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To examine the performance of a model combining maternal risk factors, uterine artery pulsatility index (UtA-PI) and estimated fetal weight (EFW) at 19-24 weeks' gestation, for predicting all antepartum stillbirths and those due to impaired placentation, in a training dataset used for development of the model and in a validation dataset.The data for this study were derived from prospective screening for adverse obstetric outcome in women with singleton pregnancy attending for routine pregnancy care at 19 + 0 to 24 + 6 weeks' gestation. The study population was divided into a training dataset used to develop prediction models for placental dysfunction-related antepartum stillbirth and a validation dataset to which the models were then applied. Multivariable logistic regression analysis was used to develop a model based on a combination of maternal risk factors, EFW Z-score and UtA-PI multiples of the normal median. We examined the predictive performance of the model by, first, the ability of the model to discriminate between the stillbirth and live-birth groups, using the area under the receiver-operating-characteristics curve (AUC) and the detection rate (DR) at a fixed false-positive rate (FPR) of 10%, and, second, calibration by measurements of calibration slope and intercept.The study population of 131 514 pregnancies included 131 037 live births and 477 (0.36%) stillbirths. There are four main findings of this study. First, 92.5% (441/477) of stillbirths were antepartum and 7.5% (36/477) were intrapartum, and 59.2% (261/441) of antepartum stillbirths were observed in association with placental dysfunction and 40.8% (180/441) were unexplained or due to other causes. Second, placental dysfunction accounted for 80.1% (161/201) of antepartum stillbirths at 32 weeks' gestation, 54.2% (52/96) at 32 + 0 to 36 + 6 weeks and 33.3% (48/144) at ≥ 37 weeks. Third, the risk of placental dysfunction-related antepartum stillbirth increased with increasing maternal weight and decreasing maternal height, was 3-fold higher in black than in white women, was 5.5-fold higher in parous women with previous stillbirth than in those with previous live birth, and was increased in smokers, in women with chronic hypertension and in parous women with a previous pregnancy complicated by pre-eclampsia and/or birth of a small-for-gestational-age baby. Fourth, in screening for placental dysfunction-related antepartum stillbirth by a combination of maternal risk factors, EFW and UtA-PI in the validation dataset, the DR at a 10% FPR was 62.3% (95% CI, 57.2-67.4%) and the AUC was 0.838 (95% CI, 0.799-0.878); these results were consistent with those in the dataset used for developing the algorithm and demonstrate high discrimination between affected and unaffected pregnancies. Similarly, the calibration slope was 1.029 and the intercept was -0.009, demonstrating good agreement between the predicted risk and observed incidence of placental dysfunction-related antepartum stillbirth. The performance of screening was better for placental dysfunction-related antepartum stillbirth at 37 weeks' gestation compared to at term (DR at a 10% FPR, 69.8% vs 29.2%).Screening at mid-gestation by a combination of maternal risk factors, EFW and UtA-PI can predict a high proportion of placental dysfunction-related stillbirths and, in particular, those that occur preterm. Such screening provides poor prediction of unexplained stillbirth or stillbirth due to other causes. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

OBJECTIVE To estimate the chorionic villus sampling (CVS)-related risk of fetal loss in twin pregnancy after adjustment for chorionicity, nuchal translucency thickness (NT), intertwin discordance in crown-rump length (CRL), maternal demographic characteristics and serum pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (β-hCG). METHODS This was a multicenter study from eight fetal medicine units in which the leadership were trained at the Harris Birthright Research Centre for Fetal Medicine in London, UK, and in which the protocols for screening, invasive testing and pregnancy management are similar. Data were obtained prospectively from women with twin pregnancy undergoing routine ultrasound examination at 11-13 weeks' gestation. Multivariable logistic regression analysis with backward stepwise elimination was used to examine whether CVS provided a significant independent contribution to the prediction of risk of fetal loss after adjusting for maternal and pregnancy characteristics, including maternal age, racial origin and weight, method of conception, smoking status, parity, chorionicity, intertwin discordance in CRL, fetal NT ≥ 95th percentile and free β-hCG and PAPP-A multiples of the median. Similarly, within the CVS group, multivariable logistic regression analysis was used to investigate the effect of the number of intrauterine needle insertions and size of the needle on the risk of fetal loss. RESULTS The study population of 8581 twin pregnancies undergoing ultrasound examination at 11-13 weeks' gestation included 316 dichorionic and 129 monochorionic twins that had CVS. First, in twin pregnancies undergoing CVS, compared to those not undergoing CVS, there was a 2-fold increased risk of fetal loss at

BACKGROUND Several cross-sectional studies have investigated the incidence of urinary Congo-red dye positivity in women with preeclampsia (PE), compared to unaffected pregnancies, and reported very high sensitivity and low false positive rate in the diagnosis of PE. OBJECTIVE To determine the performance of the urinary Congo-red dot paper test at 35-37 weeks' gestation in the prediction of delivery with PE at ≤2 and >2 weeks after assessment. METHODS This was a prospective observational study in women attending for a routine hospital visit at 35+0 to 36+6 weeks' gestation in a maternity hospital in England. Urine samples were collected and the Congo-red dot paper test was used to assess the degree of Congo-red dye positivity. The test uses a scoring system from 1 to 8 and the higher the score the greater the degree of Congo-red dye positivity. We examined and compared the degree of Congo-red dye positivity in the groups that delivered with PE at ≤2 and >2 weeks with those that remained normotensive. Reproducibility was assessed by examining the inter- and intra-observer reliability of scoring on stored images with the researchers blinded to previous results. RESULTS The study population of 2140 women included 46 (2.1%) that subsequently developed PE (2.1%). The urinary Congo-red dot test was positive in 8.3% (1/12) and 2.9% (1/34) that delivered with PE at ≤2 and >2 weeks from assessment and in 0.2% (4/2094) of the unaffected pregnancies when the cutoff for Congo-red dye positivity was ≥5. The respective values when the cutoff used was ≥3 were 66.7%, 23.5%, and 16.5%, respectively. The intraclass correlation coefficient for the inter-observer reliability was 0.926 (95% CI 0.890-0.953, p

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

OBJECTIVE To determine the optimal total serum bile acid (TSBA) threshold and sampling time for accurate intrahepatic cholestasis of pregnancy (ICP) diagnosis. DESIGN Case-control, retrospective cohort studies. SETTING Antenatal clinics, clinical research facilities. POPULATION Women with ICP or uncomplicated pregnancies. METHODS Serial TSBA measurements were performed pre-/postprandially in 42 women with ICP or uncomplicated pregnancy. Third-trimester non-fasting TSBA reference ranges were calculated from 561 women of black, south Asian and white ethnicity. Rates of adverse perinatal outcomes for women with ICP but peak non-fasting TSBA below the upper reference range limit were compared with those in healthy populations. MAIN OUTCOME MEASURES Sensitivity and specificity of common TSBA thresholds for ICP diagnosis, using fasting and postprandial TSBA. Calculation of normal reference ranges of non-fasting TSBA. RESULTS Concentrations of TSBA increased markedly postprandially in all groups, with overlap between healthy pregnancy and mild ICP (TSBA

To investigate whether first-trimester maternal plasma fetal fraction is altered in women that subsequently develop preeclampsia (PE) or gestational hypertension (GH) and to examine its potential value in improving the performance of screening for PE and GH by maternal factors and maternal serum pregnancy associated plasma protein-A (PAPP-A), mean arterial pressure (MAP) and uterine artery pulsatility index (UtA-PI).The study population of 10,131 pregnancies undergoing cell free fetal DNA testing at 11-13 weeks' gestation included 91 (0.9%) cases with preterm-PE, 222 (2.2%) cases with term-PE, 360 (3.6%) with GH and 9,458 (93.4%) cases unaffected by hypertensive disorders. Maternal plasma fetal fraction levels were expressed as multiples of the median (MoM) after adjustment for maternal factors and crown-rump length. The performance of screening for preterm-PE, term PE and GH by maternal factors and MoM values of fetal fraction, PAPP-A, UtA-PI and MAP was evaluated by receiver operating characteristic (ROC) curves.The median fetal fraction MoM was significantly lower in the preterm-PE (0.825; IQR 0.689-1.115 MoM,First trimester maternal plasma fetal fraction is not useful in screening for hypertensive disorders of pregnancy.

