the contribution of maternal variables which influence the measured level of maternal serum alpha-fetoprotein (AFP) in screening for pregnancy complications. METHODS: Maternal characteristics and medical history were recorded and serum AFP was measured in women with a singleton pregnancy attending for three routine hospital visits at 11 + 0 to 13 + 6, 19 + 0 to 24 + 6 and 30 + 0 to 34 + 6 weeks' gestation. For pregnancies delivering phenotypically normal live births or stillbirths ≥ 24 weeks' gestation, variables from maternal demographic characteristics and medical history that are important in the prediction of AFP were determined from a linear mixed-effects multiple regression. RESULTS: Serum AFP was measured in 17 071 cases in the first trimester, 8583 in the second trimester and 8607 in the third trimester. Significant independent contributions to serum AFP were provided by gestational age, maternal weight, racial origin, gestational age at delivery and birth-weight Z-score of the neonate of the previous pregnancy and interpregnancy interval. Cigarette smoking was found to significantly affect serum AFP in the first trimester only. The machine used to measure serum AFP was also found to have a significant effect. Random-effects multiple regression analysis was used to define the contribution of maternal variables that influence the measured level of serum AFP and express the values as multiples of the median (MoMs). The model was shown to provide an adequate fit of MoM values for all covariates, both in pregnancies that developed pre-eclampsia and in those without this pregnancy complication. CONCLUSIONS: a model was fitted to express measured serum AFP across the three trimesters of pregnancy as MoMs, after adjusting for variables from maternal characteristics and medical history that affect this measurement.

OBJECTIVE: to define the contribution of maternal variables which influence the measured level of maternal serum free β-human chorionic gonadotropin (β-hCG) in screening for pregnancy complications. METHODS: Maternal characteristics and medical history were recorded and serum free β-hCG was measured in women with a singleton pregnancy attending for three routine hospital visits at 11 + 0 to 13 + 6, 19 + 0 to 24 + 6 and 30 + 0 to 34 + 6 weeks' gestation. For pregnancies delivering phenotypically normal live births or stillbirths ≥ 24 weeks' gestation, variables from maternal demographic characteristics and medical history that are important in the prediction of free β-hCG were determined from a linear mixed-effects multiple regression. RESULTS: Serum free β-hCG was measured in 94 985 cases in the first trimester, 7879 in the second trimester and 8424 in the third trimester. Significant independent contributions to serum free β-hCG were provided by gestational age, maternal weight, age and racial origin, cigarette smoking, method of conception, diabetes mellitus and family history of pre-eclampsia (PE) in the mother of the patient. The effects of some variables were similar and those for others differed in each trimester. Random-effects multiple regression analysis was used to define the contribution of maternal variables that influence the measured level of serum free β-hCG and express the values as multiples of the median (MoMs). The model was shown to provide an adequate fit of MoM values for all covariates both in pregnancies that developed PE and in those without this pregnancy complication. CONCLUSIONS: a model was fitted to express measured serum free β-hCG across the three trimesters of pregnancy as MoMs after adjusting for variables from maternal characteristics and medical history that affect this measurement.

OBJECTIVE: to define the contribution of maternal variables which influence the measured level of maternal serum pregnancy-associated plasma protein-A (PAPP-A) in screening for pregnancy complications. METHODS: Maternal characteristics and medical history were recorded and serum PAPP-A was measured in women with a singleton pregnancy attending for three routine hospital visits at 11 + 0 to 13 + 6, 19 + 0 to 24 + 6 and 30 + 0 to 34 + 6 weeks' gestation. For pregnancies delivering phenotypically normal live births or stillbirths ≥ 24 weeks' gestation, variables from maternal demographic characteristics and medical history that are important in the prediction of PAPP-A were determined from a linear mixed-effects multiple regression. RESULTS: Serum PAPP-A was measured in 94,966 cases in the first trimester, 7785 in the second trimester and 8286 in the third trimester. Significant independent contributions to serum PAPP-A were provided by gestational age, maternal weight, height, racial origin, cigarette smoking, diabetes mellitus, method of conception, previous pregnancy with or without pre-eclampsia (PE) and birth-weight Z-score of the neonate in the previous pregnancy. The effects of some variables were similar and those for others differed in the three different trimesters. Random-effects multiple regression analysis was used to define the contribution of maternal variables that influence the measured level of serum PAPP-A and express the values as multiples of the median (MoMs). The model was shown to provide an adequate fit of MoM values for all covariates, both in pregnancies that developed PE and in those without this pregnancy complication. CONCLUSIONS: a model was fitted to express the measured serum PAPP-A across the three trimesters of pregnancy as MoMs, after adjusting for variables from maternal characteristics and medical history that affect this measurement.

BACKGROUND: the Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial aimed to determine whether or not oral Δ(9)-tetrahydrocannabinol (Δ(9)-THC) slowed the course of progressive multiple sclerosis (MS); evaluate safety of cannabinoid administration; and, improve methods for testing treatments in progressive MS. OBJECTIVES: There were three objectives in the CUPID study: (1) to evaluate whether or not Δ(9)-THC could slow the course of progressive MS; (2) to assess the long-term safety of Δ(9)-THC; and (3) to explore newer ways of conducting clinical trials in progressive MS. DESIGN: the CUPID trial was a randomised, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were randomised in a 2 : 1 ratio to Δ(9)-THC or placebo. Randomisation was balanced according to Expanded Disability Status Scale (EDSS) score, study site and disease type. Analyses were by intention to treat, following a pre-specified statistical analysis plan. A cranial magnetic resonance imaging (MRI) substudy, Rasch measurement theory (RMT) analyses and an economic evaluation were undertaken. SETTING: Twenty-seven UK sites. PARTICIPANTS: Adults aged 18-65 years with primary or secondary progressive MS, 1-year evidence of disease progression and baseline EDSS 4.0-6.5. INTERVENTIONS: Oral Δ(9)-THC (maximum 28 mg/day) or matching placebo. ASSESSMENT VISITS: Three and 6 months, and then 6-monthly up to 36 or 42 months. MAIN OUTCOME MEASURES: Primary outcomes were time to EDSS progression, and change in Multiple Sclerosis Impact Scale-29 version 2 (MSIS-29v2) 20-point physical subscale (MSIS-29phys) score. Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed. RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect. Economic evaluation estimated mean incremental costs and quality-adjusted life-years (QALYs). RESULTS: Effectiveness - recruitment targets were achieved. of the 498 randomised patients (332 to active and 166 to placebo), 493 (329 active and 164 placebo) were analysed. PRIMARY OUTCOMES: no significant treatment effect; hazard ratio EDSS score progression (active : placebo) 0.92 [95% confidence interval (CI) 0.68 to 1.23]; and estimated between-group difference in MSIS-29phys score (active-placebo) -0.9 points (95% CI -2.0 to 0.2 points). Secondary clinical and MRI outcomes: no significant treatment effects. Safety - at least one serious adverse event: 35% and 28% of active and placebo patients, respectively. RMT analyses - scale evaluation: MSIS-29 version 2, MS Walking Scale-12 version 2 and MS Spasticity Scale-88 were robust measurement instruments. There was no clear symptomatic or disease-modifying treatment effect. Economic evaluation - estimated mean incremental cost to NHS over usual care, over 3 years £27,443.20 per patient. No between-group difference in QALYs. CONCLUSIONS: the CUPID trial failed to demonstrate a significant treatment effect in primary or secondary outcomes. There were no major safety concerns, but unwanted side effects seemed to affect compliance. Participants were more disabled than in previous studies and deteriorated less than expected, possibly reducing our ability to detect treatment effects. RMT analyses supported performance of MS-specific rating scales as measures, enabled group- and individual person-level examination of treatment effects, but did not influence study inferences. The intervention had significant additional costs with no improvement in health outcomes; therefore, it was dominated by usual care and not cost-effective. Future work should focus on determining further factors to predict clinical deterioration, to inform the development of new studies, and modifying treatments in order to minimise side effects and improve study compliance. The absence of disease-modifying treatments in progressive MS warrants further studies of the cannabinoid pathway in potential neuroprotection. TRIAL REGISTRATION: Current Controlled Trials ISRCTN62942668. FUNDING: the National Institute for Health Research Health Technology Assessment programme, the Medical Research Council Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society and Multiple Sclerosis Trust. The report will be published in full in Health Technology Assessment; Vol. 19, No. 12. See the NIHR Journals Library website for further project information.

