Publications by authors named "Syngelaki A"

171 Publications

Prenatal incidence of isolated right aortic arch and double aortic arch.

J Matern Fetal Neonatal Med 2019 Oct 16:1-6. Epub 2019 Oct 16.

Harris Birthright Centre for Fetal Medicine, Fetal Medicine Research Institute, King's College Hospital , London , UK.

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 11 to 13 weeks' gestation in singleton pregnancies examined in a local population between January 2014 and March 2018. We examined the incidence of isolated right aortic arch (RAA) and double aortic arch (DAA) in the local, screened population and compared the groups with and without these abnormalities. The 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 from fertilization (IVF) was eight-fold higher. The prevalence of 22q11microdeletion was 5% in patients with RAA from this local population. The 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.
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http://dx.doi.org/10.1080/14767058.2019.1676413DOI Listing
October 2019

Diagnosis of fetal non-chromosomal abnormalities on routine ultrasound examination at 11-13 weeks' gestation.

Ultrasound Obstet Gynecol 2019 Oct;54(4):468-476

Fetal Medicine Research Institute, King's College Hospital, London, UK.

Objective: To examine the performance of the routine 11-13-week scan in detecting fetal non-chromosomal abnormalities.

Methods: This was a retrospective study of prospectively collected data from 100 997 singleton pregnancies attending for a routine ultrasound examination of fetal anatomy, performed according to a standardized protocol, at 11-13 weeks' gestation. All continuing pregnancies had an additional scan at 18-24 weeks and 71 754 had a scan at either 30-34 or 35-37 weeks. The final diagnosis of fetal abnormality 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 abnormalities was determined.

Results: The study population contained 1720 (1.7%) pregnancies with a fetal abnormality, including 474 (27.6%) detected on the first-trimester scan, 926 (53.8%) detected on the second-trimester scan and 320 (18.6%) detected in the third trimester or postnatally. At 11-13 weeks' gestation, we diagnosed all cases of acrania, alobar holoprosencephaly, encephalocele, tricuspid or pulmonary atresia, pentalogy of Cantrell, ectopia cordis, exomphalos, gastroschisis and body-stalk anomaly and > 50% of cases of open spina bifida, hypoplastic left heart syndrome, atrioventricular septal defect, complex heart defect, left atrial isomerism (interrupted inferior vena cava with normal intracardiac anatomy), lower urinary tract obstruction, absence of extremities, fetal akinesia deformation sequence and lethal skeletal dysplasia. Common abnormalities that were detected in < 10% of cases at 11-13 weeks included ventriculomegaly, agenesis of the corpus callosum, isolated cleft lip, congenital pulmonary airway malformation, ventricular septal defect, abdominal cysts, unilateral renal agenesis or multicystic kidney, hydronephrosis, duplex kidney, hypospadias and talipes.

Conclusions: A routine 11-13-week scan, carried out according to a standardized protocol, can identify many severe non-chromosomal fetal abnormalities. A summary statistic of the performance of the first-trimester scan is futile because some abnormalities are always detectable, whereas others are either non-detectable or sometimes detectable. To maximize prenatal detection of abnormalities, additional scans in both the second and third trimesters are necessary. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
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http://dx.doi.org/10.1002/uog.20844DOI Listing
October 2019

Two-stage approach for prediction of small-for-gestational-age neonate and adverse perinatal outcome by routine ultrasound examination at 35-37 weeks' gestation.

Ultrasound Obstet Gynecol 2019 Oct 27;54(4):484-491. Epub 2019 Aug 27.

Fetal Medicine Research Institute, King's College Hospital, London, UK.

Background: Justification of prenatal screening for small-for-gestational-age (SGA) fetuses near term is based on, first, evidence that such fetuses/neonates are at increased risk of stillbirth and adverse perinatal outcome, and, second, the expectation that these risks can be reduced by medical interventions, such as early delivery. However, there are no randomized studies demonstrating that routine screening for SGA fetuses and appropriate interventions in the high-risk group can reduce adverse perinatal outcome. Before such meaningful studies can be undertaken, it is essential that the best approach for effective identification of SGA neonates is determined, and that the contribution of SGA neonates to the overall rate of adverse perinatal outcome is established. In a previous study of pregnancies undergoing routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation, we found that, first, screening by estimated fetal weight (EFW) < 10 percentile provided poor prediction of SGA neonates and, second, prediction of > 85% of SGA neonates requires use of EFW < 40 percentile.

Objectives: To examine the contribution of SGA fetuses to the overall rate of adverse perinatal outcome and, to propose a two-stage approach for prediction of a SGA neonate at routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation.

Methods: This was a prospective study of 45 847 singleton pregnancies undergoing routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation. First, we examined the relationship between birth-weight percentile and adverse perinatal outcome, defined as stillbirth, neonatal death or admission to the neonatal unit for ≥ 48 h. Second, we used a two-stage approach for prediction of a SGA neonate and adverse perinatal outcome; in the first stage, fetal biometry was used to distinguish between pregnancies at very low risk (EFW ≥ 40 percentile) and those at increased risk (EFW < 40 percentile) and, in the second stage, the pregnancies with EFW < 40 percentile were stratified into high-, intermediate- and low-risk groups based on the results of EFW and pulsatility index in the uterine arteries, umbilical artery and fetal middle cerebral artery. Different percentiles of EFW and Doppler indices were used to define each risk category, and the performance of screening for a SGA neonate and adverse perinatal outcome in pregnancies delivered at ≤ 2, 2.1-4 and > 4 weeks after assessment was determined. We propose that the high-risk group would require monitoring from initial assessment to delivery, the intermediate-risk group would require monitoring from 2 weeks after initial assessment to delivery, the low-risk group would require monitoring from 4 weeks after initial assessment to delivery, and the very low-risk group would not require any further reassessment.

Results: First, although in neonates with low birth weight (< 10 percentile) the risk of adverse perinatal outcome is increased, 84% of adverse perinatal events occur in the group with birth weight ≥ 10 percentile. Second, in screening by EFW < 10 percentile, the predictive performance for a SGA neonate is modest for those born at ≤ 2 weeks after assessment (83% and 69% for neonates with birth weight < 3 and < 10 percentiles, respectively), but poor for those born at 2.1-4 weeks (65% and 45%, respectively) and > 4 weeks (40% and 30%, respectively) after assessment. Third, improved performance of screening, especially for those delivered at > 2 weeks after assessment, is potentially achieved by a proposed new approach for stratifying pregnancies into management groups based on findings of EFW and Doppler indices (prediction of birth weight < 3 and < 10 percentiles for deliveries at ≤ 2, 2.1-4 and > 4 weeks after assessment: 89% and 75%, 83% and 74%, and 88% and 82%, respectively). Fourth, the predictive performance for adverse perinatal outcome of EFW < 10 percentile is very poor (26%, 9% and 5% for deliveries at ≤ 2, 2.1-4 and > 4 weeks after assessment, respectively) and this is improved by the proposed new approach (31%, 22% and 29%, respectively).

Conclusions: This study presents an approach for stratifying pregnancies undergoing routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation into four management groups based on findings of EFW and Doppler indices. This approach potentially has a higher predictive performance for a SGA neonate and adverse perinatal outcome than that of screening by EFW < 10 percentile. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
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http://dx.doi.org/10.1002/uog.20391DOI Listing
October 2019

Fetal intra-abdominal bowel dilation in prediction of complex gastroschisis.