Introduction Pre-eclampsia (PE) affects 2–8% of pregnancies worldwide. Despite identification of numerous possible biomarkers, accurate prediction and early diagnosis of PE remain challenging. We examined the potential of leukotriene B4 (LTB4) and 15-hydroxyeicosatetraenoic acid (15(S)-HETE) as biomarkers of PE by comparing serum levels at three gestational age (GA) groups between normotensive pregnancies and asymptomatic women who subsequently developed preterm or term-PE. Methods This is a case-control study drawn from a prospective study of adverse pregnancy outcomes with serum samples collected at 19–24 weeks (n = 48), 30–34 weeks (n = 101) and 35–37 weeks (n = 54) GA. LTB4 and 15(S)-HETE levels were determined by ELISA. Serum level multiples of the median (MoM) were compared between normal and PE-pregnancies. Association between LTB4 and 15(S)-HETE and GA at delivery was investigated with Cox proportional-hazards models. Results Serum LTB4 levels were lower in women of East-Asian ethnicity, higher in women with PE history, and increased with GA in normotensive pregnancies, but not in PE. LTB4 was elevated at 19–24 weeks in women who developed preterm-PE. There was a negative association between LTB4 MoM and interval between sampling and delivery with PE at 19–24 weeks only. Serum 15(S)-HETE levels were not influenced by GA at testing and were elevated in women of South-Asian ethnicity. Median 15(S)-HETE levels were unchanged in preterm and term-PE at any GA. Discussion LTB4 was higher at 19–24 weeks in pregnancies that developed preterm-PE versus unaffected pregnancies, suggesting it is a potentially useful predictive marker of preterm PE in the second trimester.

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: Pre-eclampsia (PE) is a significant contributor to adverse maternal and perinatal outcome; however, accurate prediction and early diagnosis of this condition remain a challenge. The aim of this study was to compare serum levels of growth-differentiation factor-15 (GDF-15) at three different gestational ages between asymptomatic women who subsequently developed preterm or term PE and healthy controls. Methods: This was a case–control study drawn from a prospective observational study on adverse pregnancy outcomes in women attending for their routine second- and third-trimester hospital visits. Serum GDF-15 was determined in 300 samples using a commercial GDF-15 enzyme-linked immunosorbent assay: 120 samples at 19–24 weeks of gestation, 120 samples at 30–34 weeks and 60 samples at 35–37 weeks. Multiple linear regression was applied to logarithmically transformed GDF-15 control values to evaluate the influence of gestational age at blood sampling and maternal characteristics on GDF-15 results. GDF-15 multiples of the normal median (MoM) values, adjusted for gestational age and maternal characteristics, were compared between pregnancies that subsequently developed preterm or term PE and healthy controls. Results: Values of GDF-15 increased with gestational age. There were no significant differences in GDF-15 MoM values between cases of preterm or term PE and normotensive pregnancies at 19–24 or 35–37 weeks of gestation. At 30–34 weeks, GDF-15 MoM values were significantly increased in cases of preterm PE, but not in those who later developed term PE. Elevated GDF-15 MoM values were associated significantly with a shorter interval between sampling at 30–34 weeks and delivery with PE (P = 0.005). Conclusion: Serum GDF-15 levels at 19–24 or 35–37 weeks of gestation are not predictive of preterm or term PE. At 30–34 weeks, GDF-15 levels are higher in women who subsequently develop preterm PE; however, this difference is small and GDF-15 is unlikely to be useful in clinical practice when used in isolation. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Serum pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) at 11-13 weeks' gestation are reduced in pregnancies with fetal trisomy and in those that subsequently develop pre-eclampsia (PE). In screening for trisomy, the established biochemical marker is PAPP-A, whereas in screening for PE, the preferred marker is PlGF. The objective of this study was to examine the impact of replacing PAPP-A by PlGF in first-trimester screening for trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency thickness (NT) and free β-human chorionic gonadotropin (β-hCG).This was a prospective screening study in singleton pregnancies for trisomies 21, 18 and 13 by a combination of maternal age, fetal NT and serum PAPP-A and free β-hCG at 11-13 weeks' gestation in which we also measured PlGF. Multiples of the median (MoM) values were calculated for PAPP-A, free β-hCG and PlGF. The dataset was split randomly into training and test datasets of roughly equal size, and the parameters for PlGF obtained from the training dataset were used in risk calculation for the test dataset. Standardized detection rates were computed by obtaining the likelihood ratios for biochemistry and fetal NT for trisomy-21, -18 and -13 pregnancies in the sample and then applying these to each year of maternal age from 12 to 50 to estimate the age-specific detection rates. These were then weighted according to the maternal age distributions of trisomy-21, -18 and -13 pregnancies in England and Wales in 2018. Similarly, standardized false-positive rates (FPR) were computed by obtaining the likelihood ratios for biochemistry and NT, as appropriate, in normal pregnancies in the sample and then applying these to each year of maternal age from 12 to 50 to estimate the age-specific FPRs. A modeling approach was used to assess the performance of screening according to gestational age at biochemical testing.The study population of 71 266 pregnancies included 70 858 (99.4%) with normal fetal karyotype or birth of a phenotypically normal neonate and 263 with trisomy 21, 109 with trisomy 18 and 36 with trisomy 13. There are five main findings of this study. First, the performance of screening for trisomy by the first-trimester combined test or the combined test in which PAPP-A is replaced by PlGF is substantially better at 11 than at 13 weeks' gestation; for example, the detection rates of trisomy 21 by the combined test were 94%, 90% and 84%, at 5% FPR, when testing was carried out at 11, 12 and 13 weeks, respectively, and the corresponding values in screening by a test in which PAPP-A is replaced by PlGF were 90%, 87% and 86%, respectively. Second, in trisomy-21 pregnancies, the deviation of median PAPP-A MoM from normal decreases with increasing gestational age, whereas the deviation in PlGF does not change with gestational age. Third, the performance of screening for trisomy 21 during the 11In first-trimester screening for trisomy, the preferred biochemical marker is PAPP-A rather than PlGF, especially when biochemical testing is carried out during the 11