OBJECTIVE: to define the contribution of maternal variables that influence the measured uterine artery pulsatility index (UtA-PI) in screening for pregnancy complications. METHODS: Maternal characteristics and medical history were recorded, and UtA-PI was measured, in women with a singleton pregnancy attending for three routine hospital visits at 11 + 0 to 13 + 6 weeks, 19 + 0 to 24 + 6 weeks and 30 + 0 to 34 + 6 weeks or 35 + 0 to 37 + 6 weeks' gestation. For pregnancies delivering phenotypically normal live births or stillbirths at ≥ 24 weeks' gestation, variables from maternal demographic characteristics and medical history that are important in the prediction of UtA-PI were determined from linear mixed-effects multiple regression. RESULTS: UtA-PI was measured in 90 484 cases in the first trimester, 66 862 cases in the second trimester and 33 470 cases in the third trimester of pregnancy. Significant independent contributions to UtA-PI were provided by gestational age, maternal age, weight, racial origin and a history of pre-eclampsia (PE) in the previous pregnancy. Random-effects multiple regression analysis was used to define the contribution of maternal variables that influence the measured UtA-PI and express the values as multiples of the median (MoM). The model was shown to provide an adequate fit of MoM values for all covariates both in pregnancies that developed PE and in those that did not. CONCLUSIONS: a model was fitted to express the measured UtA-PI as MoMs after adjustment for variables from maternal characteristics and medical history that affect this measurement.

BACKGROUND: Using surrogate biomarkers for disease progression as endpoints in neuroprotective clinical trials may help differentiate symptomatic effects of potential neuroprotective agents from true slowing of the neurodegenerative process. A systematic review was undertaken to determine what biomarkers for disease progression in Alzheimer's disease exist and how well they perform. METHODS: MEDLINE and Embase (1950-2011) were searched using five search strategies. Abstracts were assessed to identify papers meriting review in full. Studies of participants with probable Alzheimer's disease diagnosed by formal criteria were included. We made no restriction on age, disease duration, or drug treatment. We only included studies with a longitudinal design, in which the putative biomarker and clinical measure were both measured at least twice, as this is the only appropriate study design to use when developing a disease progression biomarker. We included studies which attempted to draw associations between the changes over time in the biomarker used to investigate disease progression and a clinical measure of disease progression. RESULTS: Fifty-nine studies were finally included. The commonest biomarker modality examined was brain MRI (17/59, 29% of included studies). Median follow-up in included studies was only 1.0 (IQR 0.8-1.7) year and most studies only measured the putative biomarker and clinical measure twice. Included studies were generally of poor quality with small numbers of participants (median 31 (IQR 17 to 64)), applied excessively restrictive study entry criteria, had flawed methodologies and conducted overly simplistic statistical analyses without adjusting for confounding factors. CONCLUSIONS: We found insufficient evidence to recommend the use of any biomarker as an outcome measure for disease progression in Alzheimer's disease trials. However, further investigation into the efficacy of using MRI measurements of ventricular volume and whole brain volume appeared to be merited. A provisional 'roadmap' to improve the quality of future disease progression biomarker studies is presented.

BACKGROUND: Laboratory evidence has shown that cannabinoids might have a neuroprotective action. We investigated whether oral dronabinol (Δ(9)-tetrahydrocannabinol) might slow the course of progressive multiple sclerosis. METHODS: in this multicentre, parallel, randomised, double-blind, placebo-controlled study, we recruited patients aged 18-65 years with primary or secondary progressive multiple sclerosis from 27 UK neurology or rehabilitation departments. Patients were randomly assigned (2:1) to receive dronabinol or placebo for 36 months; randomisation was by stochastic minimisation, using a computer-generated randomisation sequence, balanced according to expanded disability status scale (EDSS) score, centre, and disease type. Maximum dose was 28 mg per day, titrated against bodyweight and adverse effects. Primary outcomes were EDSS score progression (masked assessor, time to progression of ≥1 point from a baseline score of 4·0-5·0 or ≥0·5 points from a baseline score of ≥5·5, confirmed after 6 months) and change from baseline in the physical impact subscale of the 29-item multiple sclerosis impact scale (MSIS-29-PHYS). All patients who received at least one dose of study drug were included in the intention-to-treat analyses. This trial is registered as an International Standard Randomised Controlled Trial (ISRCTN 62942668). FINDINGS: of the 498 patients randomly assigned to a treatment group, 329 received at least one dose of dronabinol and 164 received at least one dose of placebo (five did not receive the allocated intervention). 145 patients in the dronabinol group had EDSS score progression (0·24 first progression events per patient-year; crude rate) compared with 73 in the placebo group (0·23 first progression events per patient-year; crude rate); HR for prespecified primary analysis was 0·92 (95% CI 0·68-1·23; p=0·57). Mean yearly change in MSIS-29-PHYS score was 0·62 points (SD 3·29) in the dronabinol group versus 1·03 points (3·74) in the placebo group. Primary analysis with a multilevel model gave an estimated between-group difference (dronabinol-placebo) of -0·9 points (95% CI -2·0 to 0·2). We noted no serious safety concerns (114 [35%] patients in the dronabinol group had at least one serious adverse event, compared with 46 [28%] in the placebo group). INTERPRETATION: Our results show that dronabinol has no overall effect on the progression of multiple sclerosis in the progressive phase. The findings have implications for the design of future studies of progressive multiple sclerosis, because lower than expected progression rates might have affected our ability to detect clinical change. FUNDING: UK Medical Research Council, National Institute for Health Research Efficacy and Mechanism Evaluation programme, Multiple Sclerosis Society, and Multiple Sclerosis Trust.

OBJECTIVE: the aim of this study was to investigate gestational age-dependent effects of racial origin, smoking status and mode of conception on maternal serum levels of free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 7-14 weeks' gestation. METHODS: This was an analysis of data from prospective first-trimester combined screening for aneuploidies in singleton pregnancies, with β-hCG and PAPP-A measured at 7 + 1 to 14 + 3 weeks' gestation. We included 27,908 pregnancies from three centers in the U.K. and 125,461 pregnancies from 22 centers in Denmark, all with known normal fetal karyotype or resulting in the birth of a phenotypically normal neonate. Multiple regression modelling of log10 -transformed marker concentrations was used to produce log10 multiple of the median (MoM) values for free β-hCG and PAPP-A and to examine pregnancy characteristics that have significant effects on marker concentrations. RESULTS: Serum free β-hCG and PAPP-A concentrations were significantly affected by gestational age, maternal weight, racial origin, parity, smoking and mode of conception. There were significant gestational age-dependent effects attributed to Afro-Caribbean race, smoking and conception through in-vitro fertilization (IVF) on PAPP-A and free β-hCG levels. In women of Afro-Caribbean race there was a weekly increase in PAPP-A of 5.3% and in free β-hCG of 1.8%. In smokers there was a weekly decrease in PAPP-A of 2.4% and in free β-hCG of 1.6%. In cases of IVF conceptions there was a weekly increase in PAPP-A of 4.5% and in free β-hCG of 4.6%. CONCLUSIONS: Serum free β-hCG and PAPP-A concentrations at 7-14 weeks' gestation are affected by several pregnancy characteristics. The effects of Afro-Caribbean race, smoking and IVF conception change with gestational age.

OBJECTIVE: it was the aim of this study to develop models for the prediction of preeclampsia (PE) based on maternal characteristics and biophysical markers at 11-13 weeks' gestation in which gestation at the time of delivery for PE is treated as a continuous variable. METHODS: This was a screening study of singleton pregnancies at 11-13 weeks including 1,426 (2.4%) cases that subsequently developed PE and 57,458 cases that were unaffected by PE. We developed a survival time model for the time of delivery for PE in which Bayes' theorem was used to combine the prior information from maternal characteristics with the uterine artery pulsatility index (PI) and the mean arterial pressure (MAP), using multiple of the median values. RESULTS: the risk for PE increased with maternal age, weight, Afro-Caribbean and South Asian racial origin, previous pregnancy with PE, conception by in vitro fertilization and a medical history of chronic hypertension, type 2 diabetes mellitus as well as systemic lupus erythematosus or antiphospholipid syndrome. In pregnancies with PE, there was an inverse correlation between multiple of the median values of the uterine artery PI and MAP with gestational age at delivery. Screening by maternal characteristics, uterine artery PI and MAP detected 90% of PE cases requiring delivery before 34 weeks and 57% of all PE cases at a fixed false-positive rate of 10%. CONCLUSIONS: a new model has been developed for effective first-trimester screening for PE.