Ultrasound Obstet Gynecol 2019 Sep 8;54(3):376-380. Epub 2019 Aug 8.

Fetal Medicine Research Institute, King's College Hospital, London, UK.

Objective: To investigate intra-abdominal bowel dilation (IABD) in the prediction of complex gastroschisis.

Methods: This was a retrospective study of 174 singleton pregnancies with isolated fetal gastroschisis, resulting in live birth and with available ultrasound images from visits at both 20-22 and 30-32 weeks' gestation. IABD was measured as the greatest transverse diameter of the most dilated intra-abdominal bowel segment, by an operator blinded to postnatal outcome. The distribution of IABD measurements in those with complex and those with simple gastroschisis was determined and the best cut-off value to predict complex gastroschisis was selected using receiver-operating characteristics (ROC) curves. The area under the ROC curve (AUC), detection rate (DR), false-positive rate (FPR), positive predictive value (PPV) and negative predictive value (NPV) were determined.

Results: The study population included 39 (22.4%) cases of complex and 135 (77.6%) cases of simple gastroschisis. In the prediction of complex gastroschisis, the AUC at 20-22 weeks' gestation was 0.742 (95% CI, 0.628-0.856) and the respective value for 30-32 weeks was 0.820 (95% CI, 0.729-0.910). At the IABD cut-off of 7 mm at 20-22 weeks, DR, FPR, PPV and NPV for complex gastroschisis were 61.5%, 6.7%, 72.7% and 89.4%, respectively, and at IABD cut-off of 14 mm at 30-32 weeks, the respective values were 64.9%, 5.9%, 75.0% and 90.7%.

Conclusion: Measurement of IABD at 20-22 or at 30-32 weeks' gestation is useful in the prediction of complex gastroschisis. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
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http://dx.doi.org/10.1002/uog.20367DOI Listing
September 2019

First trimester combined screening in patients with systemic lupus erythematosus: impact of pre-analytical variables on risk assessment.

Clin Rheumatol 2019 May 28;38(5):1251-1255. Epub 2019 Mar 28.

Harris Birthright Research Center of Fetal Medicine, King's College Hospital, London, UK.

Background: 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).

Objectives: 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.

Method: 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.

Results: 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).

Conclusion: In first trimester screening for trisomies, the measured value of free ß-hCG should be adjusted for maternal SLE to avoid false positive results and overuse of invasive tests.
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http://dx.doi.org/10.1007/s10067-019-04525-1DOI Listing
May 2019

Prediction of small-for-gestational-age neonates at 35-37 weeks' gestation: contribution of maternal factors and growth velocity between 32 and 36 weeks.

Ultrasound Obstet Gynecol 2019 May 8;53(5):630-637. Epub 2019 Apr 8.

Fetal Medicine Research Institute, King's College Hospital, London, UK.

Objective: To assess the additive value of fetal growth velocity between 32 and 36 weeks' gestation to the performance of ultrasonographic estimated fetal weight (EFW) at 35 + 0 to 36 + 6 weeks' gestation for prediction of delivery of a small-for-gestational-age (SGA) neonate and adverse perinatal outcome.

Methods: This was a prospective study of 14 497 singleton pregnancies undergoing routine ultrasound examination at 30 + 0 to 34 + 6 and at 35 + 0 to 36 + 6 weeks' gestation. Multivariable logistic regression analysis was used to determine whether addition of growth velocity, defined as the difference in EFW Z-score or abdominal circumference (AC) Z-score between the early and late third-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, first, delivery of a SGA neonate with birth weight < 10 and < 3 percentiles within 2 weeks and at any stage after assessment and, second, a composite of adverse perinatal outcome, defined as stillbirth, neonatal death or admission to the neonatal unit for ≥ 48 h.

Results: Multivariable logistic regression analysis demonstrated that significant contributors to the prediction of a SGA neonate were EFW Z-score at 35 + 0 to 36 + 6 weeks' gestation, fetal growth velocity, by either AC Z-score or EFW Z-score, and maternal risk factors. The area under the receiver-operating characteristics curve (AUC) and detection rate (DR), at a 10% screen-positive rate, for prediction of a SGA neonate < 10 percentile born within 2 weeks after assessment achieved by EFW Z-score at 35 + 0 to 36 + 6 weeks (AUC, 0.938 (95% CI, 0.928-0.947); DR, 80.7% (95% CI, 77.6-83.9%)) were not significantly improved by addition of EFW growth velocity and maternal risk factors (AUC, 0.941 (95% CI, 0.932-0.950); P = 0.061; DR, 82.5% (95% CI, 79.4-85.3%)). Similar results were obtained when growth velocity was defined by AC rather than EFW. Similarly, there was no significant improvement in the AUC and DR, at a 10% screen-positive rate, for prediction of a SGA neonate < 10 percentile born at any stage after assessment or a SGA neonate < 3 percentile born within 2 weeks or at any stage after assessment, achieved by EFW Z-score at 35 + 0 to 36 + 6 weeks by addition of maternal factors and either EFW growth velocity or AC growth velocity. Multivariable logistic regression analysis demonstrated that the only significant contributor to adverse perinatal outcome was maternal risk factors. Multivariable logistic regression analysis in the group with EFW < 10 percentile demonstrated that significant contribution to prediction of delivery of a neonate with birth weight < 10 and < 3 percentiles and adverse perinatal outcome was provided by EFW Z-score at 35 + 0 to 36 + 6 weeks, but not by AC growth velocity < 1 decile.

Conclusion: The predictive performance of EFW at 35 + 0 to 36 + 6 weeks' gestation for delivery of a SGA neonate and adverse perinatal outcome is not improved by addition of estimated growth velocity between 32 and 36 weeks' gestation. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
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http://dx.doi.org/10.1002/uog.20267DOI Listing
May 2019

Routine ultrasound at 32 vs 36 weeks' gestation: prediction of small-for-gestational-age neonates.

Ultrasound Obstet Gynecol 2019 Jun 30;53(6):761-768. Epub 2019 Apr 30.

Fetal Medicine Research Institute, King's College Hospital, London, UK.

Objective: To evaluate and compare the performance of routine ultrasonographic estimated fetal weight (EFW) and fetal abdominal circumference (AC) at 31 + 0 to 33 + 6 and 35 + 0 to 36 + 6 weeks' gestation in the prediction of a small-for-gestational-age (SGA) neonate.

Methods: This was a prospective study of 21 989 singleton pregnancies undergoing routine ultrasound examination at 31 + 0 to 33 + 6 weeks' gestation and 45 847 undergoing routine ultrasound examination at 35 + 0 to 36 + 6 weeks' gestation. In each case, the estimated fetal weight (EFW) from measurements of fetal head circumference, AC and femur length was calculated using the Hadlock formula and expressed as a percentile according to The Fetal Medicine Foundation fetal and neonatal population weight charts. The same charts were used for defining a SGA neonate with birth weight < 10 and < 3 percentiles. For each gestational-age window, the screen-positive and detection rates, at different EFW percentile cut-offs between the 10 and 50 percentiles, were calculated for prediction of delivery of a SGA neonate with birth weight < 10 and < 3 percentiles within 2 weeks and at any stage after assessment. The areas under the receiver-operating characteristics curves (AUC) in screening for a SGA neonate by EFW and AC at 31 + 0 to 33 + 6 and at 35 + 0 to 36 + 6 weeks' gestation were compared.