Objective Serum pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) at 11-13 weeks' gestation are reduced in pregnancies with fetal trisomy and in those that subsequently develop pre-eclampsia (PE). In screening for trisomy, the established biochemical marker is PAPP-A, whereas in screening for PE, the preferred marker is PlGF. The objective of this study was to examine the impact of replacing PAPP-A by PlGF in first-trimester screening for trisomies 21, 18 and 13 by maternal age, fetal nuchal translucency thickness (NT) and free β-human chorionic gonadotropin (β-hCG). Methods This was a prospective screening study in singleton pregnancies for trisomies 21, 18 and 13 by a combination of maternal age, fetal NT and serum PAPP-A and free β-hCG at 11-13 weeks' gestation in which we also measured PlGF. Multiples of the median (MoM) values were calculated for PAPP-A, free β-hCG and PlGF. The dataset was split randomly into training and test datasets of roughly equal size, and the parameters for PlGF obtained from the training dataset were used in risk calculation for the test dataset. Standardized detection rates were computed by obtaining the likelihood ratios for biochemistry and fetal NT for trisomy-21, -18 and -13 pregnancies in the sample and then applying these to each year of maternal age from 12 to 50 to estimate the age-specific detection rates. These were then weighted according to the maternal age distributions of trisomy-21, -18 and -13 pregnancies in England and Wales in 2018. Similarly, standardized false-positive rates (FPR) were computed by obtaining the likelihood ratios for biochemistry and NT, as appropriate, in normal pregnancies in the sample and then applying these to each year of maternal age from 12 to 50 to estimate the age-specific FPRs. A modeling approach was used to assess the performance of screening according to gestational age at biochemical testing. Results The study population of 71 266 pregnancies included 70 858 (99.4%) with normal fetal karyotype or birth of a phenotypically normal neonate and 263 with trisomy 21, 109 with trisomy 18 and 36 with trisomy 13. There are five main findings of this study. First, the performance of screening for trisomy by the first-trimester combined test or the combined test in which PAPP-A is replaced by PlGF is substantially better at 11 than at 13 weeks' gestation; for example, the detection rates of trisomy 21 by the combined test were 94%, 90% and 84%, at 5% FPR, when testing was carried out at 11, 12 and 13 weeks, respectively, and the corresponding values in screening by a test in which PAPP-A is replaced by PlGF were 90%, 87% and 86%, respectively. Second, in trisomy-21 pregnancies, the deviation of median PAPP-A MoM from normal decreases with increasing gestational age, whereas the deviation in PlGF does not change with gestational age. Third, the performance of screening for trisomy 21 during the 11th and 12th gestational weeks is superior if screening includes PAPP-A rather than PlGF, whereas during the 13th week the performance is slightly higher with the use of PlGF rather than PAPP-A. Fourth, in our population with mean gestational age at testing of 12.7 weeks, screening by maternal age, fetal NT, serum free β-hCG and serum PAPP-A predicted 88%, 96% and 97% of cases of fetal trisomies 21, 18 and 13, respectively, at a FPR of 5%; the respective values in screening by a test in which PAPP-A is replaced by PlGF were 85%, 96% and 96%. Fifth, addition of serum PlGF does not improve the prediction of trisomy provided by maternal age, fetal NT and serum free β-hCG and PAPP-A. Conclusion In first-trimester screening for trisomy, the preferred biochemical marker is PAPP-A rather than PlGF, especially when biochemical testing is carried out during the 11th week of gestation or earlier. However, if PlGF was to be used rather than PAPP-A, the same detection rate can be achieved but at a higher FPR. This may be an acceptable compromise to minimize cost and achieve effective screening for both trisomy and PE. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Objective To examine the association between fetal major heart defects and increased nuchal translucency thickness (NT), tricuspid regurgitation and abnormal flow in the ductus venosus in a large population of singleton pregnancies undergoing routine ultrasound examination at 11-13 weeks' gestation. Methods This was a retrospective study of prospectively collected data from singleton pregnancies attending for a routine ultrasound scan at 11-13 weeks' gestation, which included examination of fetal anatomy, measurement of NT and assessment of blood flow across the tricuspid valve and in the ductus venosus, according to a standardized protocol. The incidence of fetal NT ≥ 95th and ≥ 99th percentiles, tricuspid regurgitation and reversed a-wave in the ductus venosus in fetuses with and those without a major heart defect was determined and the performance of each marker and their combination in the detection of major heart defects was calculated. Results The study population of 93 209 pregnancies with no apparent chromosomal abnormality included 211 (0.23%) with a fetal major heart defect and 92 998 morphologically normal neonates. In 113 (53.6%) cases with a major heart defect, the diagnosis was made at the 11-13-week scan, in 82 (38.9%) at the 18-24-week scan, in 10 (4.7%) at the third-trimester scan and in six (2.8%) postnatally. At the 11-13-week scan, we diagnosed all cases of tricuspid or pulmonary atresia and polyvalvular dysplasia, > 90% of cases of hypoplastic left heart syndrome or atrioventricular septal defect, about 60% of complex heart defects and cases of left atrial isomerism (interrupted inferior vena cava with normal intracardiac anatomy), 30-40% of cases of tetralogy of Fallot and arch abnormalities, 25% of tricuspid valve abnormalities and about 15% of cases of transposition of the great arteries, but none of aortic or pulmonary stenosis or common arterial trunk. Fetal NT ≥ 95th or ≥ 99th percentile, tricuspid regurgitation or abnormal ductus venosus flow was observed in 77 (36.5%), 45 (21.3%), 61 (28.9%) and 58 (27.5%) fetuses with a major heart defect, respectively, and in 5678 (6.1%), 857 (0.9%), 1136 (1.2%) and 1644 (1.8%) of those without a heart defect. Any one of NT ≥ 95th percentile, tricuspid regurgitation or abnormal flow in the ductus venosus was found in 117 (55.5%; 95% CI, 48.5-62.3%) fetuses with a heart defect and in 8166 (8.8%; 95% CI, 8.6-9.0%) of those without a heart defect. Any one of NT ≥ 99th percentile or the other two markers was found in 99 (46.9%; 95% CI, 40.0-53.9%) fetuses with a heart defect and in 3517 (3.8%; 95% CI, 3.7-3.9%) of those without a heart defect. Conclusion At 11-13 weeks' gestation, measurement of fetal NT and assessment of flow across the tricuspid valve and in the ductus venosus can lead to early diagnosis of major heart defect. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

OBJECTIVES First, to compare the incidence of single and double fetal death between monochorionic (MC) and dichorionic (DC) twin pregnancies with two live fetuses at 11-13 weeks' gestation and no major abnormalities. Second, to investigate the relationship between gestational age at single fetal death and interval to delivery of the cotwin. Third, to determine the rate of early preterm birth in DC and MC twin pregnancies with two live fetuses and those with single fetal death. METHODS This was a retrospective analysis of prospectively collected data on twin pregnancies undergoing routine ultrasound examination at 11-13 weeks' gestation between 2002 and 2019. The outcome measures, which were stratified by chorionicity, were: first, death of both fetuses at presentation or death of one fetus followed by delivery of a live or dead cotwin within the subsequent 3 days at

To examine the performance of the routine 11-13-week scan in detecting fetal defects in twin pregnancies and to examine if, in pregnancies with a fetal defect, compared to those with normal fetuses, there is increased incidence of nuchal translucency thickness (NT) ≥ 95This was a retrospective analysis of prospectively collected data in twin pregnancies undergoing routine ultrasound examination for fetal anatomy, according to standardized protocols, at 11-13 weeks' gestation between 2002 and 2019. Pregnancies with known chromosomal abnormality were excluded. The final diagnosis of fetal defect was based on the results of postnatal examination in cases of live birth and on the findings of the last ultrasound examination in cases of pregnancy termination, miscarriage or stillbirth. The performance of the 11-13-week scan in the detection of fetal defects was determined.The study population of 6366 twin pregnancies with two live fetuses at 11-13 weeks' gestation included 4979 (78.2%) dichorionic (DC) and 1387 (21.8%) monochorionic (MC) twin pregnancies. The main findings were: first, the overall incidence of fetal defects was higher in MC than in DC twins (2.8% vs 1.3%); second, the proportion of defects diagnosed in the first trimester was higher in MC than in DC twins (52.6% vs 27.1%); third, the pattern of defects in relation to detectability at the 11-13-week scan (always detectable, sometimes detectable and never detectable) was similar to that reported previously in singleton pregnancies; fourth, always-detectable defects included acrania, alobar holoprosencephaly, encephalocele, pentalogy of Cantrell, exomphalos, body-stalk anomaly, twin reversed arterial perfusion sequence and conjoined twins; fifth, the incidence of fetal NT ≥ 95First, fetal defects are more common in MC than in DC twin pregnancies. Second, first-trimester detection of fetal defects in DC twin pregnancies is similar to that in singleton pregnancies. Third, first-trimester detectability of defects in MC twins is higher than in DC twins. Fourth, in twin pregnancies with a fetal defect, there is higher intertwin discordance in CRL and incidence of increased NT, but the predictive performance of screening by these markers is poor. Copyright © 2019 ISUOG. Published by John WileySons Ltd.Diagnóstico de defectos del feto en embarazos de gemelos en el examen ecográfico de rutina de las 11-13 semanas OBJETIVOS: Examinar la eficacia del examen rutinario de 11-13 semanas para detectar defectos fetales en embarazos de gemelos y examinar si, en los embarazos con un defecto fetal, en comparación con los de fetos normales, hay una mayor incidencia del grosor de la translucencia nucal (TN) ≥ percentil 95妊娠11-13周常规超声检测中双胎胎儿缺陷诊断 目标: 审核评估妊娠11-13周常规检测在双胎胎儿缺陷诊断中的表现，审核评估在发现胎儿缺陷的孕妇中，(对照正常胎儿)宫颈半透明厚度(NT)≥95%和≥99%或冠臀长(CRL)脐带缠络≥10%和≥15%的机率是否增加了。 方法: 这是一项根据标准协议，针对2002至2019年间妊娠11-13周接受常规超声胎儿解剖学检测双胎孕妇的前瞻性收集数据回顾分析。排除了已知染色体异常的妊娠孕妇。胎儿缺陷最终诊断依据是(活产孕妇)产后检查结果，以及(终止妊娠、流产或死产孕妇)最后一次超声检查结果。明确了妊娠11-13周检测在胎儿缺陷诊断中的表现。 结果: 研究对象为6366名双胎妊娠孕妇(两个为妊娠11-13周活胎孕妇)，包括4979(78.2%)个双绒毛膜(DC)和1387(21.8%)个单绒毛膜(MC)双胎孕妇。主要研究结果:第一，MC双胎孕妇胎儿缺陷总发生率高于DC双胎孕妇(2.8%对 1.3%)；第二，孕早期MC双胎孕妇胎儿缺陷检出率高于DC双胎孕妇(52.6%对27.1%)；第三，妊娠11-13周检测胎儿缺陷检出模式(总是可以检出、有时可以检出、总是无法检出)类似于之前报告的单胎妊娠检出模式；第四，总是可以检出的缺陷包括无颅、无前脑畸形、脑膨出、坎特雷尔五联症、脐凸出、体柄异常、胎动脉反向灌注综合征和连体双胞胎；第五，缺陷胎儿NT≥95%发生机率高于正常胎儿(DC双胎孕妇，16.5%对4.5%；MC双胎孕妇，19.2%对5.9%)，NT≥99%也是如此(DC双胎孕妇，8.3%对1.0%；MC双胎孕妇，15.4%对2.0%)；第六，缺陷胎儿CRL紊乱≥10%发生机率高于正常胎儿(DC双胎孕妇，20.2%对7.9%；MC双胎孕妇，33.8%对9.3%)，CRL紊乱≥15%也是如此(DC双胎孕妇，10.1%对1.9%；MC双胎孕妇，28.2%对2.8%)。 结论: 第一，相比DC双胎孕妇，MC双胎孕妇出现胎儿缺陷的机率更高。第二，DC双胎孕妇孕早期发现胎儿缺陷的机率与单胎妊娠相当。第三，MC双胎孕妇孕早期胎儿缺陷检出率高于DC双胎孕妇。第四，在检出胎儿缺陷的双胎孕妇中，CRL脐带缠络机率较高，NT增加机率较高，但基于这些标志物的筛检预测性能较差。.

