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Analysis of cell‐free DNA in maternal blood in screening for aneuploidies: updated meta‐analysis
Gil, M. M.; Accurti, V.; Santacruz, B. ...
Ultrasound in obstetrics & gynecology,
September 2017, Letnik:
50, Številka:
3
Journal Article
Recenzirano
Odprti dostop
ABSTRACT
Objectives
To review clinical validation or implementation studies of maternal blood cell‐free (cf) DNA analysis and define the performance of screening for fetal trisomies 21, 18 and 13 and ...
sex chromosome aneuploidies (SCA).
Methods
Searches of PubMed, EMBASE and The Cochrane Library were performed to identify all peer‐reviewed articles on cfDNA testing in screening for aneuploidies between January 2011, when the first such study was published, and 31 December 2016. The inclusion criteria were peer‐reviewed study reporting on clinical validation or implementation of maternal cfDNA testing in screening for aneuploidies, in which data on pregnancy outcome were provided for more than 85% of the study population. We excluded case–control studies, proof‐of‐principle articles and studies in which the laboratory scientists carrying out the tests were aware of fetal karyotype or pregnancy outcome. Pooled detection rates (DRs) and false‐positive rates (FPRs) were calculated using bivariate random‐effects regression models.
Results
In total, 35 relevant studies were identified and these were used for the meta‐analysis on the performance of cfDNA testing in screening for aneuploidies. These studies reported cfDNA results in relation to fetal karyotype from invasive testing or clinical outcome. In the combined total of 1963 cases of trisomy 21 and 223 932 non‐trisomy 21 singleton pregnancies, the weighted pooled DR and FPR were 99.7% (95% CI, 99.1–99.9%) and 0.04% (95% CI, 0.02–0.07%), respectively. In a total of 563 cases of trisomy 18 and 222 013 non‐trisomy 18 singleton pregnancies, the weighted pooled DR and FPR were 97.9% (95% CI, 94.9–99.1%) and 0.04% (95% CI, 0.03–0.07%), respectively. In a total of 119 cases of trisomy 13 and 212 883 non‐trisomy 13 singleton pregnancies, the weighted pooled DR and FPR were 99.0% (95% CI, 65.8–100%) and 0.04% (95% CI, 0.02–0.07%), respectively. In a total of 36 cases of monosomy X and 7676 unaffected singleton pregnancies, the weighted pooled DR and FPR were 95.8% (95% CI, 70.3–99.5%) and 0.14% (95% CI, 0.05–0.38%), respectively. In a combined total of 17 cases of SCA other than monosomy X and 5400 unaffected singleton pregnancies, the weighted pooled DR and FPR were 100% (95% CI, 83.6–100%) and 0.004% (95% CI, 0.0–0.08%), respectively. For twin pregnancies, in a total of 24 cases of trisomy 21 and 1111 non‐trisomy 21 cases, the DR was 100% (95% CI, 95.2–100%) and FPR was 0.0% (95% CI, 0.0–0.003%), respectively.
Conclusions
Screening by analysis of cfDNA in maternal blood in singleton pregnancies could detect > 99% of fetuses with trisomy 21, 98% of trisomy 18 and 99% of trisomy 13 at a combined FPR of 0.13%. The number of reported cases of SCA is too small for accurate assessment of performance of screening. In twin pregnancies, performance of screening for trisomy 21 is encouraging but the number of cases reported is small. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.
Resumen
Análisis del ADN fetal en sangre materna para la detección de aneuploidías: un metaanálisis actualizado
Objetivos
Revisar estudios clínicos de validación o de implementación de análisis de ADN fetal (cfDNA, por sus siglas en inglés) en la sangre materna y definir el desempeño de la detección de las trisomías fetales 21, 18 y 13 y las aneuploidías de los cromosomas sexuales (SCA, por sus siglas en inglés).
Métodos
Se realizaron búsquedas en PubMed, EMBASE y The Cochrane Library para identificar todos los artículos revisados por pares sobre pruebas de cfDNA para la detección de aneuploidías entre enero de 2011, cuando se publicó el primer estudio, y el 31 de diciembre de 2016. Los criterios de inclusión fueron estudios revisados por pares sobre la validación o la implementación clínica de pruebas de cfDNA materno en la detección de aneuploidías, en los que se proporcionaban datos sobre los resultados del embarazo para más del 85% de la población estudiada. Se excluyeron los estudios de casos y controles, los artículos sobre estudios de viabilidad y los estudios donde los científicos de laboratorio que realizaron las pruebas, conocían el cariotipo fetal o el resultado del embarazo. Las tasas combinadas de detección (TD) y de falsos positivos (TFP) se calcularon utilizando modelos de regresión bivariantes de efectos aleatorios.