Results: First, the AUCs in screening by EFW for a SGA neonate with birth weight < 10 and < 3 percentiles delivered within 2 weeks and at any stage after screening at 35 + 0 to 36 + 6 weeks' gestation were significantly higher than those at 31 + 0 to 33 + 6 weeks (P < 0.001). Second, at both 35 + 0 to 36 + 6 and 31 + 0 to 33 + 6 weeks' gestation, the predictive performance for a SGA neonate with birth weight < 10 and < 3 percentiles born at any stage after screening was significantly higher using EFW Z-score than AC Z-score. Similarly, at 35 + 0 to 36 + 6 weeks, but not at 31 + 0 to 33 + 6 weeks, the predictive performance for a SGA neonate with birth weight < 10 and < 3 percentiles born within 2 weeks after screening was significantly higher using EFW Z-score than AC Z-score. Third, screening by EFW < 10 percentile at 35 + 0 to 36 + 6 weeks' gestation predicted 70% and 84% of neonates with birth weight < 10 and < 3 percentiles, respectively, born within 2 weeks after assessment, and the respective values for a neonate born at any stage after assessment were 46% and 65%. Fourth, prediction of > 85% of SGA neonates with birth weight < 10 percentile born at any stage after screening at 35 + 0 to 36 + 6 weeks' gestation requires use of EFW < 40 percentile. Screening at this percentile cut-off predicted 95% and 99% of neonates with birth weight < 10 and < 3 percentiles, respectively, born within 2 weeks after assessment, and the respective values for a neonate born at any stage after assessment were 87% and 94%.

Conclusions: The predictive performance for a SGA neonate of routine ultrasonographic examination during the third trimester is higher if, first, the scan is carried out at 35 + 0 to 36 + 6 weeks' gestation than at 31 + 0 to 33 + 6 weeks, second, the method of screening is EFW than fetal AC, third, the outcome measure is birth weight < 3 than < 10 percentile, and, fourth, if delivery occurs within 2 weeks than at any stage after assessment. Prediction of a SGA neonate by EFW < 10 percentile is modest and prediction of > 85% of cases at 35 + 0 to 36 + 6 weeks' gestation necessitates use of EFW < 40 percentile. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
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http://dx.doi.org/10.1002/uog.20258DOI Listing
June 2019

Routine assessment of cerebroplacental ratio at 35-37 weeks' gestation in the prediction of adverse perinatal outcome.

Am J Obstet Gynecol 2019 07 13;221(1):65.e1-65.e18. Epub 2019 Mar 13.

Fetal Medicine Research Institute, King's College Hospital, London, United Kingdom. Electronic address:

Background: Third-trimester studies in selected high-risk pregnancies have reported that low cerebroplacental ratio, due to high pulsatility index in the umbilical artery, and or decreased pulsatility index in the fetal middle cerebral artery, is associated with increased risk of adverse perinatal outcomes.

Objective: To investigate the predictive performance of screening for adverse perinatal outcome by the cerebroplacental ratio measured routinely at 35-37 weeks' gestation.

Study Design: This was a prospective observational study in 47,211 women with singleton pregnancies undergoing routine ultrasound examination at 35 to 37 weeks' gestation, including measurement of umbilical artery-pulsatility index and middle cerebral artery-pulsatility index. The measured umbilical artery-pulsatility index and middle cerebral artery-pulsatility index and their ratio were converted to multiples of the median after adjustment for gestational age. Multivariable logistic regression analysis was used to determine whether umbilical artery-pulsatility index, middle cerebral artery-pulsatility index, and cerebroplacental ratio improved the prediction of adverse perinatal outcome that was provided by maternal characteristics, medical history, and obstetric factors. The following outcome measures were considered: (1) adverse perinatal outcome consisting of stillbirth, neonatal death, or hypoxic-ischemic encephalopathy grades 2 and 3; (2) presence of surrogate markers of perinatal hypoxia consisting of umbilical arterial or venous cord blood pH ≤7 and ≤7.1, respectively, 5-minute Apgar score <7, or admission to the neonatal intensive care unit for >24 hours; (3) cesarean delivery for presumed fetal compromise in labor; and (4) neonatal birthweight less than the third percentile for gestational age.

Results: First, the incidence of adverse perinatal outcome, presence of surrogate markers of perinatal hypoxia, and cesarean delivery for presumed fetal compromise in labor was greater in pregnancies with small for gestational age neonates with birthweight <10th percentile compared with appropriate for gestational age neonates; however, 80%-85% of these adverse events occurred in the appropriate for gestational age group. Second, low cerebroplacental ratio <10th percentile was associated with increased risk of adverse perinatal outcome, presence of surrogate markers of perinatal hypoxia, cesarean delivery for presumed fetal compromise in labor, and birth of neonates with birthweight less than third percentile. However, multivariable regression analysis demonstrated that the prediction of these adverse outcomes by maternal demographic characteristics and medical history was only marginally improved by the addition of cerebroplacental ratio. Third, the performance of low cerebroplacental ratio in the prediction of each adverse outcome was poor, with detection rates of 13%-26% and a false-positive rate of about 10%. Fourth, the detection rates of adverse outcomes were greater in small for gestational age than in appropriate for gestational age babies and in pregnancies delivering within 2 weeks rather than at any stage after assessment; however, such increase in detection rates was accompanied by an increase in the false-positive rate. Fifth, in appropriate for gestational age neonates, the predictive accuracy of cerebroplacental ratio was low, with positive and negative likelihood ratios ranging from 1.21 to 1.82, and 0.92 to 0.98, respectively; although the accuracy was better in small for gestational age neonates, this was also low with positive likelihood ratios of 1.31-2.26 and negative likelihood ratios of 0.69-0.92. Similar values were obtained in fetuses classified as small for gestational age and appropriate for gestational age according to the estimated fetal weight.

Conclusions: In pregnancies undergoing routine antenatal assessment at 35-37 weeks' gestation, measurement of cerebroplacental ratio provides poor prediction of adverse perinatal outcome in both small for gestational age and appropriate for gestational age fetuses.
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http://dx.doi.org/10.1016/j.ajog.2019.03.002DOI Listing
July 2019

Prediction of small-for-gestational-age neonates at 35-37 weeks' gestation: contribution of maternal factors and growth velocity between 20 and 36 weeks.

Ultrasound Obstet Gynecol 2019 Apr;53(4):488-495

Fetal Medicine Research Institute, King's College Hospital, London, UK.

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 < 10 and < 3 percentiles within 2 weeks and at any stage after assessment.

Results: Screening by EFW Z-score at 35 + 0 to 36 + 6 weeks' gestation predicted 63.4% (95% CI, 62.0-64.7%) of neonates with birth weight < 10 percentile and 74.2% (95% CI, 72.2-76.1%) of neonates with birth weight < 3 percentile born at any stage after assessment, at a screen-positive rate of 10%. The respective values for SGA neonates born within 2 weeks after assessment were 76.8% (95% CI, 74.4-79.0%) and 81.3% (95% CI, 78.2-84.0%). For a desired 90% detection rate of SGA neonate delivered at any stage after assessment, the necessary screen-positive rate would be 33.7% for SGA < 10 percentile and 24.4% for SGA < 3 percentile. Multivariable logistic regression analysis demonstrated that, in the prediction of a SGA neonate with birth weight < 10 and < 3 percentiles, there was a significant contribution from EFW Z-score at 35 + 0 to 36 + 6 weeks' gestation, maternal risk factors and AC growth velocity, but not EFW growth velocity. However, the area under the receiver-operating characteristics curve for prediction of delivery of a SGA neonate by screening with maternal risk factors and EFW Z-score was not improved by addition of AC growth velocity.