OBJECTIVE: it was the aim of this study to investigate the pregnancy characteristics that influence the measured concentrations of maternal serum-free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 9(+0)-13(+6) weeks' gestation. METHODS: in singleton pregnancies attending for routine care, serum-free β-hCG and PAPP-A were measured at 9(+0)-13(+6) weeks' gestation and fetal nuchal translucency was measured at 11(+0)-13(+6) weeks. The population included 27,908 chromosomally normal and 104 trisomy 21 pregnancies. Multiple regression analysis was used to examine the pregnancy characteristics that have a significant effect on the measured concentrations of free β-hCG and PAPP-A. We also examined the impact of incorporating temporal effects on performance of screening for trisomy 21. RESULTS: Serum-free β-hCG and PAPP-A concentrations were significantly affected by gestational age, maternal weight, racial origin, parity, preexisting diabetes mellitus type 2, smoking and conception by in vitro fertilization. There was a significant gestational age-dependent effect of Afro-Caribbean race on PAPP-A levels (p = 0.0005), with a weekly increase of 4.9% (95% CI 2.1-7.8). CONCLUSIONS: Serum-free β-hCG and PAPP-A concentrations at 9(+0)-13(+6) weeks' gestation are affected by several pregnancy characteristics and the effect of Afro-Caribbean race on PAPP-A increases with gestational age.

BACKGROUND: Walking impairment has a major influence on the quality of life of people with multiple sclerosis (MS). The Multiple Sclerosis Walking Scale (MSWS-12) assesses the impact of MS on walking ability from the patient's perspective, but in its current form, is not amenable for use in many policy decision-making settings. OBJECTIVES: Statistical 'mapping' methods were used to convert MSWS-12 scores to EQ-5D health state values. METHODS: the relationship between the measures was estimated using cohort data from people with MS in South West England. Regression analyses were conducted, estimation errors assessed, and predictive performance of the best models tested using longitudinal data. RESULTS: Model performance was in line with that of other mapping studies, with the best-performing models being an ordinary least squares (OLS) model using MSWS-12 item scores, and an OLS model using the total MSWS-12 score and its squared term. CONCLUSIONS: a process has been described whereby data from a patient-reported outcome measure (MSWS-12) can be converted to (EQ-5D) health state values. These values may be used to consider the health-related quality of life of people with MS, to estimate quality adjusted life-years for use in effectiveness and cost-effectiveness analyses, and to inform health policy decisions.

OBJECTIVES: the 29-item Multiple Sclerosis Impact Scale (MSIS-29) is a psychometrically validated patient-reported outcome measure increasingly used in trials of treatments for multiple sclerosis. However, it is non-preference-based and not amenable for use across policy decision-making contexts. Our objective was to statistically map from the MSIS-29, version 2, to the EuroQol five-dimension (EQ-5D) and the six-dimension health state short form (derived from short form 36 health survey) (SF-6D) to estimate algorithms for use in cost-effectiveness analyses. METHODS: the relationships between MSIS-29, version 2, and EQ-5D and SF-6D scores were estimated by using data from a cohort of people with multiple sclerosis in South West England (n=672). Six ordinary least squares (OLS), Tobit, and censored least adjusted deviation (CLAD) regression analyses were conducted on estimation samples, including the use of subscale and item scores, squared and interaction terms, and demographics. Algorithms from models with the smallest estimation errors (mean absolute error [MAE], root mean square error [RMSE], normalized RMSE) were then assessed by using separate validation samples. RESULTS: Tobit and CLAD. For the EQ-5D, the OLS models including subscale squared terms, and item scores and demographics performed comparably (MAE 0.147, RMSE 0.202 and MAE 0.147, RMSE 0.203, respectively), and estimated scores well up to 3 years post-baseline. Estimation errors for the SF-6D were smaller (OLS model including squared terms: MAE 0.058, RMSE 0.073; OLS model using item scores and demographics: MAE 0.059, RMSE 0.08), and the errors for poorer health states found with the EQ-5D were less pronounced. CONCLUSIONS: We have provided algorithms for the estimation of health state utility values, both the EQ-5D and SF-6D, from scores on the MSIS-29, version 2. Further research is now needed to determine how these algorithms perform in practical decision-making contexts, when compared with observed EQ-5D and SF-6D values.

OBJECTIVE: to investigate the effect of associations in serum free β-hCG and PAPP-A between successive pregnancies on the performance of screening for trisomy 21 at 11-13 weeks' gestation. METHODS: in 8,499 women with two consecutive pregnancies, including 49 women with fetal trisomy 21 in the second pregnancy, the correlation in serum free β-hCG multiples of the median (MoM) and PAPP-A MoM between pregnancies was determined, and the effects of correcting for the correlation on the performance of screening was estimated. RESULTS: There were significant associations between pregnancies in free β-hCG MoM (r = 0.4435) and PAPP-A MoM (r = 0.4796). In screening by maternal age and biochemistry at a risk cutoff of 1 in 100, in the second pregnancies the false-positive rate was 35.5% for those with screen-positive results in the first pregnancy, and this was reduced to 17.1% after adjustment for the results of the first pregnancy. Similarly, in women with screen-negative results in the first pregnancy, adjustment for the results improved the detection rate in the second pregnancy from 66.7 to 81.2%. CONCLUSIONS: in screening for trisomy 21, adjustment for the biochemical findings in a previous pregnancy has major effects on individual patient-specific risks, increases the detection rate and reduces the false-positive rate.

OBJECTIVE: to examine the effect of bias in median multiples of the median (MoM) levels of pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (β-hCG) on first-trimester combined screening for trisomy 21. METHODS: the effects of deviations in the MoM levels of free β-hCG and PAPP-A were investigated by simulating nuchal translucency (NT) at 12 weeks and MoM values for PAPP-A and free β-hCG for 500 000 euploid and 500 000 trisomy 21 pregnancies at 9 and at 12 weeks of gestation. Likelihoods were calculated using the mixture model for NT and the standard Gaussian model for log MoM PAPP-A and free β-hCG values. Deviations in MoM marker levels were simulated by applying percentage changes of 5% to 20% to MoM values. Detection and false-positive rates were calculated with and without adjustments of the maternal serum marker levels by taking the proportion of euploid and aneuploid cases above given thresholds for each maternal age and then taking a weighted average with respect to the maternal age distribution. RESULTS: with median MoM levels on target, the modeled detection and false-positive rates in combined screening for trisomy 21 at 12 weeks of gestation with a fixed risk cut-off of 1 in 100 were 85% and 2.5%, respectively. For median MoM levels of free β-hCG and PAPP-A between 0.8 and 1.2 MoM, detection rates ranged from 77% to 91%, with corresponding false-positive rates ranging from 1.0% to 6.1%. CONCLUSION: in first-trimester screening for trisomy 21, biases in the serum marker MoM levels of 10% can increase false-positive rates by over 50%, whilst biases of 20% can more than double false-positive rates.

OBJECTIVE: to examine the distribution of fetal nuchal translucency (NT) thickness in dichorionic twins and investigate the effect of the correlation between NT measurements in each twin pair on the performance of screening for trisomies. METHODS: the distribution of fetal NT for crown-rump length (CRL) was examined in 5646 dichorionic twin pregnancies, including 103 with fetal trisomies 21, 18 or 13. The correlation in fetal NT in each euploid twin pregnancy was estimated. RESULTS: the distribution of NT in both euploid and trisomic fetuses was consistent with the mixture model in singleton pregnancies. In the euploid pregnancies, there was a correlation in log NT measurements in each twin pair (r = 0.42, 95% CI: 0.39-0.45) and, after removal of the effect of the operator, this correlation was reduced to 0.34. Allowing for this correlation in risk assessment for trisomies had a major impact on the estimated patient-specific risk but had little effect on the overall performance of screening. CONCLUSIONS: in dichorionic twin pregnancies, the mixture model of distributions of NT can be applied as in singletons. In screening for trisomies, the correlation in NT measurements between the fetuses should be taken into account in the estimation of patient-specific risks.

