Publications by authors named "A Syngelaki"

170 Publications

Reference Ranges for the Pulsed wave Doppler of the Fetal Cardiac Inflow and Outflow Tracts from 13 to 36 Weeks Gestation: Short title: Zidere, Fetal inflow and outflow tract, Pulsed wave Doppler, z scores.

J Am Soc Echocardiogr 2021 May 3. Epub 2021 May 3.

Medway Fetal and Maternal Medicine Centre, Medway Maritime Hospital, Gillingham, Kent, United Kingdom; Institute of Medical Sciences, Canterbury Christ Church University, Rowan William's Court, Chatham, Kent ME4 4UF.

Objective: Doppler assessment ventricular filling and outflow tract velocities are an integral part of the fetal echocardiogram, to assess diastolic function, systolic function and outflow tract obstruction. There is a paucity of prospective data from a large sample of normal fetuses in the published literature. We report reference ranges for pulsed wave Doppler flow of the mitral valve, tricuspid valve, aortic valve and pulmonary valve as well as heart rate, in a large number of fetuses prospectively examined at a single tertiary fetal cardiology centre.

Methods: The study population comprised 7885 fetuses at 13 to 36 weeks' gestation with no detectable abnormalities from pregnancies resulting in normal live births. Prospective pulsed wave Doppler blood flow measurements were taken of the mitral, tricuspid, aortic and pulmonary valves. The fetal heart rate was recorded at the time of each assessment. Regression analysis, with polynomial terms to assess for linear and nonlinear contributors, was used to establish the relationship between each measurement and gestational age.

Results: The measurement for each cardiac Doppler measurement 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 inflow and outflow tracts.

Conclusions: The study establishes reference ranges for fetal cardiac Doppler measurements and heart rate between 13 to 36 weeks' gestation that may be useful in clinical practice.
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http://dx.doi.org/10.1016/j.echo.2021.04.017DOI Listing
May 2021

Competing risks model for prediction of small for gestational age neonates from biophysical markers at 19-24 weeks' gestation.

Am J Obstet Gynecol 2021 Apr 23. Epub 2021 Apr 23.

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

Background: Antenatal identification of women at high-risk to deliver small for gestational age (SGA) neonates, may improve the management of the condition. The traditional but ineffective methods for SGA 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 pre-specified cut-offs of birth weight percentile and gestational age at delivery. However, such models have led to an arbitrary dichotomization of the condition; different models for different SGA definitions are required and adding new biomarkers or examining other cut-offs requires re-fitting of the whole model. An alternative approach for prediction of SGA neonates is to consider SGA as a spectrum disorder whose severity is continuously reflected in both the gestational age at delivery and z-score in birth weight for gestational age.

Objective: To develop a new competing risks model for prediction of SGA neonates based on a combination of maternal demographic characteristics and medical history with sonographic estimated fetal weight (EFW), uterine artery pulsatility index (UtA-PI) and mean arterial pressure (MAP) at 19-24 weeks of gestation.

Study Design: This was a prospective observational study in 96,678 women with singleton pregnancies undergoing routine ultrasound examination at 19-24 weeks of gestation, which included recording of EFW, UtA-PI and MAP. The competing risks model for SGA is based on a prior joint distribution of gestational age at delivery (GA) and birth weight Z score (Z), according to maternal demographic characteristics and medical history. The likelihoods of the EFW, UtA-PI and MAP were fitted conditionally to both GA and Z and modified the prior distribution, according to Bayes theorem, to obtain an individualized posterior distribution for GA and Z and therefore patient specific risks for any desired cut-offs for Z and GA. The model was internally validated by randomly dividing the data into a training dataset, to obtain the parameters of the model, and a test dataset to evaluate the model. The discrimination and calibration of the model were also examined.

Results: The EFW was described by a regression model with an interaction term between GA and Z. Folded plane regression models were fitted for UtA-PI and MAP. The prediction of SGA by maternal factors improved by adding biomarkers and for increasing degree of prematurity, higher severity of smallness and for co-existence of preeclampsia. Screening by maternal factors EFW, UtA-PI and MAP, predicted 41%, 56% and 70% of SGA neonates with birth weight <10 percentile delivered at ≥37, <37 and <32 weeks' gestation, at 10% false positive rate. The respective rates for birth weight <3 percentile were 47%, 65% and 77%. The rates in the presence of preeclampsia were 41%, 72% and 91% for SGA neonates with birth weight <10th percentile and 50%, 75% and 92% for SGA neonates with birth weight <3rd percentile. Overall the model was well calibrated. The detection rates and the calibration indices were similar in the training and test datasets, demonstrating the internal validity of the model.