Conclusion: Screening for SGA neonates by EFW at 35 + 0 to 36 + 6 weeks' gestation and use of the 10 percentile as the cut-off predicts 63% of affected neonates. Prediction of 90% of SGA neonates necessitates classification of about 35% of the population as being screen positive. The predictive performance of EFW is not improved by addition of estimated growth velocity between the second and third trimesters of pregnancy. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.
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http://dx.doi.org/10.1002/uog.20243DOI Listing
April 2019

Prediction of imminent preeclampsia at 35-37 weeks gestation.

Am J Obstet Gynecol 2019 06 7;220(6):584.e1-584.e11. Epub 2019 Feb 7.

Harris Birthright Research Centre for Fetal Medicine, King's College, London, UK. Electronic address:

Background: In the weeks preceding the clinical onset of preeclampsia, the maternal serum level of the angiogenic placental growth factor is decreased and that of the antiangiogenic factor soluble fms-like tyrosine kinase-1 is increased. Women presenting at specialist clinics with signs or symptoms of hypertensive disorders have been stratified according to concentrations of placental growth factor or the ratio of concentrations of soluble fms-like tyrosine kinase-1 and placental growth factor to determine clinical management for the subsequent 1-4 weeks. An alternative approach for the prediction of preeclampsia is use of the competing risks model, a Bayes' theorem based method, to derive patient-specific risk for preeclampsia by various combinations of maternal characteristics and medical history with multiples of the median values of biomarkers.

Objective: The purpose of this study was to compare the performance of screening for delivery with preeclampsia at ≤2 and ≤4 weeks after assessment at 35-36 weeks gestation between the use of percentile cut-offs in placental growth factor alone or the soluble fms-like tyrosine kinase-1/placental growth factor ratio and the competing risks model.

Study Design: This was a prospective observational study in women who attended a routine hospital visit at 35-36 weeks gestation in 2 maternity hospitals in England. The visits included the recording of maternal demographic characteristics and medical history and the measurement of serum placental growth factor and soluble fms-like tyrosine kinase-1 and mean arterial pressure. The areas under the receiver operating characteristics curves were used to compare the predictive performance for preeclampsia with delivery at ≤2 and ≤4 weeks from assessment of screening by placental growth factor alone and the soluble fms-like tyrosine kinase-1/placental growth factor ratio with that of a previously developed competing risks model with a combination of maternal factors, placental growth factor, soluble fms-like tyrosine kinase-1, and mean arterial pressure (triple test).

Results: First, the study population of 15,247 pregnancies included 326 pregnancies (2.1%) that subsequently experienced preeclampsia. Second, in the screening for delivery with preeclampsia at ≤2 and ≤4 weeks from assessment, the performance of the triple test was superior to that of placental growth factor alone or the soluble fms-like tyrosine kinase-1/placental growth factor ratio. The area under the receiver operating characteristics curves for preeclampsia at ≤2 weeks in screening by the triple test (0.975; 95% confidence interval, 0.964-0.985) was higher than that of placental growth factor alone (0.900; 95% confidence interval, 0.866-0.935; P<.0001) and the soluble fms-like tyrosine kinase-1/placental growth factor ratio (0.932; 95% confidence interval, 0.904-0.960; P=.0001). Similarly, the areas under the receiver operating characteristics curves for preeclampsia at ≤4 weeks in screening by the triple test (0.907; 95% confidence interval, 0.886-0.928) was higher than that of placental growth factor alone (0.827; 95% confidence interval, 0.800-0.854; P<.0001) or the soluble fms-like tyrosine kinase-1/placental growth factor ratio (0.857; 95% confidence interval, 0.830-0.883; P<.0001). Third, at most, screen-positive rates of 2-30% the detection rate of delivery with preeclampsia at ≤2 and ≤4 weeks that was achieved by the triple test was approximately 10% higher than that of the soluble fms-like tyrosine kinase-1/placental growth factor ratio and 20% higher than that of placental growth factor alone; the negative predictive value was similar for the 3 tests.

Conclusion: At 35-36 weeks gestation, the performance of screening for imminent delivery with preeclampsia by the competing risks model is superior to that of placental growth factor alone or the soluble fms-like tyrosine kinase-1/placental growth factor ratio.
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http://dx.doi.org/10.1016/j.ajog.2019.01.235DOI Listing
June 2019

Prediction of small for gestational age neonates: screening by maternal factors, fetal biometry, and biomarkers at 35-37 weeks' gestation.

Am J Obstet Gynecol 2019 05 29;220(5):486.e1-486.e11. Epub 2019 Jan 29.

Fetal Medicine Research Institute, King's College Hospital, London, UK. Electronic address:

Background: Small for gestational age (SGA) neonates are at increased risk for perinatal mortality and morbidity; however, the risks can be substantially reduced if the condition is identified prenatally, because in such cases close monitoring and appropriate timing of delivery and prompt neonatal care can be undertaken. The traditional approach of identifying pregnancies with SGA fetuses is maternal abdominal palpation and serial measurements of symphysial-fundal height, but the detection rate of this approach is less than 30%. A higher performance of screening for SGA is achieved by sonographic fetal biometry during the third trimester; screening at 30-34 weeks' gestation identifies about 80% of SGA neonates delivering preterm but only 50% of those delivering at term, at a screen-positive rate of 10%. There is some evidence that routine ultrasound examination at 36 weeks' gestation is more effective than that at 32 weeks in predicting birth of SGA neonates.

Objective: To investigate the potential value of maternal characteristics and medical history, sonographically estimated fetal weight (EFW) and biomarkers of impaired placentation at 35- 36 weeks' gestation in the prediction of delivery of SGA neonates.

Materials And Methods: A dataset of 19,209 singleton pregnancies undergoing screening at 35-36 weeks' gestation was divided into a training set and a validation set. The training dataset was used to develop models from multivariable logistic regression analysis to determine whether the addition of uterine artery pulsatility index (UtA-PI), umbilical artery PI (UA-PI), fetal middle cerebral artery PI (MCA-PI), maternal serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFLT) would improve the performance of maternal factors and EFW in the prediction of delivery of SGA neonates. The models were then tested in the validation dataset to assess performance of screening.

Results: First, in the training dataset, in the SGA group, compared to those with birthweight in ≥10th percentile, the median multiple of the median (MoM) values of PlGF and MCA-PI were reduced, whereas UtA-PI, UA-PI, and sFLT were increased. Second, multivariable regression analysis demonstrated that in the prediction of SGA in <10th percentile there were significant contributions from maternal factors, EFW Z-score, UtA-PI MoM, MCA-PI MoM, and PlGF MoM. Third, in the validation dataset, prediction of 90% of SGA neonates delivering within 2 weeks of assessment was achieved by a screen-positive rate of 67% (95% confidence interval [CI], 64-70%) in screening by maternal factors, 23% (95% CI, 20-26%) by maternal factors, and EFW and 21% (95% CI, 19-24%) by the addition of biomarkers. Fourth, prediction of 90% of SGA neonates delivering at any stage after assessment was achieved by a screen-positive rate of 66% (95% CI, 65-67%) in screening by maternal factors, 32% (95% CI, 31-33%) by maternal factors and EFW and 30% (95% CI, 29-31%) by the addition of biomarkers.