OBJECTIVES: to provide estimates and confidence intervals for the performance (detection and false-positive rates) of screening for Down's syndrome using repeated measures of biochemical markers from first and second trimester maternal serum samples taken from the same woman. DESIGN: Stored serum on Down's syndrome cases and controls was used to provide independent test data for the assessment of screening performance of published risk algorithms and for the development and testing of new risk assessment algorithms. SETTING: 15 screening centres across the USA, and at the North York General Hospital, Toronto, Canada. PARTICIPANTS: 78 women with pregnancy affected by Down's syndrome and 390 matched unaffected controls, with maternal blood samples obtained at 11-13 and 15-18 weeks' gestation, and women who received integrated prenatal screening at North York General Hospital at two time intervals: between 1 December 1999 and 31 October 2003, and between 1 October 2006 and 23 November 2007. INTERVENTIONS: Repeated measurements (first and second trimester) of maternal serum levels of human chorionic gonadotrophin (hCG), unconjugated estriol (uE3) and pregnancy-associated plasma protein a (PAPP-A) together with alpha-fetoprotein (AFP) in the second trimester. MAIN OUTCOME MEASURES: Detection and false-positive rates for screening with a threshold risk of 1 in 200 at term, and the detection rate achieved for a false-positive rate of 2%. RESULTS: Published distributional models for Down's syndrome were inconsistent with the test data. When these test data were classified using these models, screening performance deteriorated substantially through the addition of repeated measures. This contradicts the very optimistic results obtained from predictive modelling of performance. Simplified distributional assumptions showed some evidence of benefit from the use of repeated measures of PAPP-A but not for repeated measures of uE3 or hCG. Each of the two test data sets was used to create new parameter estimates against which screening test performance was assessed using the other data set. The results were equivocal but there was evidence suggesting improvement in screening performance through the use of repeated measures of PAPP-A when the first trimester sample was collected before 13 weeks' gestation. A Bayesian analysis of the combined data from the two test data sets showed that adding a second trimester repeated measurement of PAPP-A to the base test increased detection rates and reduced false-positive rates. The benefit decreased with increasing gestational age at the time of the first sample. There was no evidence of any benefit from repeated measures of hCG or uE3. CONCLUSIONS: If realised, a reduction of 1% in false-positive rate with no loss in detection rate would give important benefits in terms of health service provision and the large number of invasive tests avoided. The Bayesian analysis, which shows evidence of benefit, is based on strong distributional assumptions and should not be regarded as confirmatory. The evidence of potential benefit suggests the need for a prospective study of repeated measurements of PAPP-A with samples from early in the first trimester. A formal clinical effectiveness and cost-effectiveness analysis should be undertaken. This study has shown that the established modelling methodology for assessing screening performance may be optimistically biased and should be interpreted with caution.

OBJECTIVE: to establish an algorithm for first-trimester combined screening for trisomy 21 with biochemical testing from 7 to 14 weeks' gestation and ultrasound testing at 11-13 weeks. METHODS: This was a multicenter study of 886 pregnancies with trisomy 21 and 222 475 unaffected pregnancies with measurements of free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 7-14 weeks' gestation. Multiple regression modeling of log-transformed marker values was used to produce log multiples of the median (MoM) values for PAPP-A and free β-hCG. The models included terms for the center attended and the machine used for biochemical analysis, gestational age, maternal racial origin, maternal weight, smoking status and method of conception. Bivariate Gaussian distributions were fitted to log MoM PAPP-A and log MoM free β-hCG in trisomy 21 and in unaffected pregnancies. In each case the patient-specific risk for trisomy 21 was estimated by multiplying the individual maternal age-related risk with the likelihood ratio (LR) for fetal nuchal translucency (NT) according to the mixture model and the combined LR for maternal serum free β-hCG and PAPP-A. Estimates of detection rates for trisomy 21 and false-positive rates were calculated for combined screening with measurements of NT at 12 weeks together with measurements of free β-hCG and PAPP-A from 8 to 13 weeks. RESULTS: in trisomy 21 pregnancies the mean log MoM free β-hCG increased linearly with gestation between 7 and 14 weeks, whereas the relation between log MoM PAPP-A and gestation was fitted by a quadratic equation such that the maximum separation between trisomy 21 and unaffected pregnancies occurs at 9-10 weeks. At a false-positive rate of 3% the detection rate of combined screening at 12 weeks was 86% and this increased to 90% by biochemical testing at 9 weeks and ultrasound scanning at 12 weeks. The detection rate increased to 92% by measuring PAPP-A at 9 weeks and free β-hCG at the time of the scan at 12 weeks. CONCLUSION: the performance of first-trimester biochemical screening for trisomy 21 is best at 9-10 weeks rather than at 7-8 or 11-14 weeks.

OBJECTIVE: Fetal nuchal translucency (NT) thickness increases with crown-rump length (CRL). In screening for chromosomal defects patient-specific risks are derived by multiplying the a priori maternal age-related risk by a likelihood ratio, determined from the deviation of the measured NT from the expected median. To quantify this deviation the measured NT is either subtracted (delta NT) or divided by the expected median (multiple of the median method, MoM). This study examines the validity of these methods. METHODS: NT was prospectively measured at 11 + 0 to 13 + 6 weeks in screening for chromosomal defects. The distribution of NT in euploid and chromosomally abnormal fetuses was examined. RESULTS: There were 37 078 normal pregnancies and 264 with trisomy 21, 81 with trisomy 18, 38 with trisomy 13 and 27 with Turner syndrome. We found that firstly, contrary to the assumption underlying the delta NT method, the distribution of delta NT changes with CRL and secondly, contrary to the assumption underlying the MoM method the distribution of NT was not Gaussian. Fetal NT followed two distributions, one that was dependent on CRL and one that was independent of CRL. The distribution in which NT increases with CRL was observed in about 95% of euploid fetuses, 5% with trisomy 21, 30% with trisomy 18, 15% with trisomy 13 and 10% with Turner syndrome. The median CRL-independent NT was 2.0 mm for the euploid group and 3.4, 5.5, 4.0 and 7.8 mm for trisomies 21, 18, 13 and Turner syndrome, respectively. CONCLUSIONS: the NT thickness in chromosomally normal and abnormal fetuses follows a mixture of a gestation-dependent and gestation-independent distribution.

AIMS: at any given time, people with diabetes occupy approximately 5-10% of acute hospital beds. In addition, diabetes is associated with a greater length of stay (LOS). This is partially because of increased complexity of the cases but also because of unfamiliarity of dealing with the condition by other specialist teams. METHODS: in 2002, with increasing pressure on acute hospital beds, a team was established to improve the care of inpatients with diabetes admitted to Derriford Hospital. The team consisted of five diabetes specialist nurses dedicated to inpatient care, supported by a consultant and specialist registrar diabetologist. A link nurse responsible for diabetes was appointed on every ward and each individual with a diagnosis of diabetes was identified on admission. We have compared LOS of all patients with diabetes admitted between January 2002 and December 2006. RESULTS: LOS fell from a mean +/- se of 8.3 +/- 0.18 days in 2002 to 7.7 +/- 0.10 days in 2006 (P = 0.002). Significant falls were seen for emergency admissions (9.7 +/- 0.23 vs. 9.2 +/- 0.20, P < 0.001) but not elective admissions. The data show significant reductions in LOS for medical admissions (9.2 +/- 0.24 vs. 8.4 +/- 0.20, P < 0.001) but not surgical admissions. Over the same period, LOS for the total hospital population fell by 0.3 days (P < 0.001). CONCLUSION: in conclusion, a team specifically employed to focus on inpatient diabetes care has a significant impact on LOS of this patient group.

Using a decision-analytic model, we evaluated the effectiveness and cost-effectiveness of surveillance for hepatocellular carcinoma (HCC) in individuals with cirrhosis. Separate cohorts with cirrhosis due to alcoholic liver disease, hepatitis B and hepatitis C were simulated. Results were also combined to approximate a mixed aetiology population. Comparisons were made between a variety of surveillance algorithms using alpha-foetoprotein (AFP) assay and/or ultrasound at 6- and 12-monthly intervals. Parameter estimates were obtained from comprehensive literature reviews. Uncertainty was explored using one-way and probabilistic sensitivity analyses. In the mixed aetiology cohort, 6-monthly AFP+ultrasound was predicted to be the most effective strategy. The model estimates that, compared with no surveillance, this strategy may triple the number of people with operable tumours at diagnosis and almost halve the number of people who die from HCC. The cheapest strategy employed triage with annual AFP (incremental cost-effectiveness ratio (ICER): 20,700 pounds per quality-adjusted life-year (QALY) gained). At a willingness-to-pay threshold of 30,000 pounds per QALY the most cost-effective strategy used triage with 6-monthly AFP (ICER: 27,600 pounds per QALY gained). The addition of ultrasound to this strategy increased the ICER to 60,100 pounds per QALY gained. Surveillance appears most cost-effective in individuals with hepatitis B-related cirrhosis, potentially due to younger age at diagnosis of cirrhosis. Our results suggest that, in a UK NHS context, surveillance of individuals with cirrhosis for HCC should be considered effective and cost-effective. The economic efficiency of different surveillance strategies is predicted to vary markedly according to cirrhosis aetiology.