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.

OBJECTIVE To investigate the value of intertwin discordance in fetal crown-rump length (CRL) at the 11-13-week scan in the prediction of adverse outcome in dichorionic (DC), monochorionic diamniotic (MCDA) and monochorionic monoamniotic (MCMA) twin pregnancies. METHODS This was a retrospective analysis of prospectively collected data on twin pregnancies undergoing routine ultrasound examination at 11-13 weeks' gestation between 2002 and 2019. In pregnancies with no major abnormalities, we examined the value of intertwin discordance in fetal CRL in DC, MCDA and MCMA twins in the prediction of fetal loss at

Objective To investigate the potential value of routine ultrasound examination at 35-37 weeks' gestation in the diagnosis of previously unknown fetal abnormalities. Methods This was a prospective study of 52 400 singleton pregnancies attending for a routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation; all pregnancies had a previous scan at 18-24 weeks and 47 214 also had a scan at 11-13 weeks. We included pregnancies resulting in live birth or stillbirth but excluded those with known chromosomal abnormality. Abnormalities were classified according to the affected major organ system, and the type and incidence of new abnormalities were determined. Results In the study population, the incidence of fetal abnormality was 1.9% (995/52 400), including 674 (67.7%) that had been diagnosed previously during the first and/or second trimester, 247 (24.8%) that were detected for the first time at 35-37 weeks and 74 (7.4%) that were detected for the first time postnatally. The most common abnormalities that were diagnosed during the first and/or second trimester and that were also observed at 35-37 weeks included ventricular septal defect, talipes, unilateral renal agenesis and/or pelvic kidney, hydronephrosis, duplex kidney, unilateral multicystic kidney, congenital pulmonary airway malformation, ventriculomegaly, cleft lip and palate, polydactyly and abdominal cyst or gastroschisis. The most common abnormalities first seen at 35-37 weeks were hydronephrosis, mild ventriculomegaly, ventricular septal defect, duplex kidney, ovarian cyst and arachnoid cyst. The incidence of abnormalities first seen at 35-37 weeks was 0.5% and those that were detected exclusively for the first time at this examination were ovarian cyst, microcephaly, achondroplasia, dacryocystocele and hematocolpos. The incidence of abnormalities first seen postnatally was 0.1% and the most common were isolated cleft palate, polydactyly or syndactyly and ambiguous genitalia or hypospadias; prenatal examination of the genitalia was not a compulsory part of the protocol. Conclusions A high proportion of fetal abnormalities are detected for the first time during a routine ultrasound examination at 35-37 weeks' gestation. Such diagnosis and subsequent management, including selection of timing and place for delivery and postnatal investigations, could potentially improve postnatal outcome. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Small for gestational age (SGA) fetuses/neonates are characterized by the increased risk for adverse outcomes that can be reduced if the condition is identified antenatally. We have recently developed a new approach in SGA prediction that considers SGA a spectrum condition that is reflected in two dimensions: gestational age at delivery and Z score in birth weight for gestational age. The new method has a better predictive ability than the traditionally used risk-scoring systems and logistic regression models. In this prospective study in 40241 singleton pregnancies, at 19–24 weeks’ gestation, we examined the potential value of the antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and the ratio of sFlt-1 to the angiogenic placental growth factor (PlGF) in the prediction of SGA. We found that first, sFlt-1 did not improve the performance of screening by maternal risk factors, and second, the ratio of sFlt-1/PlGF had a worse performance than PlGF alone in the prediction of SGA. Consequently, second trimester sFlt-1 and sFlt-1/PlGF are not useful in screening for SGA.

We previously reported a logistic regression model for prediction of GDM from maternal characteristics and medical history in 75,161 singleton pregnancies. In this study of 1376 twin and 13,760 singleton pregnancies recruited at 11–13 weeks’ gestation, we extend the model to include terms for twin pregnancies. We found the respective odds of GDM in dichorionic and monochorionic twin pregnancies to be 1.36 (95% CI: 1.02–1.81) and 2.78 (95% CI: 1.72–4.48) times higher than in singleton pregnancies. In both singleton and twin pregnancies, the risk for GDM increased with maternal age and weight and birth weight z-score of a baby in a previous pregnancy and is higher in women with a previous pregnancy complicated by GDM, in those with a first- or second-degree relative with diabetes mellitus, in women of Black, East Asian, and South Asian racial origin, and in pregnancies conceived through the use of ovulation-induction drugs. In singleton pregnancies, at 10% and 20% false-positive rate, the detection rate was 43% and 58%, respectively. In twin pregnancies, using risk cut-offs corresponding to 10% and 20% false-positive rates in singletons, the respective false-positive rates were 27% and 47%, and the detection rates were 63% and 81%.

OBJECTIVE To explore the possibility of carrying out routine screening for pre-eclampsia (PE) with delivery at

Preeclampsia, characterized by the onset of hypertension with significant proteinuria after 20 weeks’ gestation, is one of the leading causes of maternal and perinatal morbidity and mortality. Prophylactic low-dose aspirin treatment reduces the rate of preterm preeclampsia in high-risk women, but a significant proportion still develops preeclampsia. The mechanism of the prophylactic response is unknown. Here, the untargeted metabolomics analysis of 144 plasma samples from high-risk pregnant women before (11–13 weeks) and after (20–23 weeks) aspirin/placebo treatment elucidated metabolic effects of aspirin and metabolic differences potentially associated with the variation of the treatment response. We demonstrated that aspirin treatment resulted in a strong drug-associated metabolomics signature and that the preeclamptic or nonpreeclamptic outcome in response to treatment was significantly associated with the level of internal aspirin exposure ascertained from metabolomics data ( t test, P =0.0083). Comparing women with and without preeclampsia after aspirin treatment, differences in 73 metabolites were detected, some of which involve pathways whose regulation is of importance in pregnancy and placental functions, such as glycerophospholipids metabolism, polyunsaturated fatty acid metabolism, and steroid hormone biosynthesis. To further examine the hypothesis that aspirin delays gestational age advancement and thus the onset of preeclampsia, we constructed a metabolic clock on pretreatment and placebo-treated samples that estimated gestational age with high accuracy and found that aspirin significantly decelerated metabolic gestational age by 1.27 weeks (95% CI, 0.66–1.88 weeks), and partially reversed one-fourth of the metabolites changed over gestational age advancement, suggesting that aspirin treatment slowed down the metabolic clock of gestation.