Conclusion: The addition of biomarkers of impaired placentation only marginally improves the predictive performance for delivery of SGA neonates achieved by maternal factors and fetal biometry at 35-36 weeks' gestation.
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http://dx.doi.org/10.1016/j.ajog.2019.01.227DOI Listing
May 2019

Predictive performance of the competing risk model in screening for preeclampsia.

Am J Obstet Gynecol 2019 02 14;220(2):199.e1-199.e13. Epub 2018 Nov 14.

Harris Birthright Research Centre for Fetal Medicine, King's College, London, United Kingdom. Electronic address:

Background: The established method of screening for preeclampsia is to identify risk factors from maternal demographic characteristics and medical history; in the presence of such factors the patient is classified as high risk and in their absence as low risk. However, the performance of such an approach is poor. We developed a competing risks model, which allows combination of maternal factors (age, weight, height, race, parity, personal and family history of preeclampsia, chronic hypertension, diabetes mellitus, systemic lupus erythematosus or antiphospholipid syndrome, method of conception and interpregnancy interval), with biomarkers to estimate the individual patient-specific risks of preeclampsia requiring delivery before any specified gestation. The performance of this approach is by far superior to that of the risk scoring systems.

Objective: The objective of the study was to examine the predictive performance of the competing risks model in screening for preeclampsia by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor, referred to as the triple test, in a training data set for the development of the model and 2 validation studies.

Study Design: The data for this study were derived from 3 previously reported prospective, nonintervention, multicenter screening studies for preeclampsia in singleton pregnancies at 11 to 13 weeks' gestation. In all 3 studies, there was recording of maternal factors and biomarkers and ascertainment of outcome by appropriately trained personnel. The first study of 35,948 women, which was carried out between February 2010 and July 2014, was used to develop the competing risks model for prediction of preeclampsia and is therefore considered to be the training set. The 2 validation studies were comprised of 8775 and 16,451 women, respectively, and they were carried out between February and September 2015 and between April and December 2016, respectively. Patient-specific risks of delivery with preeclampsia at <34, <37, and <41 weeks' gestation were calculated using the competing risks model and the performance of screening for preeclampsia by maternal factors alone and the triple test in each of the 3 data sets was assessed. We examined the predictive performance of the model by first, the ability of the model to discriminate between the preeclampsia and no-preeclampsia groups using the area under the receiver operating characteristic curve and the detection rate at fixed screen-positive rate of 10%, and second, calibration by measurements of calibration slope and calibration in the large.

Results: The detection rate at the screen-positive rate of 10% of early-preeclampsia, preterm-preeclampsia, and all-preeclampsia was about 90%, 75%, and 50%, respectively, and the results were consistent between the training and 2 validation data sets. The area under the receiver operating characteristic curve was >0.95, >0.90, and >0.80, respectively, demonstrating a very high discrimination between affected and unaffected pregnancies. Similarly, the calibration slopes were very close to 1.0, demonstrating a good agreement between the predicted risks and observed incidence of preeclampsia. In the prediction of early-preeclampsia and preterm-preeclampsia, the observed incidence in the training set and 1 of the validation data sets was consistent with the predicted one. In the other validation data set, which was specifically designed for evaluation of the model, the incidence was higher than predicted, presumably because of better ascertainment of outcome. The incidence of all-preeclampsia was lower than predicted in all 3 data sets because at term many pregnancies deliver for reasons other than preeclampsia, and therefore, pregnancies considered to be at high risk for preeclampsia that deliver for other reasons before they develop preeclampsia can be wrongly considered to be false positives.

Conclusion: The competing risks model provides an effective and reproducible method for first-trimester prediction of early preeclampsia and preterm preeclampsia as long as the various components of screening are carried out by appropriately trained and audited practitioners. Early prediction of preterm preeclampsia is beneficial because treatment of the high-risk group with aspirin is highly effective in the prevention of the disease.
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http://dx.doi.org/10.1016/j.ajog.2018.11.1087DOI Listing
February 2019

Two-stage screening for preterm preeclampsia at 11-13 weeks' gestation.

Am J Obstet Gynecol 2019 02 7;220(2):197.e1-197.e11. Epub 2018 Nov 7.

Harris Birthright Research Centre for Fetal Medicine, King's College, London, United Kingdom. Electronic address:

Background: Screening for preeclampsia at 11-13 weeks' gestation by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, and serum placental growth factor (triple test) can predict about 90% of preeclampsia, with delivery at <32 weeks (early-preeclampsia), and 75% of preeclampsia with delivery at <37 weeks (preterm preeclampsia), at a screen-positive rate of 10%. In pregnancies identified as being at high risk for preeclampsia by such screening, administration of aspirin (150 mg/d from 11 to 14 weeks' gestation to 36 weeks) reduces the rate of early preeclampsia by about 90% and preterm preeclampsia by about 60%. Recording of maternal history and blood pressure are part of routine prenatal care, but measurement of uterine artery pulsatility index and placental growth factor require additional costs.

Objective: To explore the possibility of carrying out first-stage screening in the whole population by maternal factors alone or a combination of maternal factors, mean arterial pressure and uterine artery pulsatility index or maternal factors, mean arterial pressure, and placental growth factor and proceeding to second-stage screening by the triple test only for a subgroup of the population selected on the basis of the risk derived from first-stage screening.

Study Design: The data for this study were derived from prospective nonintervention screening for preeclampsia at 11 to 13 weeks' gestation in 61,174 singleton pregnancies. Patient-specific risks of delivery with preeclampsia at <37 and <32 weeks' gestation were calculated using the competing risks model to combine the prior distribution of the gestational age at delivery with preeclampsia, obtained from maternal characteristics and medical history, with various combinations of multiple of the median values of mean arterial pressure, uterine artery pulsatility index, and placental growth factor. We estimated the detection rate of preterm-preeclampsia and early-preeclampsia at overall screen-positive rate of 10%, 15%, and 20% from a policy in which first-stage screening of the whole population is carried out by some of the components of the triple test and second-stage screening by the full triple test on women selected on the basis of results from first-stage screening.

Results: If the method of first-stage screening is maternal factors, then measurements of mean arterial pressure, uterine artery pulsatility index, and placental growth factor can be reserved for only 70% of the population, achieving similar detection rate and screen-positive rate as with screening the whole population with the triple test. In the case of first-stage screening by maternal factors, mean arterial pressure, and uterine artery pulsatility index, then measurement of placental growth factor can be reserved for only 30-40% of the population, and if first-stage screening is by maternal factors, mean arterial pressure, and placental growth factor, measurement of uterine artery pulsatility index can be reserved for only 20-30% of the population. Empirical results were consistent with model-based performance.

Conclusion: Two-stage screening and biomarker testing for only part of the population will have financial benefits over conducting the test for the entire population.
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http://dx.doi.org/10.1016/j.ajog.2018.10.092DOI Listing
February 2019

Fetal Medicine Foundation reference ranges for umbilical artery and middle cerebral artery pulsatility index and cerebroplacental ratio.

Ultrasound Obstet Gynecol 2019 Apr 13;53(4):465-472. Epub 2019 Feb 13.

Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, UK.

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.
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http://dx.doi.org/10.1002/uog.20157DOI Listing
April 2019

Impaired placental perfusion and major fetal cardiac defects.

Ultrasound Obstet Gynecol 2019 Jan 29;53(1):68-72. Epub 2018 Nov 29.

Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, UK.

Objective: 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).

Methods: 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.

Results: 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.