OBJECTIVE: to investigate the potential utility of first trimester screening for Down syndrome using Free beta-hCG, total hCG and PAPP-A. MATERIALS AND METHODS: Using estimates from the literature, a simulation study was undertaken to estimate the performance of tests incorporating, Free beta-hCG, total hCG and PAPP-A at gestations of 8-12 weeks. We used sensitivity analysis to assess the effect of departures from the assumed model. RESULTS: We estimate that detection rates in excess of 75% for a false positive rate (FPR) of 3% can be achieved with first trimester measures of PAPP-A, total hCG and Free beta-hCG at 8 weeks-the addition of total hCG adding 11%. Detection rates of around 90% for a FPR of 3% can be achieved through the inclusion of nuchal translucency (NT) at 12 weeks to these early first trimester biochemical markers. Our analysis indicates that the marginal benefit of adding total hCG diminishes rapidly with gestational age and that there is little benefit from adding total hCG later than 10 weeks of gestation. CONCLUSION: the performance of first trimester screening using early combinations of total hCG, Free beta-hCG and PAPP-A should be assessed in further studies.

Objectives: to evaluate the effectiveness, cost-effectiveness and cost-utility of surveillance of patients with cirrhosis [alcoholic liver disease (ALD)-, hepatitis B (HBV)- and C virus (HCV)-related], using periodic serum α-fetoprotein (AFP) testing and/or liver ultrasound examination, to detect hepatocellular carcinoma (HCC), followed by treatment with liver transplantation or resection, where appropriate. Data sources: Electronic databases were searched up to March 2006. Review methods: a systematic review was carried out using standard methodological guidelines. A computerised decision-analytic model was then developed to compare various surveillance strategies. Results: No studies were identified that met the criteria of the systematic review. Based on the assumptions used in the model, the most effective surveillance strategy uses a combination of AFP testing and ultrasound at 6-monthly intervals. Compared with no surveillance, this strategy is estimated to more than triple the number of people with operable HCC tumours at time of diagnosis, and almost halves the number of deaths from HCC. On all effectiveness measures and at both testing frequencies, AFP- and ultrasound-led surveillance strategies are very similar. This may be because test sensitivity was varied according to tumour size, which means that AFP testing is capable of identifying many more small tumours than ultrasound. The best available evidence suggests that AFP tests will detect approximately six times as many small tumours as ultrasound. Increasing the frequency of either test to 6-monthly intervals is more effective than performing combined testing on an annual basis. The undiscounted lifetime cost of the surveillance strategies, including all care and treatment costs, ranges from £40,300 (annual AFP triage) to £42,900 (6-monthly AFP and ultrasound). The equivalent discounted costs are £28,400 and £30,400. Only a small proportion of these total costs results from the cost of the screening tests. However, screening test costs, and the cost of liver transplants and caring for people post-transplant, accounted for most of the incremental cost differences between alternative surveillance strategies. The results suggest that different surveillance strategies may provide the best value for money in patient groups of different cirrhosis aetiologies. The surveillance of people with HBV-related cirrhosis for HCC provides the best value for money, while surveillance in people with ALD-related cirrhosis provides the poorest value for money. In people with HBV-related cirrhosis, at an assumed maximum willingness to pay (WTP) for a quality-adjusted life-year (QALY) of £30,000, both the deterministic and probabilistic cost-utility analyses suggest the optimal surveillance strategy would be 6-monthly surveillance with the combination of AFP testing and ultrasound. In contrast, for those with ALD-related cirrhosis, annual screening with AFP as a triage test is the only surveillance strategy that is likely to be considered cost-effective at this WTP. The probabilistic analysis implies that the estimated benefits of a 6-monthly AFP triage strategy will only be worth the cost in those with ALD when society's WTP for a QALY exceeds around £40,000. For people with HCV-related cirrhosis, the model suggests that the most cost-effective surveillance strategy at a WTP threshold of £30,000/ QALY would be surveillance with a 6-monthly AFP triage strategy. Conclusions: in a mixed-aetiology cohort, the most effective surveillance strategy is to screen each patient with AFP assay and ultrasound imaging on a 6-monthly basis. However, when costs are taken into account it is doubtful whether ultrasound should be routinely offered to those with blood AFP of less than 20 ng/ml, unless policy-makers are prepared to pay over £60,000 per QALY for the benefits achieved. Furthermore, the cost-effectiveness of surveillance for HCC varies considerably depending on the aetiology of cirrhosis; it is much more likely to be cost-effective in those with HBV-related cirrhosis, and much less likely to be cost-effective in those with ALD-related cirrhosis. Further development of the model would help to enable refinement of an optimal screening strategy. Research into the use of contrast-enhanced ultrasound technology for HCC detection would also be valuable, as would research into the epidemiology and natural history of ALD-related cirrhosis. Studies are also needed to investigate the influence of cirrhosis aetiology on tumour AFP expression. © Queen's Printer and Controller of HMSO 2007. All rights reserved.

To evaluate the effectiveness, cost-effectiveness and cost-utility of surveillance of patients with cirrhosis [alcoholic liver disease (ALD)-, hepatitis B (HBV)- and C virus (HCV)-related], using periodic serum alpha-fetoprotein (AFP) testing and/or liver ultrasound examination, to detect hepatocellular carcinoma (HCC), followed by treatment with liver transplantation or resection, where appropriate. Electronic databases were searched up to March 2006. A systematic review was carried out using standard methodological guidelines. A computerised decision-analytic model was then developed to compare various surveillance strategies. No studies were identified that met the criteria of the systematic review. Based on the assumptions used in the model, the most effective surveillance strategy uses a combination of AFP testing and ultrasound at 6-monthly intervals. Compared with no surveillance, this strategy is estimated to more than triple the number of people with operable HCC tumours at time of diagnosis, and almost halves the number of deaths from HCC. On all effectiveness measures and at both testing frequencies, AFP- and ultrasound-led surveillance strategies are very similar. This may be because test sensitivity was varied according to tumour size, which means that AFP testing is capable of identifying many more small tumours than ultrasound. The best available evidence suggests that AFP tests will detect approximately six times as many small tumours as ultrasound. Increasing the frequency of either test to 6-monthly intervals is more effective than performing combined testing on an annual basis. The undiscounted lifetime cost of the surveillance strategies, including all care and treatment costs, ranges from 40,300 pounds (annual AFP triage) to 42,900 pounds (6-monthly AFP and ultrasound). The equivalent discounted costs are 28,400 pounds and 30,400 pounds. Only a small proportion of these total costs results from the cost of the screening tests. However, screening test costs, and the cost of liver transplants and caring for people post-transplant, accounted for most of the incremental cost differences between alternative surveillance strategies. The results suggest that different surveillance strategies may provide the best value for money in patient groups of different cirrhosis aetiologies. The surveillance of people with HBV-related cirrhosis for HCC provides the best value for money, while surveillance in people with ALD-related cirrhosis provides the poorest value for money. In people with HBV-related cirrhosis, at an assumed maximum willingness to pay (WTP) for a quality-adjusted life-year (QALY) of 30,000 pounds, both the deterministic and probabilistic cost-utility analyses suggest the optimal surveillance strategy would be 6-monthly surveillance with the combination of AFP testing and ultrasound. In contrast, for those with ALD-related cirrhosis, annual screening with AFP as a triage test is the only surveillance strategy that is likely to be considered cost-effective at this WTP. The probabilistic analysis implies that the estimated benefits of a 6-monthly AFP triage strategy will only be worth the cost in those with ALD when society's WTP for a QALY exceeds around 40,000 pounds. For people with HCV-related cirrhosis, the model suggests that the most cost-effective surveillance strategy at a WTP threshold of 30,000 pounds/QALY would be surveillance with a 6-monthly AFP triage strategy. In a mixed-aetiology cohort, the most effective surveillance strategy is to screen each patient with AFP assay and ultrasound imaging on a 6-monthly basis. However, when costs are taken into account it is doubtful whether ultrasound should be routinely offered to those with blood AFP of less than 20 ng/ml, unless policy-makers are prepared to pay over 60,000 pounds per QALY for the benefits achieved. Furthermore, the cost-effectiveness of surveillance for HCC varies considerably depending on the aetiology of cirrhosis; it is much more likely to be cost-effective in those with HBV-related cirrhosis, and much less likely to be cost-effective in those with ALD-related cirrhosis. Further development of the model would help to enable refinement of an optimal screening strategy. Research into the use of contrast-enhanced ultrasound technology for HCC detection would also be valuable, as would research into the epidemiology and natural history of ALD-related cirrhosis. Studies are also needed to investigate the influence of cirrhosis aetiology on tumour AFP expression.