First, to investigate the additive value of second trimester placental growth factor (PlGF) for the prediction of small for gestational age (SGA) neonates. Second, to examine second trimester contingency screening strategies. This is a prospective observational study in 40,241 women with singleton pregnancies undergoing routine ultrasound examination at 19 - 24 weeks' gestation. We used the competing risks model for prediction of SGA. The parameters for the prior model and the likelihoods for estimated fetal weight (EFW) and uterine artery pulsatility index (UtA-PI) were those presented in previous studies. A folded plane regression model was fitted in the dataset of this study to describe the likelihood of PlGF. We compared the prediction of screening by maternal risk factors and EFW against the prediction provided by a combination of maternal risk factors EFW, UtA-PI and PlGF. We also examined the additive value of PlGF in a policy that uses maternal risk factors, EFW and UtA-PI. Overall, the prediction of SGA improved for increasing degree of prematurity, for higher severity of smallness and for coexistence of preeclampsia. The combination of maternal risk factors EFW, UtA-PI and PlGF improved significantly the prediction provided by maternal risk factors and EFW for all the examined cut-offs. Screening by a combination of maternal risk factors plus serum PIGF improved the prediction of SGA when compared to screening by maternal risk factors alone. However, the incremental improvement in prediction was decreased when PIGF was added to screening by a combination of maternal risk factors, EFW, and UtA-PI. If first line screening for SGA neonates with birth weight

Objective To expand the limited knowledge on cell-free DNA (cfDNA) analysis of maternal blood for trisomies 21, 18 and 13 in twin pregnancy by updating the data from The Fetal Medicine Foundation (FMF) on prospective first-trimester screening and those identified in a systematic review of the literature. Methods The FMF data were derived from prospective screening for trisomies 21, 18 and 13 in twin pregnancies at 10 + 0 to 14 + 1 weeks' gestation using the Harmony® prenatal test. A search of MEDLINE, EMBASE, CENTRAL (The Cochrane Library), ClinicalTrials.gov and the International Clinical Trials Registry Platform (World Health Organization) was carried out to identify all peer-reviewed publications on clinical validation or implementation of maternal cfDNA testing for trisomies 21, 18 and 13 in twin pregnancy, irrespective of gestational age at testing, in which data on pregnancy outcome were provided for at least 85% of the study population. Meta-analysis was performed using the FMF data and data from the studies identified by the literature search. This review was registered in the PROSPERO international database for systematic reviews Results In the FMF study, cfDNA testing was carried out in 1442 twin pregnancies and a result was obtained, after first or second sampling, in 1367 (94.8%) cases. In 93.1% (1272/1367) of cases, there was prenatal or postnatal karyotyping or birth of phenotypically normal babies; 95 cases were excluded from further analysis either because the pregnancy ended in termination, miscarriage or stillbirth with no known karyotype (n = 56) or there was loss to follow-up (n = 39). In the 1272 pregnancies included in the study, there were 20 cases with trisomy 21, 10 with trisomy 18, two with trisomy 13 and 1240 without trisomy 21, 18 or 13. The cfDNA test classified correctly 19 (95.0%) of the 20 cases of trisomy 21, nine (90.0%) of the 10 cases of trisomy 18, one (50.0%) of the two cases of trisomy 13 and 1235 (99.6%) of the 1240 cases without any of the three trisomies. The literature search identified 12 relevant studies, excluding our papers because their data are included in the current study. In the combined populations of our study and the 12 studies identified by the literature search, there were 137 trisomy-21 and 7507 non-trisomy-21 twin pregnancies; the pooled weighted detection rate (DR) and false-positive rate (FPR) were 99.0% (95% CI, 92.0–99.9%) and 0.02% (95% CI, 0.001–0.43%), respectively. In the combined total of 50 cases of trisomy 18 and 6840 non-trisomy-18 pregnancies, the pooled weighted DR and FPR were 92.8% (95% CI, 77.6–98.0%) and 0.01% (95% CI, 0.00–0.44%), respectively. In the combined total of 11 cases of trisomy 13 and 6290 non-trisomy-13 pregnancies, the pooled weighted DR and FPR were 94.7% (95% CI, 9.14–99.97%) and 0.10% (95% CI, 0.03–0.39%), respectively. Conclusions In twin pregnancy, the reported DR of trisomy 21 by cfDNA testing is high, but lower than that in singleton pregnancy, whereas the FPR appears to be equally low. The number of cases of trisomy 18 and more so trisomy 13 was too small for accurate assessment of the predictive performance of the cfDNA test. © 2021 International Society of Ultrasound in Obstetrics and Gynecology. pre-print 364 KB

Objective: To evaluate and compare the performance of routine ultrasonographic estimated fetal weight (EFW) and fetal abdominal circumference (AC) at 31+0 - 33+6 and 35+0 - 36+6 weeks’ gestation in the prediction of small for gestational age (SGA) neonates. Methods: This was a prospective study of 21,989 singleton pregnancies that had undergone routine ultrasound examination at 31+0 - 33+6 weeks’ gestation and 45,847 that had undergone routine ultrasound examination at 35+0 - 36+6 weeks’ gestation. In each case the estimated fetal weight (EFW) from measurements of fetal head circumference (HC), AC and femur length (FL) was calculated by the Hadlock formula and this was expressed as percentile according to the Fetal Medicine Foundation fetal and neonatal population weight charts. The same charts were used for defining SGA neonates with birthweight

OBJECTIVES To evaluate the performance of ultrasonographic estimated fetal weight (EFW) at 35 + 0 to 36 + 6 weeks' gestation in the prediction of delivery of a small-for-gestational-age (SGA) neonate and assess the additive value of, first, maternal risk factors and, second, fetal growth velocity between 20 and 36 weeks' gestation in improving such prediction. METHODS This was a prospective study of 44 043 singleton pregnancies undergoing routine ultrasound examination at 19 + 0 to 23 + 6 and at 35 + 0 to 36 + 6 weeks' gestation. Multivariable logistic regression analysis was used to determine whether addition of maternal risk factors and growth velocity, the latter defined as the difference in EFW Z-score or fetal abdominal circumference (AC) Z-score between the third- and second-trimester scans divided by the time interval between the scans, improved the performance of EFW Z-score at 35 + 0 to 36 + 6 weeks in the prediction of delivery of a SGA neonate with birth weight

Prenatal diagnosis of fetal trisomy 21 and other chromosomal abnormalities is based on invasive tests, such as amniocentesis and chorionic villus sampling, which are carried out in women identified through screening as being at high risk for these abnormalities. The most widely used method of screening is the first-trimester combined test which utilizes maternal age, and measurements of fetal nuchal translucency thickness (NT) and maternal serum pregnancy-associated plasma protein-A (PAPP-A) and free β-human chorionic gonadotropin (hCG). To assess the influence of SLE on the levels of NT, PAPP-A, and β-hCG and whether any alterations in such levels may increase the rate of false positives and the subsequent number of invasive tests. This was a prospective first-trimester screening study for trisomies 21, 18, and 13 by a combination of maternal age, fetal nuchal translucency thickness, and serum PAPP-A and β-hCG at King’s College Hospital, London, between March 2006 and February 2011. The study population included 47 cases with maternal SLE and 45,493 without SLE. The results of biomarkers in the SLE and non-SLE groups were compared. In the SLE group, compared to the non-SLE group, there were no significant differences in median maternal age, fetal NT, or serum PAPP-A MoM, but serum free β-hCG MoM was increased (1.402, IQR 0.872–2.290 vs 0.994, IQR 0.676–1.508). In first trimester screening for trisomies, the measured value of free s-hCG should be adjusted for maternal SLE to avoid false positive results and overuse of invasive tests.

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.

Rationale & Objective Lecithin-cholesterol acyltransferase (LCAT) catalyzes the maturation of high-density lipoprotein. Homozygosity for loss-of-function mutations causes familial LCAT deficiency (FLD), characterized by corneal opacities, anemia, and renal involvement. This study sought to characterize kidney biopsy findings and clinical outcomes in a family with FLD. Study Design Prospective observational study. Setting & Participants 2 (related) index patients with clinically apparent FLD were initially identified. 110 of 122 family members who consented to genetic analysis were also studied. Predictors Demographic and laboratory parameters (including lipid profiles and LCAT activity) and full sequence analysis of the LCAT gene. Kidney histologic examination was performed with samples from 6 participants. Outcomes Cardiovascular and renal events during a median follow-up of 12 years. Estimation of annual rate of decline in glomerular filtration rate. Analytical Approach Analysis of variance, linear regression analysis, and Fine-Gray competing-risk survival analysis. Results 9 homozygous, 57 heterozygous, and 44 unaffected family members were identified. In all affected individuals, full sequence analysis of the LCAT gene revealed a mutation (c.820C>T) predicted to cause a proline to serine substitution at amino acid 274 (P274S). Homozygosity caused a complete loss of LCAT activity. Kidney biopsy findings demonstrated lipid deposition causing glomerular basement membrane thickening, mesangial expansion, and "foam-cell" infiltration of kidney tissue. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with worse kidney outcomes. Estimated glomerular filtration rate deteriorated among homozygous family members at an average annual rate of 3.56 mL/min/1.73 m2. The incidence of cardiovascular and renal complications was higher among homozygous family members compared with heterozygous and unaffected members. Mild thrombocytopenia was a common finding among homozygous participants. Limitations The presence of cardiovascular disease was mainly based on medical history. Conclusions The P274S LCAT mutation was found to cause FLD with renal involvement. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with a worse renal prognosis.