Conclusions: 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 Wiley & Sons Ltd.
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http://dx.doi.org/10.1002/uog.20149DOI Listing
January 2019

Reference Ranges for the Size of the Fetal Cardiac Outflow Tracts From 13 to 36 Weeks Gestation: A Single-Center Study of Over 7000 Cases.

Circ Cardiovasc Imaging 2018 07;11(7):e007575

Harris Birthright Centre for Fetal Medicine, Fetal Medicine Research Institute, King's College Hospital NHS Foundation Trust, London, United Kingdom (T.V.V., R.A., A.S., M.C., L.D.A., K.H.N., V.Z., J.M.S.).

Background: Assessment of the outflow tract views is an integral part of routine fetal cardiac scanning. For some congenital heart defects, notably coarctation of the aorta, pulmonary valve stenosis, and aortic valve stenosis, the size of vessels is important both for diagnosis and prognosis. Existing reference ranges of fetal outflow tracts are derived from a small number of cases.

Methods And Results: The study population comprised 7945 fetuses at 13 to 36 weeks' gestation with no detectable abnormalities from pregnancies resulting in normal live births. Prospective measurements were taken of (1) the aortic and pulmonary valves in diastole at the largest diameter with the valve closed, (2) the distal transverse aortic arch on the 3 vessel and trachea view beyond the trachea at the distal point at its widest systolic diameter, and (3) the arterial duct on the 3 vessel and trachea view at its widest systolic diameter. Regression analysis, with polynomial terms to assess for linear and nonlinear contributors, was used to establish the relationship between each measurement and gestational age. The measurement for each cardiac diameter was expressed as a z score (difference between observed and expected value divided by the fitted SD corrected for gestational age) and percentile. Analysis included calculation of gestation-specific SDs. Regression equations are provided for the cardiac outflow tracts and for the distal transverse aortic arch:arterial duct ratio.

Conclusions: The study established reference ranges for fetal outflow tract measurements at 13 to 36 weeks' gestation that are useful in clinical practice.
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http://dx.doi.org/10.1161/CIRCIMAGING.118.007575DOI Listing
July 2018

Management of pregnancies after combined screening for pre-eclampsia at 19-24 weeks' gestation.

Ultrasound Obstet Gynecol 2018 Sep 25;52(3):365-372. Epub 2018 Jun 25.

Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, UK.

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

Methods: This was a prospective observational study of women attending for an ultrasound scan at 19-24 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE at < 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.

Results: 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.

Conclusion: 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 Wiley & Sons Ltd.
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http://dx.doi.org/10.1002/uog.19099DOI Listing
September 2018

Screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation.

Ultrasound Obstet Gynecol 2018 08 11;52(2):186-195. Epub 2018 Jul 11.

King's College Hospital, London, UK.

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 < 37 weeks' gestation. The performance of such screening was estimated.

Results: In pregnancies that developed PE, compared to those without PE, the MoM values of UtA-PI and MAP were increased and those of PAPP-A and PlGF were decreased, and the deviation from normal was greater for early than late PE for all four biomarkers. Combined screening by maternal factors, UtA-PI, MAP and PlGF predicted 90% of early PE, 75% of preterm PE and 41% of term PE, at a screen-positive rate of 10%; inclusion of PAPP-A did not improve the performance of screening. The performance of screening depended on the racial origin of the women; on screening by a combination of maternal factors, MAP, UtA-PI and PlGF and using a risk cut-off of 1 in 100 for PE at < 37 weeks in Caucasian women, the screen-positive rate was 10% and detection rates for early, preterm and term PE were 88%, 69% and 40%, respectively. With the same method of screening and risk cut-off in women of Afro-Caribbean racial origin, the screen-positive rate was 34% and detection rates for early, preterm and term PE were 100%, 92% and 75%, respectively.

Conclusion: Screening by maternal factors and biomarkers at 11-13 weeks' gestation can identify a high proportion of pregnancies that develop early and preterm PE. © 2018 Crown copyright. Ultrasound in Obstetrics & Gynecology © 2018 ISUOG.
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http://dx.doi.org/10.1002/uog.19112DOI Listing
August 2018

Screening for pre-eclampsia at 35-37 weeks' gestation.

Ultrasound Obstet Gynecol 2018 Oct 27;52(4):501-506. Epub 2018 Aug 27.

Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, UK.

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.
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http://dx.doi.org/10.1002/uog.19111DOI Listing
October 2018

Diet and exercise for preeclampsia prevention in overweight and obese pregnant women: systematic review and meta-analysis.

J Matern Fetal Neonatal Med 2019 Oct 6;32(20):3495-3501. Epub 2018 Sep 6.

a Harris Birthright Research Centre for Fetal Medicine , Fetal Medicine Research Institute, King's College Hospital , London , UK.

To investigate the effect of diet and/or exercise in overweight or obese pregnant women on the risk of preeclampsia (PE). We performed a systematic review and meta-analysis of randomized controlled trials examining the effect of diet and/or exercise interventions in overweight and obese pregnant women on the risk of PE and hypertensive disorders. We completed a literature search through PubMed, Embase, Cinahl, Web of science, Cochrane CENTRAL Library from their earliest entries to November 2017 and from references of other systematic reviews. No language restrictions were applied. Relative risks (RR) with random effect were calculated with their 95% confidence intervals (CI). There were 23 eligible trials (7236 participants), including 11 (5023 participants) investigating the effect of diet and three (387 participants) investigating the effect of exercise on risk of PE, 14 (4345 participants) investigating the effect of diet, five (884 participants) investigating the effect of exercise and one (304 participants) investigating the effect of diet and exercise on risk of hypertensive disorders. Most studies were considered to be at low risk of bias for random sequence allocation and incomplete outcome data but at high risk of bias for blinding of participant and personnel. The heterogeneity of the studies on PE was low ( = 0-11%), but the heterogeneity of the studies on hypertensive disorders was variable ( = 0-53%). In women randomized to diet and/or exercise, compared to expectant management, there was no significant difference in the risk of PE (RR 1.01, 95% CI 0.80-1.27;  = .96) or hypertensive disorders of pregnancy (RR 0.87, 95% CI 0.70-1.06;  = .17). In the intervention group, compared to expectant management, gestational weight gain was significantly lower (-1.47 kg, 95% CI -1.97 to -0.97;  < .00001). Metaregression weighted by the size of the studies showed no significant association between gestational weight gain and the risk of PE or hypertensive disorders ( = .314 and  = .124, respectively). Diet and exercise in overweight or obese pregnant women are beneficial in reducing gestational weight gain. However, these interventions do not reduce the risk of PE or hypertensive disorders of pregnancy.
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http://dx.doi.org/10.1080/14767058.2018.1481037DOI Listing
October 2019

First-trimester metabolomic prediction of stillbirth.

J Matern Fetal Neonatal Med 2019 Oct 30;32(20):3435-3441. Epub 2018 Apr 30.

b Department of Obstetrics and Gynecology , King's College Hospital , London , England.