OBJECTIVE: Offspring of mothers with diabetes have increased birth weight and higher rates of obesity in early childhood. The relative role of maternal glycemia and maternal obesity is uncertain. We therefore studied the impact of maternal glycemia and maternal obesity on offspring birth measures and early postnatal growth in nondiabetic pregnancies. RESEARCH DESIGN AND METHODS: We studied 547 full-term singleton babies of nondiabetic parents. Data available included parental height and weight; maternal prepregnant weight; maternal fasting plasma glucose (FPG) at 28 weeks of gestation; and offspring weight and length at birth, 12 weeks of age, and 1 and 2 years of age. Relationships between parental and offspring measures were estimated using Pearson correlations. RESULTS: Maternal FPG was correlated with offspring birth weight (r = 0.25, P < 0.001), length (r = 0.17, P < 0.001), and BMI (r = 0.2, P < 0.001) but was not correlated with offspring growth at 12 weeks. Maternal prepregnancy BMI was significantly correlated with offspring weight (r = 0.26, P < 0.001), length (r = 0.12, P = 0.01), and BMI at birth (r = 0.26, P < 0.001) and remained correlated with offspring weight (r = 0.13-0.14, P = 0.007-0.002) and BMI (r = 0.14-0.19, P = 0.002 to

AIM: to evaluate the diagnostic accuracy of 16-detector row computed tomography (CT) in assessing haemodynamically significant coronary artery stenoses in patients under evaluation for aortic stenosis pre-aortic valve replacement. SUBJECTS AND METHODS: Forty consecutive patients under evaluation for severe aortic stenosis and listed for cardiac catheterization before potential aortic valve replacement underwent coronary artery calcium (CAC) scoring and retrospective electrocardiogram (ECG)-gated multi-detector row computed tomographic coronary angiography (MDCTA) using a GE Lightspeed 16-detector row CT within 1 month of invasive coronary angiography (ICA) for comparative purposes. All 13 major coronary artery segments of the American Heart Association model were evaluated for the presence of > or =50% stenosis and compared to the reference standard. Data were analysed on a segment-by-segment basis and also in "whole patient" terms. RESULTS: a total of 412/450 segments from 35 patients were suitable for analysis. The overall accuracy of MDCTA for detection of segments with > or =50% stenosis was high, with a sensitivity of 81.3%, specificity 95.0%, positive predictive value (PPV) 57.8%, and negative predictive value (NPV) 98.4%. On a "whole-patient" basis, 100% (19/19) of patients with significant coronary disease were correctly identified and there were no false-negatives. Excluding patients with CAC >1000 from the analysis improved the accuracy of MDCTA to: sensitivity 90%, specificity 98.1%, PPV 60%, NPV 99.7%. CONCLUSION: Non-invasive 16-detector row MDCTA accurately excludes significant coronary disease in patients with severe aortic stenosis undergoing evaluation before aortic valve replacement and in whom ICA can therefore be avoided. Its segment-by-segment accuracy is improved further if CAC>1000 is used as a gatekeeper to MDCTA.

BACKGROUND: Birth weight is a composite of skeletal size and soft tissue. These components are likely to have different growth patterns. The aim of this paper is to investigate the association between established determinants of birth weight and these separate components. METHODS: Weight, length, crown-rump, knee-heel, head circumference, arm circumference, and skinfold thicknesses were measured at birth in 699 healthy, term, UK babies recruited as part of the Exeter Family Study of Childhood Health. Corresponding measurements were taken on both parents. Principal components analysis with varimax rotation was used to reduce these measurements to two independent components each for mother, father and baby: one highly correlated with measures of fat, the other with skeletal size. RESULTS: Gestational age was significantly related to skeletal size, in both boys and girls (r = 0.41 and 0.52), but not fat. Skeletal size at birth was also associated with parental skeletal size (maternal: r = 0.24 (boys), r = 0.39 (girls) ; paternal: r = 0.16 (boys), r = 0.25 (girls)), and maternal smoking (0.4 SD reduction in boys, 0.6 SD reduction in girls). Fat was associated with parity (first borns smaller by 0.45 SD in boys; 0.31 SD in girls), maternal glucose (r = 0.18 (boys); r = 0.27 (girls)) and maternal fat (r = 0.16 (boys); r = 0.36 (girls)). CONCLUSION: Principal components analysis with varimax rotation provides a useful method for reducing birth weight to two more meaningful components: skeletal size and fat. These components have different associations with known determinants of birth weight, suggesting fat and skeletal size may have different regulatory mechanisms, which would be important to consider when studying the associations of birth weight with later adult disease.

AIM: to explore the effects of maternal glucose on birthweight, infant and childhood growth in non-diabetic pregnant women using routinely collected data. METHODS: Routinely collected data were extracted retrospectively from two clinical databases. These data comprised measurements of maternal random plasma glucose, infant birthweight, infant and child weight and height at 6-8 weeks, 24-36 weeks and 96-120 weeks in 6263 cases. After data cleaning, 4681 were analysed. RESULTS: When the data were analysed in thirds, a positive association between birthweight standard deviation scores (SDS), weight SDS and height SDS with maternal random plasma glucose (RPG) was observed. Regression analysis of birthweight SDS and RPG was significant (P < 0.001). Babies were approximately 48 g heavier at birth for each 1 mmol/l increase of mother's RPG. Infants who showed 'catch-up' growth (as shown by change in weight SDS) at 2 years were born to mothers with lower glucose levels than infants who showed 'catch-down' growth (P < 0.001). CONCLUSIONS: Random maternal glucose concentrations (taken at 28 weeks' gestation) in the normal range are positively related to birthweight. Glucose concentrations also predict greater weight and length in infancy. Despite this, babies born to mothers with higher glucose concentrations within the normal range show significant 'catch-down' growth in infancy as shown by a fall in weight SDS.

OBJECTIVE: to test whether cannabinoids reduce urge incontinence episodes without affecting voiding in patients with multiple sclerosis. This was part of the multicentre trial of the Cannabinoids in Multiple Sclerosis (CAMS) study. SUBJECTS AND METHODS: the CAMS study randomised 630 patients to receive oral administration of cannabis extract, Delta(9)-tetrahydrocannabinol (THC) or matched placebo. For this substudy subjects completed incontinence diaries. RESULTS: all three groups showed a significant reduction, p

OBJECTIVE: to demonstrate the potential value of three-stage sequential screening for Down syndrome. METHODS: Protocols were considered in which maternal serum pregnancy associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (hCG) measurements were taken on all women in the first trimester. Those women with very low Down syndrome risks were screened negative at that stage and nuchal translucency (NT) was measured on the remainder and the risk reassessed. Those with very low risk were then screened negative and those with very high risk were offered early diagnostic testing. Those with intermediate risks received second-trimester maternal serum alpha-fetoprotein, free beta-hCG, unconjugated estriol and inhibin-A. Risk was then reassessed and those with high risk were offered diagnosis. Detection rates and false-positive rates were estimated by multivariate Gaussian modelling using Monte-Carlo simulation. RESULTS: the modelling suggests that, with full adherence to a three-stage policy, overall detection rates of nearly 90% and false-positive rates below 2.0% can be achieved. Approximately two-thirds of pregnancies are screened on the basis of first-trimester biochemistry alone, five out of six women complete their screening in the first trimester, and the first-trimester detection rate is over 60%. CONCLUSION: Three-stage contingent sequential screening is potentially highly effective for Down syndrome screening. The acceptability of this protocol and its performance in practice, should be tested in prospective studies.