Resultados
En total, se identificaron 35 estudios relevantes que se usaron para el metaanálisis sobre el desempeño de la prueba de cfDNA en la detección de aneuploidías. Estos estudios informaron sobre los resultados del cfDNA en relación con el cariotipo fetal a partir de pruebas invasivas o resultados clínicos. En el total combinado de 1963 casos de trisomía 21 y 223 932 embarazos con feto único sin trisomía 21, las TD y TFP ponderadas combinadas fueron del 99,7% (IC 95%, 99,1–99,9%) y del 0,04% (IC 95%, 0,02–0,07 %), respectivamente. En un total de 563 casos de trisomía 18 y 222 013 embarazos con feto único sin trisomía 18, las TD y TFP ponderadas combinadas fueron del 97,9% (IC 95%, 94,9–99,1%) y del 0,04% (IC 95%, 0,03–0,07%), respectivamente. En un total de 119 casos de trisomía 13 y 212 883 embarazos con feto único sin trisomía 13, las TD y TFP ponderadas combinadas fueron del 99,0% (IC 95%, 65,8‐100%) y del 0,04% (IC 95%, 0,02–0,07%), respectivamente. En un total de 36 casos de monosomía X y 7676 embarazos con feto único no afectados, las TD y TFP ponderadas combinadas fueron del 95,8% (IC 95%, 70,3–99,5%) y del 0,14% (IC 95%, 0,05–0,38%), respectivamente. En un total combinado de 17 casos de SCA distintos de los de monosomía X y los 5400 embarazos con feto único no afectados, las TD y TFP ponderadas combinadas fueron del 100% (IC 95%, 83,6–100%) y 0,004% (IC 95%, 0,0–0,08% ), respectivamente. Para los embarazos de gemelos, en un total de 24 casos de trisomía 21 y 1111 casos sin trisomía 21, la TD fue del 100% (IC 95%, 95,2–100%) y la TFP fue del 0,0% (IC 95%, 0,0–0,003%), respectivamente.
Conclusiones
El cribado mediante el análisis del cfDNA en la sangre materna en embarazos con feto único podría detectar >99% de fetos con trisomía 21, un 98% con trisomía 18 y un 99% con trisomía 13, con una TFP combinado del 0,13%. El número de casos notificados de SCA es insuficiente para una evaluación precisa del desempeño del cribado. En los embarazos de gemelos, el rendimiento del cribado de la trisomía 21 es alentador, pero el número de casos notificados es pequeño.
摘要
通过分析母体血液游离DNA筛查非整倍体:最新的meta分析结果
目的
回顾对母体血液游离(cell‐free,cf)DNA进行分析的临床验证或应用研究,确定其对胎儿21、18、13三体和性染色体非整倍体(sex chromosome aneuploidies,SCA)的筛查能力。
方法
检索PubMed、EMBASE和The Cochrane Library,查找2011年1月(此类研究首次发表时间)至2016年12月31日间发表的通过检测cfDNA筛查非整倍体的所有同行评议文献。纳入标准为经同行评议的通过检测母体cfDNA筛查非整倍体的临床验证或应用研究,其中给出了85%以上的研究人群的妊娠结局。排除病例对照研究、原理验证文献以及进行检测的实验室人员知晓胎儿核型或妊娠结局的研究。采用双变量随机效应回归模型计算合并检出率(detection rates,DRs)和假阳性率(false‐positive rates,FPRs)。
结果
共检索到35项相关研究,将其纳入cfDNA检测对非整倍体筛查能力的meta分析中。研究报道了通过侵入性检查或临床结局获得的与胎儿核型有关的cfDNA结果。总共1963例 21三体和223 932例非21三体单胎妊娠,加权合并DR和FPR分别为99.7%(95% CI,99.1%~99.9%)和0.04%(95% CI,0.02%~0.07%)。共563例18三体和222 013例非18三体单胎妊娠,加权合并DR和FPR分别为97.9%(95% CI,94.9%~99.1%)和0.04%(95% CI,0.03%~0.07%)。共119例13三体和212 883例非13三体单胎妊娠,加权合并DR和FPR分别为99.0%(95% CI,65.8%~100%)和0.04%(95% CI,0.02%~0.07%)。共36例X 单体和7676例非X 单体的单胎妊娠,加权合并DR和FPR分别为95.8%(95% CI,70.3%~99.5%)和0.14%(95% CI,0.05%~0.38%)。总共17例SCA(除外X单体)和5400例非SCA单胎妊娠,加权合并DR和FPR分别为100%(95% CI,83.6%~100%)和0.004%(95% CI,0.0%~0.08%)。双胎妊娠中,共24例21三体和1111例非21三体,DR为100%(95% CI,95.2%~100%),FPR为0.0%(95% CI,0.0%~0.003%)。
结论
单胎妊娠中,通过分析母体血液cfDNA进行筛查,21三体胎儿检出率>99%,18三体检出率为98%,13三体检出率为99%,合并FPR为0.13%。由于报道的SCA例数过少,不能准确评估筛查能力。双胎妊娠中, 21三体的筛查能力值得关注,但报道的病例数较少。
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Does exercise during pregnancy impact on maternal weight gain and fetal cardiac function? A randomized controlled trial