Stillbirth remains a major problem in both developing and developed countries. Omics evaluation of stillbirth has been highlighted as a top research priority. To identify new putative first-trimester biomarkers in maternal serum for stillbirth prediction using metabolomics-based approach. Targeted, nuclear magnetic resonance (NMR) and mass spectrometry (MS), and untargeted liquid chromatography-MS (LC-MS) metabolomic analyses were performed on first-trimester maternal serum obtained from 60 cases that subsequently had a stillbirth and 120 matched controls. Metabolites by themselves or in combination with clinical factors were used to develop logistic regression models for stillbirth prediction. Prediction of stillbirths overall, early (<28 weeks and <32 weeks), those related to growth restriction/placental disorder, and unexplained stillbirths were evaluated. Targeted metabolites including glycine, acetic acid, L-carnitine, creatine, lysoPCaC18:1, PCaeC34:3, and PCaeC44:4 predicted stillbirth overall with an area under the curve [AUC, 95% confidence interval (CI)] = 0.707 (0.628-0.785). When combined with clinical predictors the AUC value increased to 0.740 (0.667-0.812). First-trimester targeted metabolites also significantly predicted early, unexplained, and placental-related stillbirths. Untargeted LC-MS features combined with other clinical predictors achieved an AUC (95%CI) = 0.860 (0.793-0.927) for the prediction of stillbirths overall. We found novel preliminary evidence that, verruculotoxin, a toxin produced by common household molds, might be linked to stillbirth. We have identified novel biomarkers for stillbirth using metabolomics and demonstrated the feasibility of first-trimester prediction.
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http://dx.doi.org/10.1080/14767058.2018.1465552DOI Listing
October 2019

Prediction and prevention of small-for-gestational-age neonates: evidence from SPREE and ASPRE.

Ultrasound Obstet Gynecol 2018 07 5;52(1):52-59. Epub 2018 Jun 5.

Kings College Hospital, London, UK.

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 < 10 , < 5 and < 3 percentile for gestational age. We also used the data from SPREE to estimate the proportion of SGA in the pregnancies with a risk for preterm PE of > 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 < 10 percentile born at < 37 weeks' gestation (preterm) and 56% of those born at < 32 weeks (early); the overall screen-positive rate was 12.2% (2014 of 16 451 pregnancies). In the ASPRE trial, use of aspirin reduced the overall incidence of SGA < 10 percentile by about 40% in babies born at < 37 weeks' gestation and by about 70% in babies born at < 32 weeks; in babies born at ≥ 37 weeks, aspirin did not have a significant effect on incidence of SGA. The aspirin-related decrease in incidence of SGA was mainly due to its incidence decreasing in pregnancies with PE, for which the decrease was about 70% in babies born at < 37 weeks' gestation and about 90% in babies born at < 32 weeks. On the basis of these results, it was estimated that first-trimester screening for preterm PE and use of aspirin in the high-risk group would potentially reduce the incidence of preterm and early SGA by about 20% and 40%, respectively.

Conclusion: First-trimester screening for PE by the combined test identifies a high proportion of cases of preterm SGA that can be prevented by the prophylactic use of aspirin. © 2018 Crown copyright. Ultrasound in Obstetrics & Gynecology © 2018 ISUOG.
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http://dx.doi.org/10.1002/uog.19077DOI Listing
July 2018

Fetal Medicine Foundation fetal and neonatal population weight charts.

Ultrasound Obstet Gynecol 2018 07 30;52(1):44-51. Epub 2018 May 30.

Medway Maritime Hospital, Gillingham, UK.

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 < 3 , < 5 , < 10 , > 90 , > 95 and > 97 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 3 , 5 and 10 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.
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http://dx.doi.org/10.1002/uog.19073DOI Listing
July 2018

Ultrasonographic estimation of fetal weight: development of new model and assessment of performance of previous models.

Ultrasound Obstet Gynecol 2018 07 3;52(1):35-43. Epub 2018 Jun 3.

Department of Fetal Medicine, King's College Hospital, London, UK.

Objectives: To develop a new formula for ultrasonographic estimation of fetal weight and evaluate the accuracy of this and all previous formulae in the prediction of birth weight.

Methods: The study population consisted of 5163 singleton pregnancies with fetal biometry at 22-43 weeks' gestation and live birth of a phenotypically normal neonate within 2 days of the ultrasound examination. Multivariable fractional polynomial analysis was used to determine the combination of variables that provided the best-fitting models for estimated fetal weight (EFW). A systematic review was also carried out of articles reporting formulae for EFW and comparing EFW to actual birth weight. The accuracy of each model for EFW was assessed by comparing mean percentage error, absolute mean error (AE), proportion of pregnancies with AE ≤ 10% and Euclidean distance.

Results: The most accurate models, with the lowest Euclidean distance and highest proportion of AE ≤ 10%, were provided by the formulae incorporating ≥ 3 rather than < 3 biometrical measurements. The systematic review identified 45 studies describing a total of 70 models for EFW by various combinations of measurements of fetal head circumference (HC), biparietal diameter, femur length (FL) and abdominal circumference (AC). The most accurate model with the lowest Euclidean distance and highest proportion of AE ≤ 10% was provided by the formula of Hadlock et al., published in 1985, which incorporated measurements of HC, AC and FL; there was a highly significant linear association between EFW and birth weight (r = 0.959; P < 0.0001), and EFW was within 10% of birth weight in 80% of cases. The performance of the best model developed in this study, utilizing HC, AC and FL, was very similar to that of Hadlock et al. CONCLUSION: Despite many efforts to develop new models for EFW, the one reported in 1985 by Hadlock et al., from measurements of HC, AC and FL, provides the most accurate prediction of birth weight and can be used for assessment of all babies, including those suspected to be either small or large. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.
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http://dx.doi.org/10.1002/uog.19066DOI Listing
July 2018

Imaging single DNA molecules for high precision NIPT.

Sci Rep 2018 03 14;8(1):4549. Epub 2018 Mar 14.

Vanadis Diagnostics, a PerkinElmer company, Stockholms Lan, Sweden.

Cell-free DNA analysis is becoming adopted for first line aneuploidy screening, however for most healthcare programs, cost and workflow complexity is limiting adoption of the test. We report a novel cost effective method, the Vanadis NIPT assay, designed for high precision digitally-enabled measurement of chromosomal aneuploidies in maternal plasma. Reducing NIPT assay complexity is achieved by using novel molecular probe technology that specifically label target chromosomes combined with a new readout format using a nanofilter to enrich single molecules for imaging and counting without DNA amplification, microarrays or sequencing. The primary objective of this study was to assess the Vanadis NIPT assay with respect to analytical precision and clinical feasibility. Analysis of reference DNA samples indicate that samples which are challenging to analyze with low fetal-fraction can be readily detected with a limit of detection determined at <2% fetal-fraction. In total of 286 clinical samples were analysed and 30 out of 30 pregnancies affected by trisomy 21 were classified correctly. This method has the potential to make cost effective NIPT more widely available with more women benefiting from superior detection and false positive rates.
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http://dx.doi.org/10.1038/s41598-018-22606-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852104PMC
March 2018

Comparison of diagnostic accuracy of early screening for pre-eclampsia by NICE guidelines and a method combining maternal factors and biomarkers: results of SPREE.

Ultrasound Obstet Gynecol 2018 Jun 14;51(6):743-750. Epub 2018 Mar 14.

King's College Hospital, London, UK.

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.
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http://dx.doi.org/10.1002/uog.19039DOI Listing
June 2018

A retrospective multicenter study of the natural history of fetal ovarian cysts.

J Pediatr Surg 2018 Oct 12;53(10):2019-2022. Epub 2018 Feb 12.

Stem Cells and Regenerative Medicine, DBC, UCL Institute of Child Health and Great Ormond Street Hospital London, UK. Electronic address:

Aim: We investigated the natural history of fetal ovarian cysts to estimate the risk of torsion according to size.