OBJECTIVE: to test the effectiveness and long term safety of cannabinoids in multiple sclerosis (MS), in a follow up to the main Cannabinoids in Multiple Sclerosis (CAMS) study. METHODS: in total, 630 patients with stable MS with muscle spasticity from 33 UK centres were randomised to receive oral Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabis extract, or placebo in the main 15 week CAMS study. The primary outcome was change in the Ashworth spasticity scale. Secondary outcomes were the Rivermead Mobility Index, timed 10 metre walk, UK Neurological Disability Score, postal Barthel Index, General Health Questionnaire-30, and a series of nine category rating scales. Following the main study, patients were invited to continue medication, double blinded, for up to 12 months in the follow up study reported here. RESULTS: Intention to treat analysis of data from the 80% of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months (Delta(9)-THC mean reduction 1.82 (n = 154, 95% confidence interval (CI) 0.53 to 3.12), cannabis extract 0.10 (n = 172, 95% CI -0.99 to 1.19), placebo -0.23 (n = 176, 95% CI -1.41 to 0.94); p = 0.04 unadjusted for ambulatory status and centre, p = 0.01 adjusted). There was suggestive evidence for treatment effects of Delta(9)-THC on some aspects of disability. There were no major safety concerns. Overall, patients felt that these drugs were helpful in treating their disease. CONCLUSIONS: These data provide limited evidence for a longer term treatment effect of cannabinoids. A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS.

OBJECTIVE: to demonstrate the potential value of screening for Down's Syndrome using highly correlated repeated measures of serum markers taken in the first and second trimesters of pregnancy. DESIGN: a Monte Carlo simulation study. POPULATION: Detection rates and false positive rates relating to the maternal age distribution of England and Wales for the period 1996 to 1998 were obtained using marker distributions from the SURUSS study. RESULTS: Screening using first trimester nuchal translucency and repeated measures of uE3 and PAPP-A in the first and second trimester has an estimated false positive rate of 0.3% for an 85% detection rate. This should be compared with the integrated test with an estimated false positive rate of 1.2% for the same detection rate. CONCLUSIONS: the performance of repeated measures screening tests, and their acceptability to women, should be assessed in further prospective studies.

BACKGROUND: the long-term treatment of Parkinson disease (PD) may be complicated by the development of levodopa-induced dyskinesia. Clinical and animal model data support the view that modulation of cannabinoid function may exert an antidyskinetic effect. The authors conducted a randomized, double-blind, placebo-controlled crossover trial to examine the hypothesis that cannabis may have a beneficial effect on dyskinesia in PD. METHODS: a 4-week dose escalation study was performed to assess the safety and tolerability of cannabis in six PD patients with levodopa-induced dyskinesia. Then a randomized placebo-controlled crossover study (RCT) was performed, in which 19 PD patients were randomized to receive oral cannabis extract followed by placebo or vice versa. Each treatment phase lasted for 4 weeks with an intervening 2-week washout phase. The primary outcome measure was a change in Unified Parkinson's Disease Rating Scale (UPDRS) (items 32 to 34) dyskinesia score. Secondary outcome measures included the Rush scale, Bain scale, tablet arm drawing task, and total UPDRS score following a levodopa challenge, as well as patient-completed measures of a dyskinesia activities of daily living (ADL) scale, the PDQ-39, on-off diaries, and a range of category rating scales. RESULTS: Seventeen patients completed the RCT. Cannabis was well tolerated, and had no pro- or antiparkinsonian action. There was no evidence for a treatment effect on levodopa-induced dyskinesia as assessed by the UPDRS, or any of the secondary outcome measures. CONCLUSIONS: Orally administered cannabis extract resulted in no objective or subjective improvement in dyskinesias or parkinsonism.

OBJECTIVE: to present a first and second trimester Down syndrome screening strategy, whereby second-trimester marker determination is contingent on the first-trimester results. Unlike non-disclosure sequential screening ('the Integrated test'), which requires all women to have markers in both trimesters, this allows a large proportion of the women to complete screening in the first trimester. METHODS: Two first-trimester risk cut-offs defined three types of results: positive and referred for early diagnosis; negative with screening complete; and intermediate, needing second-trimester markers. Multivariate Gaussian modelling with Monte Carlo simulation was used to estimate the false-positive rate for a fixed 85% detection rate. The false-positive rate was evaluated for various early detection rates and early test completion rates. Model parameters were taken from the SURUSS trial. RESULTS: Completion of screening in the first trimester for 75% of women resulted in a 30% early detection rate and a 55% second trimester detected rate (net 85%) with a false-positive rate only 0.1% above that achievable by the Integrated test. The screen-positive rate was 0.1% in the first trimester and 4.7% for those continuing to be tested in the second trimester. If the early detection rate were to be increased to 45% or the early completion rate were to be increased to 80%, there would be a further 0.1% increase in the false-positive rate. CONCLUSION: Contingent screening can achieve results comparable with the Integrated test but with earlier completion of screening for most women. Both strategies need to be evaluated in large-scale prospective studies particularly in relation to psychological impact and practicability.

Routinely collected weight measurements from 4665 Plymouth children born 1996-97 were compared with the British Growth Reference Charts (BGRC). The children were 0.33 SDS heavier on average than the reference population at 24-30 months, an actual excess of 460 g.

AIM: to investigate secular changes in neonatal resuscitation at birth. METHODS: Single centre observational study of 17 890 infants born between May 1993 and April 1997. T-piece ventilation was introduced in April 1995. OBSERVATIONS: Rates and modes of ventilatory resuscitation, early neonatal encephalopathy, neonatal convulsions, and meconium aspiration syndrome; 1 and 5 min Apgar scores; maternal age and method of delivery; paediatric attendance at delivery and resuscitation. RESULTS: the rate of all forms of ventilatory resuscitation fell during the four year period from 11.0% to 8.9%. The rate of intubation fell from 2.4% to 1.2%. A reduced rate of intubation was seen at all gestations of 30 weeks and above. There was no difference in rates of relevant neonatal problems during the period except for a reduction in neonatal convulsions. The introduction of T-piece ventilation did not contribute to the reduction in intubation in a logistic regression model that included time trend. CONCLUSION: a marked reduction in the rate of intubation was observed, without any reduction in the efficacy of resuscitation. This may reflect improvements and changing emphasis in resuscitation training.

OBJECTIVE: to compare expected date of delivery (EDD) and gestational age (GA) obtained by midwives with those calculated using the Confidential Enquiry into Stillbirths and Death in Infancy (CESDI) recommended formula. DESIGN: retrospective study of obstetric records and prospective study of clinical cases examined by multiple midwives. SETTING: postnatal wards, Maternity Unit, Plymouth, Devon, UK. PARTICIPANTS: two studies were performed. The first was a retrospective analysis of 115 sets of obstetric records. The second, a prospective study which included five clinical cases and 19 qualified midwives whose experience ranged from six months to 25 years. FINDINGS: in the retrospective study, 68 (59%) of the 115 obstetric case notes had sufficient information to apply the CESDI formula. The midwives'calculated EDD was interpreted to a GA and 35 (52.5%) agreed to within three days of the GA derived from the CESDI formula EDD. In the prospective study, the midwives' calculation of EDD was in good agreement with the CESDI formula in cases where last menstrual period (LMP) was known and menstrual cycle was 28 days with 17 (90%) of the 19 midwives providing the EDD to within three days of the CESDI formula. In the clinical case where LMP was known but menstrual cycle length was 33 days only two (10%) of the 19 calculated the EDD within three days of the CESDI formula. KEY CONCLUSIONS: when LMP is known and the cycle length is 28 days, midwives produce results consistent with the CESDI formula. However, when the menstrual cycle differs from 28 days or LMP is unknown, inaccurate or ambiguous and obstetric ultrasound scan (USS) information is used to calculate the EDD, the midwives show varying degrees of departure from the CESDI formula. Further, we found that the midwives tended to produce underestimates when calculating GA from EDD. This bias occurs across the range of gestations covered, including early gestations when such biases may have more important medical implications. IMPLICATIONS FOR PRACTICE: midwives' calculation of EDD and estimation of GA showed both random and systematic errors; in some cases, the errors were so large that they may have important medical consequences. If the CESDI-recommended formula for calculating EDD were used there would be improved accuracy and reliability of EDD and the calculation of GA.