To investigate the relationship between fetal congenital heart defects (CHD) and placental perfusion assessed by uterine artery pulsatility index (UtA-PI), in relation to development of pre-eclampsia (PE).This was a prospective screening study of singleton pregnancies at 19-24 weeks' gestation. Transvaginal ultrasound was used to measure UtA-PI and the values were converted into multiples of the normal median (MoM). Median MoM values in pregnancies with a fetus with isolated major CHD were compared to those without CHD, in relation to development of PE.The 91 407 singleton pregnancies fulfilling the entry criteria included 206 (0.23%) with isolated major fetal CHD and 91 201 without CHD. The prevalence of PE was 4.4% in pregnancies with fetal CHD and 2.7% in those without CHD (relative risk (RR), 1.6 (95% CI, 0.84-3.04); P = 0.150); the respective values for preterm PE with delivery at 37 weeks' gestation were 2.4% and 0.7% (RR, 3.4 (95% CI, 1.42-8.09); P = 0.006). In the total population, median UtA-PI MoM was significantly higher in those that developed PE compared to those without PE (1.22 (interquartile range (IQR), 0.94-1.57) vs 1.00 (IQR, 0.84-1.19); P 0.0001) and, in the PE group, the median UtA-PI MoM was inversely related to gestational age at delivery (r = -0.458; P 0.0001). The same pattern of inverse relationship between UtA-PI MoM and gestational age at delivery with PE was observed in pregnancies with and those without CHD, but, in the CHD group, compared to those without CHD, UtA-PI was significantly higher both in pregnancies with and in those without PE.In pregnancies both with and without fetal CHD that develop PE, impedance to flow in the UtAs is increased and this increase is particularly marked in those with preterm PE. The prevalence of preterm PE is more than three times higher in pregnancies with than those without fetal major CHD, and the prevalence of major CHD in pregnancies with preterm PE is also more than three times higher than in those without PE. However, 97% of pregnancies with fetal CHD do not develop preterm PE and 99% of pregnancies with preterm PE are not associated with fetal CHD. Copyright © 2018 ISUOG. Published by John WileySons Ltd.

OBJECTIVE We have proposed previously that all pregnant women should have assessment of risk for pre-eclampsia (PE) at 20 and 36 weeks' gestation and that the 20-week assessment should be used to define subgroups requiring additional monitoring and reassessment at 28 and 32 weeks. The objective of this study was to examine the potential improvement in screening at 19-24 weeks' gestation for PE with delivery at

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.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.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.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 of10th percentile delivered at ≥37,37, and32 weeks' gestation, at a 10% false-positive rate. The respective rates for a birthweight of3rd percentile were 47%, 65%, and 77%. The rates in the presence of preeclampsia were 41%, 72%, and 91% for small-for-gestational-age neonates with birthweights of10th percentile and 50%, 75%, and 92% for small-for-gestational-age neonates with birthweights of3rd percentile. Overall, the model was well calibrated. The detection rates and calibration indices were similar in the training and test data sets, demonstrating the internal validity of the model.The performance of screening for small-for-gestational-age neonates by a competing risks model that combines maternal factors with estimated fetal weight, uterine artery pulsatility index, and mean arterial pressure was superior to that of screening by maternal characteristics and medical history alone.

OBJECTIVES There were two objectives of this study. First, to examine the value of uterine artery pulsatility index (UtA-PI) at 19-24 weeks' gestation in the prediction of subsequent development of pre-eclampsia (PE) and to compare the performance of screening between the use of, first, fixed cut-offs of UtA-PI, second, percentile cut-offs of UtA-PI adjusted for gestational age, third, a competing-risks model combining maternal demographic characteristics and medical history with UtA-PI, and, fourth, a competing-risks model combining maternal factors with UtA-PI and mean arterial pressure (MAP). Second, to stratify pregnancy care based on the estimated risk of PE at 19-24 weeks' gestation from UtA-PI and combinations of maternal factors with UtA-PI and MAP. METHODS This was a prospective, non-intervention study in women attending for an ultrasound scan at 19-24 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE at

Objective To estimate the risk of fetal loss associated with chorionic villus sampling (CVS) in twin pregnancy, using propensity score analysis. Methods This was a multicenter cohort study of women with twin pregnancy undergoing ultrasound examination at 11–13 weeks' gestation, performed in eight fetal medicine units in which the leadership were trained at the Harris Birthright Research Centre for Fetal Medicine in London, UK, and in which the protocols for screening, invasive testing and pregnancy management are similar. The risk of death of at least one fetus was compared between pregnancies that had and those that did not have CVS, after propensity score matching (1:1 ratio). This procedure created two comparable groups by balancing the maternal and pregnancy characteristics that lead to CVS being performed, similar to how randomization operates in a randomized clinical trial. Results The study population of 8581 twin pregnancies included 445 that had CVS. Death of one or two fetuses at any stage during pregnancy occurred in 11.5% (51/445) of pregnancies in the CVS group and in 6.3% (515/8136) in the non-CVS group (P

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: 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 in singletons and in this respect all twins are at increased risk of preterm birth. However, six trials in unselected twin pregnancies reported that vaginal progesterone from mid-gestation 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 which 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-blinded trial (EVENTS) was designed to test the hypothesis that, among women with twin pregnancies, vaginal progesterone at a dose of 600 mg per day from 11-14 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. Methods: 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 participating center. 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 incidence of spontaneous birth between 24+0 and 33+6 weeks’ gestation between the progesterone and placebo groups, adjusting for the effect of participating centre, chrorionicity, parity and method of conception. Prespecified tests of treatment interaction effects with chrorionicity, 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 1,194 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) 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, chrorionicity, parity and method of conception, 1.35; 95% CI 0.88 - 2.05; p=0.17). There was no evidence of interaction between the effects of treatment and chorionicity (p=0.28), parity (p=0.35) method of conception (p=0.56) and adherence (p=0.34); however, there was weak evidence of an interaction with cervical length (p=0.08) suggestive of harm to those with cervical length ≥30 mm (odds ratio 1.61, 95% CI 1.01-2.59) and potential benefit for those with cervical length

Preeclampsia is a serious pregnancy-induced disorder unique to humans. The etiology of preeclampsia is poorly understood; however, poor placental formation is thought causal. Galectin-7 is produced by trophoblast and is elevated in first-trimester serum of women who subsequently develop preeclampsia. We hypothesized that elevated placental galectin-7 may be causative of preeclampsia. Here, we demonstrated increased galectin-7 production in chorionic villous samples from women who subsequently develop preterm preeclampsia compared with uncomplicated pregnancies. In vitro, galectin-7 impaired human first-trimester trophoblast outgrowth, increased placental production of the antiangiogenic sFlt-1 splice variant, sFlt-1-e15a , and reduced placental production and secretion of ADAM12 (a disintegrin and metalloproteinase12) and angiotensinogen. In vivo, galectin-7 administration (E8–E12) to pregnant mice caused elevated systolic blood pressure, albuminuria, impaired placentation (reduced labyrinth vascular branching, impaired decidual spiral artery remodeling, and a proinflammatory placental state demonstrated by elevated IL1β, IL6 and reduced IL10), and dysregulated expression of renin-angiotensin system components in the placenta, decidua, and kidney, including angiotensinogen, prorenin, and the angiotensin II type 1 receptor. Collectively, this study demonstrates that elevated galectin-7 during placental formation contributes to abnormal placentation and suggests that it leads to the development of preeclampsia via altering placental production of sFlt-1 and renin-angiotensin system components. Targeting galectin-7 may be a new treatment option for preeclampsia.