Conclusion: The performance of screening for SGA neonates by a competing risks model that combines maternal factors with EFW, UtA-PI and MAP is superior to that of screening by maternal characteristics and medical history alone.
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http://dx.doi.org/10.1016/j.ajog.2021.04.247DOI Listing
April 2021

Cell-free DNA testing of maternal blood in screening for trisomies in twin pregnancy: cohort study at 10-14 weeks and updated meta-analysis.

Ultrasound Obstet Gynecol 2021 Apr 10. Epub 2021 Apr 10.

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

Objective: To expand the limited knowledge on cell-free (cf)DNA analysis of maternal blood for trisomies 21, 18 and 13 in twin pregnancies by updating the data from the Fetal Medicine Foundation (FMF) on prospective first trimester screening and those arising from 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 -14 weeks' gestation using the Harmony® prenatal test of Roche/Ariosa Diagnostics, Inc. Search of Medline, Embase, CENTRAL (The Cochrane Library), ClinicalTrials.gov and ICTRP (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 pregnancies, irrespective of gestational age at testing, in which data on pregnancy outcome were provided for more than 85% of the study population. Meta-analysis was then performed using the FMF data and data from the studies identified by the literature search. This review was registered in 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) cases there was prenatal or postnatal karyotyping or the birth of phenotypically normal babies; 95 cases were excluded from further analysis either because the pregnancies 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, 2 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, 9 (90.0%) of 10 of trisomy 18, 1 (50.0%) of 2 of trisomy 13 and 1235 (99.6%) of 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 total 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 pregnancies the reported DR of trisomy 21 by cfDNA testing is high, but lower than in singleton pregnancies, whereas the FPR appears to be equally low. The number of cases of trisomy 18 and more so trisomy 13 is too small for accurate assessment of the predictive performance of the cfDNA test. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/uog.23648DOI Listing
April 2021

Stratification of pregnancy care based on risk of pre-eclampsia derived from biophysical and biochemical markers at 19-24 weeks' gestation.

Ultrasound Obstet Gynecol 2021 Apr 1. Epub 2021 Apr 1.

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

Objective: We have previously proposed that all pregnant women should have assessment of risk for preeclampsia (PE) at 20 and 36 weeks' gestation and that the 20 weeks assessment should be used to define subgroups requiring additional monitoring and reassessment at 28 and 32 weeks. The objective of this study is to examine the potential improvement in screening for PE with delivery at <28, <32, <36 and ≥36 weeks' gestation at 19-24 weeks' gestation by the addition of serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFLT-1) to the combination of maternal demographic characteristics and medical history, uterine artery pulsatility index (UtA-PI) and mean arterial pressure (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 <36 weeks' gestation were calculated using the competing risks model to combine the prior distribution of the gestational age at delivery with PE, obtained from maternal characteristics and medical history, with multiple of the median (MoM) values of UtA-PI, MAP, PlGF and sFLT-1. Different risk cut-offs were used to vary the proportion of the population stratified into each of four risk categories (very high-risk, high-risk, intermediate-risk and low-risk) with the intention of detecting about 80%, 85%, 90% and 95% of the cases of delivery with PE at <28, <32 and <36 weeks' gestation. The performance of screening was assessed by plotting the detection rate against the screen positive rate and calculating the areas under these curves and by proportion stratified to a given group for fixed detection rates. Model based estimates of screening performance for these various combinations of markers were also produced.