BACKGROUND: Refinements in the configuration of mesh may ease handling and placement and reduce postoperative discomfort. MATERIAL AND METHODS: a total of 206 patients were randomly and blindly allocated to receive the Prolene Hernia System (PHS) or Lichtenstein patch. Collected data included: surgical incision size, procedure time, pain scores, analgesic medication, complications, return to activity and work, and quality of life as measured by Short-Form 36 on days 3 and 14. RESULTS: Immediate post-operative pain was significantly lower with PHS than with the patch. The proportion of PHS patients taking longer than 3 days to return to normal activity was 15.5%, compared to 28.4% of patch patients. Operating time was significantly shorter with PHS (34.1 vs. 38.3 min). There was no treatment effect on any of the quality of life scales as measured by Short-Form 36. There were two recurrences in the patch group. CONCLUSIONS: the study indicates a reduction in operating time (4 min) and postoperative recovery with the PHS compared with patch.

AIM: to determine whether patient triggered ventilation (PTV) leads to greater exposure to significant hypocarbia than conventional ventilation (CMV) in premature infants during the first 72 hours of life. METHODS: Infants of 32 weeks gestation or less were included. Randomisation yielded 74 infants on PTV and 68 infants on CMV. Arterial PaCO(2) measurements were taken four hourly for the first 72 hours of life. RESULTS: the mean PaCO(2) levels on days 1, 2, and 3 were not significantly different between the two groups. The proportion of infants with PaCO(2) levels of 3.33 kPa or less did not differ between PTV and CMV infants. Mean percentages of infants with this level of hypocarbia at any time were 31.4%, 18.9%, 8.8% on days 1, 2, and 3 respectively. Cumulative hypocarbia, below a 3.33 kPa threshold, was 0.0084 kPa.h (PTV) versus 0.0263 kPa.h (CMV) per hour ventilated during the first 24 hours (p = 0.259). Risk factors associated with hypocarbia on day 1 were peak inspiratory pressure below 14 cm H(2)O (odds ratio 4.79) as well as FiO(2) below 0.30 (odds ratio 3.42). CONCLUSION: Exposure to hypocarbia (PaCO(2) 3.33 kPa or below) was not significantly different between PTV and CMV infants during the first 72 hours of life. Hypocarbia was common in both groups on day 1 and to a lesser extent on day 2. Infants with the least requirements for ventilatory support were at highest risk of hypocarbia on day 1 of life. Preterm infants with mild hyaline membrane disease require a more aggressive approach to weaning on both modes of ventilation, followed by extubation to limit the risk of hypocarbia.

Published reviews and industrywide anecdotal reports have suggested an association between exposure to some volatile organic compounds (VOCs) and altered mood states. In this paper we report a unique study of boat-builders exposed to styrene. Two hundred and thirteen employees exposed to solvents and 144 who were not exposed completed questionnaires related to mood states. Additionally, for 23 of the 213 employees, the air concentrations of styrene were measured at their workplaces, and urinary concentrations of mandelic acid (a metabolite of styrene) were determined in order to assess biological exposure. Special features of this study included the use of the Prolife of Mood States (POMS) questionnaire and the availability of sound historical data. A weak association is demonstrated between styrene exposure and aggression/hostility. That this is found to be most marked in the earliest years of exposure suggests that selection characteristics might be a more important association than solvent exposure.

BACKGROUND: Estimates of maternal age-specific prevalence of Down's syndrome are needed for the assessment of environmental factors, for counselling and monitoring screening programmes. The estimates should relate to populations of women who have not received prenatal screening. This is normally achieved by using data collected before the widespread use of screening. The problem of under-ascertainment in some data-sets has been recognised in the literature, but has not been dealt with satisfactorily in the statistical models used to estimate live-birth prevalence. METHODS: in this paper we develop a model that takes explicit account of under-ascertainment and apply this model to data from nine published studies. The primary aim of our analysis is to provide an improved model for live-birth prevalence. A secondary aim is to examine the ascertainment rates in the nine studies. RESULTS: the proposed model provides a good fit to all but one of the nine studies, although exclusion of this study does not affect the estimated risks. The estimate of risk weighted across the maternal age distribution is 1.41 in 1000 live-births [90% confidence interval (CI) 1.37-1.49]. DISCUSSION: Comparing this figure with those obtained from published rate schedules suggests that the proposed model predicts rates that are some 10% higher than those obtained when ascertainment is assumed to be complete in all studies. The predicted rates are similar to those calculated when only those studies known to have high levels of acertainment are included.

In this paper we present an analysis of nine data sets in which ascertainment and maternal age risk of Down syndrome are estimated jointly using maximum likelihood. We include data on 4825 Down syndrome cases from nine previously published data sets. These include data from studies carried out before the introduction of prenatal screening and from recent studies involving women who had not received prenatal testing. Our results show that, allowing for under-ascertainment, there is a good degree of consistency between the different data sets. We compare the three- and five-parameter constant plus exponential model with a three-parameter logistic model for maternal age-specific risk. We show that the three-parameter logistic model provides a good fit to the data and compare rates from this model with those derived from published studies of uncertain completeness (Cuckle et al. 1987) and those from data sets believed to be complete (Halliday et al. 1995; Hecht and Hook, 1994, 1996). In general, our results agree closely with those of the latter, but achieve greater precision because of the inclusion of additional data. Our derived rates are considerably higher than those of Cuckle et al. (1987), which are embedded in many computer systems for generating risks.

AIM: to determine the perinatal factors associated with initial illness severity (measured by the CRIB (clinical risk index for babies) score) and its relation to survival to discharge. METHODS: a retrospective study was made of intensive care nursing records on 380 inborn babies, of less than 31 weeks gestation or 1501 g birthweight, admitted to one unit between 1984-6 and 1991-4. RESULTS: Between the two time periods mean initial illness severity score increased significantly from 2.8 to 3.9. This was the result of an increase in the maximum appropriate inspired oxygen concentration in the first 12 hours. Risk adjusted survival did not improve over time after accounting for gestation but was significantly greater after accounting for CRIB score. Illness severity score was also significantly inversely associated with gestation and 1 and 5 minute Apgar scores, using multiple regression analysis. Between the two time periods there was also a 92% increase in the admission rate of babies under 31 weeks gestation, higher median 1 and 5 minute Apgar scores (6 vs 5 and 9 vs 8, respectively), more multiple births, and more caesarean section deliveries. CONCLUSIONS: the increase in illness severity score and admission rate may reflect changes in obstetric practice. The increase in illness severity score may also reflect changes in early neonatal care. However, after adjusting for CRIB score, risk adjusted mortality fell significantly, suggesting that neonatal care 12 hours from birth onwards had improved with time.

Current software used for assessment of the risk of Down's syndrome may give misleading risk estimates if applied to other abnormalities. Often the abnormality is reflected in maternal serum alpha-fetoprotein and human chorionic gonadotrophin levels and is then translated into a low risk for Down's syndrome that may not be recognized as significantly atypical of normality. We regard this as a serious deficiency in the current Down's syndrome risk reporting algorithm, and suggest a modification that allows the problem to be overcome.

A histological study of 63 specimens of gingival margin from 20 cadavers showed that almost all sections had an accumulation of leucocytes at the base of the sulcus just deep to and infiltrating the epithelial border. Saliva specimens of 2 min duration obtained successively over a total collection time of 20 min were provided by 9 caries-free and 10 caries-active subjects and the rate of entry of leucocytes into the mouth studied. Differences in intact leucocyte counts between the two groups appear to be related to differences in numbers present in the gingival sulcus. This appears to act as a reservoir of these cells and must be a major site of their entry into the mouth. © 1964.

Phase contrast microscope studies of fresh specimens of saliva from fifty edentulous subjects showed that the count of leucocytes is low (approximately one-fifth) compared with samples similarly collected from subjects with teeth. Previous experiments have shown that infants also have few leucocytes in their saliva. Neither of these groups without teeth have gingival sulci and the findings thus support the view that the gingival sulcus must represent a major source of leucocytes entering the mouth. © 1962.

KESEL et al.1,2,3 have stated that saliva from caries-free individuals, when incubated for eight days in a beef broth medium, produces a higher concentration of ammonia (estimated by the 'Permutit' method) than does saliva similarly treated from caries-susceptible subjects. They also stated that high concentrations of alkaline ammonium salts or Seitz filtrates of incubated caries-free saliva are lethal to the Hadley strain of Lactobacillus acidophilus, and conclude that high ammonia production in the dental plaque may be responsible for the natural freedom from caries which a few individuals enjoy. © 1950 Nature Publishing Group.