Introduction Altered placental expression of high temperature requirement factor A1 (HtrA1) is implicated in abnormal trophoblastic invasion and endothelial dysfunction in pre-eclampsia (PE). Serum levels of HtrA1 have been proposed as a novel biomarker to improve the prediction of PE. This study assesses serum HtrA1 levels in prospectively collected samples of women who developed PE compared to normotensive pregnancies. Methods This was a case-control study of serum HtrA1 levels in second and third trimester samples in women who later developed preterm or term PE compared to controls. Overall, 300 serum samples were drawn from a prospective observational study of adverse pregnancy outcomes in three different gestational age windows (19–24, 30-34 and 35–37 weeks) at the Fetal Medicine Research Institute, King's College Hospital, London. Serum HtrA1 levels were determined by enzyme-linked immunosorbent assay (ELISA) by a blinded laboratory professional. Median HtrA1 MoM values, adjusted for gestational age and maternal characteristics, were compared between cases and controls at each gestational age group. Results Women who later developed PE, compared to controls, had significantly higher maternal weight and more frequently had chronic hypertension or a history of PE in a previous pregnancy. In normotensive pregnancies, serum HtrA1 increased with increasing gestational age, whereas, in PE pregnancies HtrA1 levels remained stable, but were not significantly different from control pregnancies at any gestational age. Discussion Serum HtrA1 levels are not significantly different in women who develop PE compared to controls.

Any definition of preeclampsia should identify women and babies at greatest risk of adverse outcomes.This study aimed to investigate the ability of the American College of Obstetricians and Gynecologists and International Society for the Study of Hypertension in Pregnancy definitions of preeclampsia at term gestational age (≥37 0/7 weeks) to identify adverse maternal and perinatal outcomes.In this prospective cohort study at 2 maternity hospitals in England, women attending a routine hospital visit at 35 0/7 to 36 6/7 weeks' gestation underwent assessment that included history; ultrasonographic estimated fetal weight; Doppler measurements of the pulsatility index in the uterine, umbilical, and fetal middle cerebral arteries; and serum placental growth factor-to-soluble fms-like tyrosine kinase-1 ratio. Obstetrical records were examined for all women with chronic hypertension and those who developed new-onset hypertension, with preeclampsia (de novo or superimposed on chronic hypertension) defined in 5 ways: traditional, based on new-onset proteinuria; American College of Obstetricians and Gynecologists 2013 definition; International Society for the Study of Hypertension in Pregnancy maternal factors definition; International Society for the Study of Hypertension in Pregnancy maternal factors plus fetal death or fetal growth restriction definition, defined according to the 35 0/7 to 36 6/7 weeks' gestation scan as either estimated fetal weight3rd percentile or estimated fetal weight at the 3rd to 10th percentile with any of uterine artery pulsatility index95th percentile, umbilical artery pulsatility index95th percentile, or middle cerebral artery pulsatility index5th percentile; and International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance definition, defined as placental growth factor5th percentile or soluble fms-like tyrosine kinase-1-to-serum placental growth factor95th percentile. Detection rates for outcomes of interest (ie, severe maternal hypertension, major maternal morbidity, perinatal mortality or major neonatal morbidity, neonatal unit admission ≥48 hours, and birthweight10th percentile) were compared using the chi-square test, and P.05 was considered significant.Among 15,248 singleton pregnancies, the identification of women with preeclampsia varied by definition: traditional, 15 of 281 (1.8%; 248); American College of Obstetricians and Gynecologists, 15 of 326 (2.1%; 248); International Society for the Study of Hypertension in Pregnancy maternal factors, 15 of 400 (2.6%; 248); International Society for the Study of Hypertension in Pregnancy maternal-fetal factors, 15 of 434 (2.8%; 248); and International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance, 15 of 500 (3.3%; 248). Compared with the traditional definition of preeclampsia, the International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance best identified the adverse outcomes: severe hypertension (40.6% [traditional] vs 66.9% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance, P.0001], 59.2% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors, P=.004], 56.2% [International Society for the Study of Hypertension in Pregnancy maternal factors, P=.013], 46.1% [American College of Obstetricians and Gynecologists, P=.449]); P.0001); composite maternal severe adverse event (72.2% [traditional] vs 100% for all others; P=.046); composite of perinatal mortality and morbidity (46.9% [traditional] vs 71.1% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance, P=.002], 62.2% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors, P=.06], 59.8% [International Society for the Study of Hypertension in Pregnancy maternal factors, P=.117], 49.4% [American College of Obstetricians and Gynecologists, P=.875]); neonatal unit admission for ≥48 hours (51.4% [traditional] vs 73.4% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance, P=.001], 64.5% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors, P=.070], 60.7% [International Society for the Study of Hypertension in Pregnancy maternal factors, P=.213], 53.3% [American College of Obstetricians and Gynecologists, P=.890]); birthweight10th percentile (40.5% [traditional] vs 78.7% [International Society for the Study of Hypertension in Pregnancy maternal-fetal factors plus angiogenic imbalance, P.0001], 70.1% [International Society for the Study of Hypertension in Pregnancy maternal-fetal, P.0001], 51.3% [International Society for the Study of Hypertension in Pregnancy maternal factors, P=.064], 46.3% [American College of Obstetricians and Gynecologists, P=.349]).Our findings present an evidence base for the broad definition of preeclampsia. Our data suggest that compared with a traditional definition, a broad definition of preeclampsia can better identify women and babies at risk of adverse outcomes. Compared with the American College of Obstetricians and Gynecologists definition, the more inclusive International Society for the Study of Hypertension in Pregnancy definition of maternal end-organ dysfunction seems to be more sensitive. The addition of uteroplacental dysfunction to the broad definition optimizes the identification of women and babies at risk, particularly when angiogenic factors are included.

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

IntroductionGestational diabetes mellitus (GDM) is a common disorder of pregnancy and contributes to adverse pregnancy outcomes. Metformin is often used for the prevention and management of GDM; however, its use in pregnancy continues to be debated. The Metformin in Pregnancy Study aims to use individual patient data (IPD) meta-analysis to clarify the efficacy and safety of metformin use in pregnancy and to identify relevant knowledge gaps.Methods and analysisMEDLINE, EMBASE and all Evidence-Based Medicine will be systematically searched for randomised controlled trials (RCT) testing the efficacy of metformin compared with placebo, usual care or other interventions in pregnant women. Two independent reviewers will assess eligibility using prespecified criteria and will conduct data extraction and quality appraisal of eligible studies. Authors of included trials will be contacted and asked to contribute IPD. Primary outcomes include maternal glycaemic parameters and GDM, as well as neonatal hypoglycaemia, anthropometry and gestational age at delivery. Other adverse maternal, birth and neonatal outcomes will be assessed as secondary outcomes. IPD from these RCTs will be harmonised and a two-step meta-analytic approach will be used to determine the efficacy and safety of metformin in pregnancy, with a priori adjustment for covariates and subgroups to examine effect moderators of treatment outcomes. Sensitivity analyses will assess heterogeneity, risk of bias and the impact of trials which have not provided IPD.Ethics and disseminationAll IPD will be deidentified and studies contributing IPD will have ethical approval from their respective local ethics committees. This study will provide robust evidence regarding the efficacy and safety of metformin use in pregnancy, and may identify subgroups of patients who may benefit most from this treatment modality. Findings will be published in peer-reviewed journals and disseminated at scientific meetings, providing much needed evidence to inform clinical and public health actions in this area.

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.

Maternal obesity increases the risk for pregnancy complications and adverse neonatal outcome and has been associated with long-lasting adverse effects in the offspring, including increased body fat mass, insulin resistance, and increased risk for premature cardiovascular disease. Lifestyle interventions in pregnancy have produced no or modest effects in the reduction of adverse pregnancy outcomes in obese mothers. The Metformin in Obese Pregnant Women trial was associated with reduced adverse pregnancy outcomes and had no effect on birthweight. However, the long-term implications of metformin on the health of offspring remain unknown.The purpose of this study was to assess whether prenatal exposure to metformin can improve the cardiovascular profile and body composition in the offspring of obese mothers.In 151 children from the Metformin in Obese Pregnant Women trial, body composition, peripheral blood pressure, and arterial pulse wave velocity were measured. Central hemodynamics (central blood pressure and augmentation index) were estimated with the use of an oscillometric device. Left ventricular cardiac function and structure were assessed by echocardiography.Children were 3.9±1.0 years old, and 77 of them had been exposed to metformin prenatally. There was no significant difference in peripheral blood pressure, arterial stiffness, and body composition apart from gluteal and tricep circumferences, which were lower in the metformin group (P.05). The metformin group, compared with the placebo group, had lower central hemodynamics (mean adjusted decrease, -0.707 mm Hg for aortic systolic blood pressure, -1.65 mm Hg for aortic pulse pressure, and -2.68% for augmentation index; P.05 for all) and lower left ventricular diastolic function (adjusted difference in left atrial area, -0.525 cmChildren of obese mothers who were exposed prenatally to metformin, compared with those who were exposed to placebo, had lower central hemodynamic and cardiac diastolic indices. These results suggest that the administration of metformin in obese pregnant women potentially may have a beneficial cardiovascular effect for their offspring.