Results: In the study population of 37886 singleton pregnancies there were 1130 (3.0%) that subsequently developed PE, including 160 (0.4%) that delivered at <36 weeks' gestation. In both the modelled and empirical results there was incremental improvement in the performance of screening with the addition of PlGF and sFLT-1 to the combination of maternal factors, UtA-PI and MAP. If the objective of screening was to identify about 90% of cases of PE with delivery at <28, <32 and <36 weeks and the method of screening was a combination of maternal factors, UtA-PI and MAP, the respective screen positive rates would be 3.1%, 8.5%, and 19.1%. The respective values for screening by maternal factors, UtA-PI, MAP and PlGF were 0.2%, 0.7% and 10.6% and for screening by maternal factors, UtA-PI, MAP, PlGF and sFLT-1 were 0.1%, 0.4% and 9.5%. The empirical results were consistent with the modelled ones. There was good agreement between the predicted risk and observed incidence of PE <36 weeks' gestation with all three strategies of screening.

Conclusion: The performance of screening for PE with delivery at <28, <32 and <36 weeks' gestation at 19-24 weeks' gestation achieved by a combination of maternal demographic characteristics and medical history, UtA-PI and MAP is improved by the addition of serum PlGF and sFLT-1. The performance of screening for PE at ≥36 weeks' gestation is poor irrespective of the method of screening at 19-24 weeks. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/uog.23640DOI Listing
April 2021

Stratification of pregnancy care based on risk of pre-eclampsia derived from uterine artery Doppler at 19-24 weeks' gestation.

Ultrasound Obstet Gynecol 2021 Mar 1. Epub 2021 Mar 1.

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

Objective: There are two objectives to the 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 preeclampsia (PE) and compare the performance of screening between the use of first, fixed cut-offs of UtA-PI, second, percentile cut-offs in UtA-PI adjusted for gestational age, third, competing risks model combining maternal demographic characteristics and medical history with UtA-PI, and fourth, competing risks model combining maternal factors with UtA-PI and mean arterial pressure (MAP). Second, to stratify pregnancy care based on estimated risk of preeclampsia (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 <36 weeks' gestation were calculated using the competing risks model to combine the prior distribution of the gestational age at delivery with PE, obtained from maternal characteristics and medical history, with multiple of the median (MoM) values of UtA-PI and MAP. Different risk cut-offs were used to vary the proportion of the population stratified into each risk category (very high-risk, high-risk, intermediate-risk and low-risk) with the intention of detecting about 80%, 85%, 90% and 95% of the cases of delivery with PE at <28, <32 and <36 weeks' gestation. We also examined the performance of screening by maternal factors and UtA-PI MoM, fixed cut-offs of UtA-PI and percentile cut-offs in UtA-PI adjusted for gestational age. Calibration for risks for PE <36 weeks' gestation by the combination of maternal factors, UtA-PI MoM and MAP MoM was assessed by plotting the observed incidence of PE against that predicted. Additionally, we developed reference ranges of transabdominal and transvaginal UtA-PI with gestational age.

Results: In the study population of 96678 singleton pregnancies there were 2866 (3.0%) that subsequently developed PE, including 467 (0.5%) that delivered at <36 weeks' gestation. If the objective of screening was to identify about 90% of cases of delivery with PE at <28, <32 and <36 weeks and the method of screening was a combination of maternal factors, UtA-PI MoM and MAP MoM, the proportion of the population stratified into the very high-risk, the high-risk and the intermediate-risk groups should be 2.4%, 6.3%, and 24.1%; the respective values were 6.0%, 9.0% and 30% if screening was by maternal factors and UtA-PI MoM, 5.7%, 13.2% and 63.0% if screening was by fixed cut-offs of UtA-PI and 6.9%, 12.1% and 61.1% if screening was by percentile cut-offs in UtA-PI. There was good agreement between the predicted and observed incidence of PE <36 weeks' gestation. In the validation of the prediction model based on a combination of maternal factors and MoM values of UtA-PI and MAP calibration plots demonstrated good agreement between the predicted risks and observed incidence of PE.

Conclusion: All pregnant women should have screening for PE at 20 and 36 weeks' gestation. The findings at 20 weeks can be used to identify the subgroups that require additional monitoring and reassessment at 28 and 32 weeks. The performance of screening by a combination of maternal factors and MoM values of UtA-PI and MAP at 19-24 weeks for delivery with PE at <28, <32 and <36 weeks' gestation is superior to that of screening by a combination of maternal factors and UtA-PI MoM or fixed cut-offs of UtA-PI or percentile cut-offs in UtA-PI. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/uog.23623DOI Listing
March 2021