Methods: Cases were identified from 1/1/2000 until 1/1/2015. Data were collected pre- and postnatally on cyst size and sonographic features until an outcome of surgery, torsion, or resolution. Fisher's exact test for categorical data and logistic regression for continuous data were used to test the significance of size on torsion; P value <0.05 was considered significant.

Results: 37 patients with unilateral ovarian cysts were included. 12 (32%) resolved spontaneously prenatally, 14 (38%) resolved spontaneously postnatally, 5 (14%) underwent surgery postnatally and 6 (16%) cases underwent torsion. Rate of torsion increased with size from 0% (n=0) in cysts ≤20mm to 33% (n=2) in cysts >50mm; however, the overall trend failed to reach statistical significance (P=0.1). Cysts of 0-40mm had a significantly higher rate of spontaneous resolution (90% vs. 44% in >40mm, P=0.003), but the rate of torsion was not significantly different (10% in 0-40mm vs. 25% in >40mm, P=0.26). The median time to postnatal resolution was 10 (5-27) weeks in those treated conservatively.

Conclusion: Cysts >40mm are significantly less likely to resolve spontaneously; however torsion showed no significant correlation with cyst size. No complications were observed in cysts <20mm.

Level Of Evidence: IV, case series with no comparison group.
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http://dx.doi.org/10.1016/j.jpedsurg.2018.02.049DOI Listing
October 2018

Aspirin for Evidence-Based Preeclampsia Prevention trial: effect of aspirin on length of stay in the neonatal intensive care unit.

Am J Obstet Gynecol 2018 06 2;218(6):612.e1-612.e6. Epub 2018 Mar 2.

King's College Hospital, London, United Kingdom. Electronic address:

Background: Preeclampsia is a major pregnancy complication with adverse short- and long-term implications for both the mother and baby. Screening for preeclampsia at 11-13 weeks' gestation by a combination of maternal demographic characteristics and medical history with measurements of biomarkers can identify about 75% of women who develop preterm preeclampsia with delivery at <37 weeks' gestation and 90% of those with early preeclampsia at <32 weeks, at a screen-positive rate of 10%. A recent trial (Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention) has reported that in women identified by first-trimester screening as being at high risk for preeclampsia, use of aspirin (150 mg/d from the first to the third trimester), compared to placebo, reduced the incidence of preterm preeclampsia, which was the primary outcome, by 62% (95% confidence interval, 26-80%) and the incidence of early preeclampsia by 89% (95% confidence interval, 53-97%). The surprising finding of the trial was that despite the reduction in preeclampsia the incidence of admission to the neonatal intensive care unit, which was one of the secondary outcomes, was not significantly affected (odds ratio, 0.93; 95% confidence interval, 0.62-1.40).

Objective: We sought to examine the effect of prophylactic use of aspirin during pregnancy in women at high risk of preeclampsia on length of stay in the neonatal intensive care unit.

Study Design: This was a secondary analysis of data from the Aspirin for Evidence-Based Preeclampsia Prevention trial to assess evidence of differences in the effect of aspirin on length of stay in neonatal intensive care. Bootstrapping was used for the comparison of mean length of stay between the aspirin and placebo groups. Logistic regression was used to assess treatment effects on stay in the neonatal intensive care unit.

Results: In the trial there were 1620 participants and 1571 neonates were liveborn. The total length of stay in neonatal intensive care was substantially longer in the placebo than aspirin group (1696 vs 531 days). This is a reflection of significantly shorter mean lengths of stay in babies admitted to the neonatal intensive care unit from the aspirin than the placebo group (11.1 vs 31.4 days), a reduction of 20.3 days (95% confidence interval, 7.0-38.6; P = .008). Neonatal intensive care of babies born at <32 weeks' gestation contributed 1856 (83.3%) of the total of 2227 days in intensive care across both treatment arms. These occurred in 9 (1.2%) of the 777 livebirths in the aspirin group and in 23 (2.9%) of 794 in the placebo group (odds ratio, 0.42; 95% confidence interval, 0.19-0.93; P = .033). Overall, in the whole population, including 0 lengths of stay for those not admitted to the neonatal intensive care unit, the mean length of stay was longer in the placebo than aspirin group (2.06 vs 0.66 days; reduction of 1.4 days; 95% confidence interval, 0.45-2.81; P = .014). This corresponds to a reduction in length of stay of 68% (95% confidence interval, 20-86%).

Conclusion: In pregnancies at high risk of preeclampsia administration of aspirin reduces the length of stay in the neonatal intensive care unit by about 70%. This reduction could essentially be attributed to a decrease in the rate of births at <32 weeks' gestation, mainly because of prevention of early preeclampsia. The findings have implications for both short- and long-term health care costs as well as infant survival and handicap.
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http://dx.doi.org/10.1016/j.ajog.2018.02.014DOI Listing
June 2018

Early Detection of Preeclampsia Using Circulating Small non-coding RNA.

Sci Rep 2018 02 21;8(1):3401. Epub 2018 Feb 21.

Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Preeclampsia is one of the most dangerous pregnancy complications, and the leading cause of maternal and perinatal mortality and morbidity. Although the clinical symptoms appear late, its origin is early, and hence detection is feasible already at the first trimester. In the current study, we investigated the abundance of circulating small non-coding RNAs in the plasma of pregnant women in their first trimester, seeking transcripts that best separate the preeclampsia samples from those of healthy pregnant women. To this end, we performed small non-coding RNAs sequencing of 75 preeclampsia and control samples, and identified 25 transcripts that were differentially expressed between preeclampsia and the control groups. Furthermore, we utilized those transcripts and created a pipeline for a supervised classification of preeclampsia. Our pipeline generates a logistic regression model using a 5-fold cross validation on numerous random partitions into training and blind test sets. Using this classification procedure, we achieved an average AUC value of 0.86. These findings suggest the predictive value of circulating small non-coding RNA in the first trimester, warranting further examination, and lay the foundation for producing a novel early non-invasive diagnostic tool for preeclampsia, which could reduce the life-threatening risk for both the mother and fetus.
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http://dx.doi.org/10.1038/s41598-018-21604-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821867PMC
February 2018

Association between insulin resistance and preeclampsia in obese non-diabetic women receiving metformin.

Obstet Med 2017 Dec 16;10(4):170-173. Epub 2017 Oct 16.

Epsom and St Helier University Hospitals NHS Trust, Surrey, UK.

Objectives: To examine whether the reduced incidence of preeclampsia in non-diabetic obese pregnant women treated with metformin is mediated by changes in insulin resistance.

Methods: This was a secondary analysis of obese pregnant women in a randomised trial (MOP trial). Fasting plasma glucose and insulin were measured in 384 of the 400 women who participated in the MOP trial. Homeostasis model assessment of insulin resistance (HOMA-IR) was compared in the metformin and placebo groups and in those that developed preeclampsia versus those that did not develop preeclampsia.

Results: At 28 weeks, median HOMA-IR was significantly lower in the metformin group. Logistic regression analysis demonstrated that there was a significant contribution in the prediction of preeclampsia from maternal history of chronic hypertension and gestational weight gain, but not HOMA-IR either at randomisation ( = 0.514) or at 28 weeks ( = 0.643).

Conclusions: Reduced incidence of preeclampsia in non-diabetic obese pregnant women treated with metformin is unlikely to be due to changes in insulin resistance.
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http://dx.doi.org/10.1177/1753495X17725465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5714110PMC
December 2017