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 investigate the value of increased fetal nuchal translucency thickness (NT) at the 11-13-week scan in the prediction of adverse outcome in dichorionic (DC), monochorionic diamniotic (MCDA) and monochorionic monoamniotic (MCMA) twin pregnancies. METHODS This was a retrospective analysis of prospectively collected data on twin pregnancies undergoing routine ultrasound examination at 11-13 weeks' gestation between 2002 and 2019. In pregnancies with no major defects or chromosomal abnormalities, we examined the value of increased NT ≥ 95th percentile in one or both fetuses in the prediction of, first, miscarriage or death of one or both fetuses at < 20 and < 24 weeks' gestation in DC, MCDA and MCMA twin pregnancies, second, death of one or both fetuses or neonates at ≥ 24 weeks in DC, MCDA and MCMA twin pregnancies, third, development of twin-twin transfusion syndrome (TTTS) or selective fetal growth restriction (sFGR) treated by endoscopic laser surgery at < 20 and ≥ 20 weeks' gestation in MCDA pregnancies, and, fourth, either fetal loss or laser surgery at < 20 weeks' gestation in MCDA pregnancies. RESULTS The study population of 6225 twin pregnancies included 4896 (78.7%) DC, 1274 (20.5%) MCDA and 55 (0.9%) MCMA pregnancies. The incidence of NT ≥ 95th percentile in one or both fetuses in DC twin pregnancies was 8.3%; in MCDA twins the incidence was significantly higher (10.4%; P = 0.016), but in MCMA twins it was not significantly different (9.1%; P = 0.804) from that in DC twins. In DC twin pregnancies, the incidence of high NT was not significantly different between those with two survivors and those with adverse outcome. In MCMA twin pregnancies, the number of cases was too small for meaningful assessment of the relationship between high NT and adverse outcome. In MCDA twin pregnancies with at least one fetal death or need for endoscopic laser surgery at < 20 weeks' gestation, the incidence of NT ≥ 95th percentile was significantly higher than in those with two survivors (23.5% vs 9.8%; P < 0.0001). Kaplan-Meier analysis in MCDA twin pregnancies showed that, in those with NT ≥ 95th percentile, there was significantly lower survival at < 20 weeks' gestation than in those with NT < 95th percentile (P = 0.001); this was not the case for survival at ≥ 20 weeks (P = 0.960). The performance of screening by fetal NT ≥ 95th percentile for prediction of either fetal loss or need for endoscopic laser surgery at < 20 weeks' gestation was poor, with a detection rate of 23.5% at a false-positive rate of 8.9%, and the relative risk, in comparison to fetal NT < 95th percentile, was 2.640 (95% CI, 1.854-3.758; P < 0.0001). In MCDA twin pregnancies, the overall rate of fetal loss or need for laser surgery at < 20 weeks' gestation was 10.7% but, in the subgroups with NT ≥ 95th and NT ≥ 99th percentiles, which constituted 10.4% and 3.3% of the total, the rates increased to 24.1% and 40.5%, respectively. CONCLUSIONS In MCDA twin pregnancies with no major fetal abnormalities, measurement of NT at the 11-13-week scan is a poor screening test for adverse pregnancy outcome. However, the finding in one or both fetuses of NT ≥ 95th percentile, and more so ≥ 99th percentile, is associated with a substantially increased risk of fetal loss or need for endoscopic laser surgery at < 20 weeks' gestation. The extent to which closer monitoring and earlier intervention in the high-risk group can reduce these complications remains to be determined. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

To define the incidence of variants of aortic arch sidedness in fetuses undergoing routine first trimester ultrasound examination.The data for this study were derived from prospective routine ultrasound examination at 11The study population of 33,202 pregnancies included 18 (5.4 per 10,000) cases with isolated RAA and 5 (1.5 per 10,000) with DAA. In the group with isolated RAA or DAA, compared to those without, the median maternal age was higher and the incidence of conceptions fromThe incidence of isolated RAA and DAA in a local population undergoing routine first-trimester ultrasound examination is 2-3-fold higher than that reported in postnatal studies and the risk for these abnormalities is substantially increased in fetuses conceived by IVF.

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.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 32 and at 36 weeks' gestation were calculated using the competing-risks model to combine the prior distribution of gestational age at delivery with PE, obtained from maternal characteristics and medical history, with multiples of the median (MoM) values of MAP, UtA-PI, PlGF and sFlt-1. Different risk cut-offs were used to vary the proportion of the population stratified into high-, intermediate- and low-risk groups, and the performance of screening for delivery with PE at 32 weeks' gestation and at 32 + 0 to 35 + 6 weeks was estimated.The study population of 16 254 singleton pregnancies included 467 (2.9%) that subsequently developed PE (23 delivered at 32 weeks, 58 delivered at 32 + 0 to 35 + 6 weeks and 386 delivered at ≥ 36 weeks). Using a risk of 1 in 25 for PE at 32 weeks' gestation and risk of 1 in 150 for PE at 36 weeks, the proportion of the population stratified into the high-risk group was about 1% of the total, and the proportion of cases of PE at 32 weeks' gestation contained within this high-risk group varied from about 35% with screening by maternal factors and MAP, to 78% with maternal factors, MAP and UtA-PI, and up to 100% with maternal factors, MAP, UtA-PI and PlGF, with or without sFlt-1. Similarly, the proportion of the population requiring reassessment of risk at 32 weeks' gestation and the proportion of cases of PE at 32 + 0 to 35 + 6 weeks contained within this population varied, respectively, from about 18% and 79% with screening by maternal factors and MAP, to 10% and 90% with maternal factors, MAP, UtA-PI and PlGF, with or without sFlt-1.In the new pyramid of pregnancy care, assessment of risk for PE at 19-24 weeks' gestation can stratify the population into those requiring intensive monitoring at 24-31 weeks and those in need of reassessment at 32 weeks. Copyright © 2018 ISUOG. Published by John WileySons Ltd.

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 1 in 100. RESULTS In SPREE, screening for preterm PE by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index and serum placental growth factor identified a high-risk group that contained about 46% of SGA neonates

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 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 estimate the risk for fetal trisomy 21 (T21) and other chromosomal abnormalities at 11-13 week's gestation using computational intelligence classification methods. Methods As a first step, we train the artificial neural networks with 72054 euploid pregnancies, 295 cases of T21 and 305 of other chromosomal abnormalities (OCA). Then, we sort the cases into two categories of “no-risk” and “risk”. The cases of “no-risk” are no further examined, while the cases with “risk” are forwarded in Stage 2 for further examination where we classify them in three types of risk, namely “no-risk”, “moderate-risk” and “high-risk”. Results Of a total of 36328 unknown to the system pregnancies, in the first Stage, 17512 euploid, 2 T21 and 18 other chromosomal abnormalities are classified as “no-risk”. The remaining 18796 (51.4% FPR) cases are reassigned in Stage 2 where 7895 euploid, 2 T21 and 2 OCA are classified as “no-risk”, 10464 euploid, 83 T21 and 61 OCA as “moderate-risk” and 187 euploid, 50 T21 and 52 OCA as “high-risk”. The sensitivity and the specificity for T21 in Stage 2 are 97.1% and 99.5% respectively, assuming that cell-free DNA test can identify all the euploid and aneuploid cases. Conclusion We propose a method for the early diagnosis of chromosomal abnormalities, which ensures that most of the T21 are classified as “high-risk” at any Stage. At the same time, we minimize the euploid cases that have to undergo invasive or cell-free DNA examinations through a routine procedure offered in two Stages. Our method is minimally invasive and of relatively low cost, highly effective on T21 identification and it performs better than other existing statistical methods.