Brik, M.; Fernández‐Buhigas, I.; Martin‐Arias, A. ...
Ultrasound in obstetrics & gynecology,
20/May , Letnik:
53, Številka:
5
Journal Article
Recenzirano
Odprti dostop
ABSTRACT
Objective
To evaluate the association between physical exercise during pregnancy and maternal gestational weight gain and fetal cardiac function.
Methods
This was a randomized controlled ...
trial of women with a singleton pregnancy managed from the first trimester at the Hospital de Torrejón, Madrid, between November 2014 and June 2015. Women were randomized to either follow a supervised physical conditioning program, consisting of a 60‐min session 3 days per week for the duration of pregnancy, or not attend any exercise program (controls). The primary outcome was maternal weight gain during pregnancy. Secondary outcomes included fetal cardiac function parameters evaluated at 20, 28 and 36 weeks' gestation, Cesarean section, preterm delivery, induction of labor and birth weight. A sample size of 45 in each group was planned to detect differences in maternal weight gain of at least 1 kg, with a power of > 80% and α of 0.05.
Results
During the study period, 120 women were randomized into the exercise (n = 75) and control (n = 45) groups. Following exclusions, the final cohort consisted of 42 women in the exercise group and 43 in the control group. Baseline characteristics (maternal age, prepregnancy body mass index, parity, conception by in‐vitro fertilization, Caucasian ethnicity, physical exercise prior to pregnancy and smoker) were similar between the two groups. No differences were found between the groups in maternal weight at 20, 28, 36 and 38 weeks' gestation or in weight gain at 38 weeks. However, the proportion of women with weight loss ≥ 9 kg at 6 weeks postpartum was higher in the exercise compared with the control group (68.2% vs 42.8%; relative risk 1.593; P = 0.02). The ductus arteriosus pulsatility index (DA‐PI) at 20 weeks (2.43 ± 0.40 vs 2.26 ± 0.33, P < 0.05) and the ejection fraction (EF) at 36 weeks (0.85 ± 0.13 vs 0.81 ± 0.11, P < 0.05) were higher in the exercise compared with the control group. All other evaluated fetal cardiac function parameters were similar between the two groups.
Conclusions
Performing exercise during pregnancy is not associated with a reduction in maternal weight gain but increases weight loss at 6 weeks postpartum. Physical exercise during pregnancy is associated with increased fetal DA‐PI at 20 weeks and EF at 36 weeks, which could reflect adaptive mechanisms. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.
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Validation of machine‐learning model for first‐trimester prediction of pre‐eclampsia using cohort from PREVAL study
Gil, M. M.; Cuenca‐Gómez, D.; Rolle, V. ...
Ultrasound in obstetrics & gynecology,
January 2024, 2024-01-00, 20240101, Letnik:
63, Številka:
1
Journal Article
Recenzirano
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ABSTRACT
Objective
Effective first‐trimester screening for pre‐eclampsia (PE) can be achieved using a competing‐risks model that combines risk factors from the maternal history with multiples of the ...
median (MoM) values of biomarkers. A new model using artificial intelligence through machine‐learning methods has been shown to achieve similar screening performance without the need for conversion of raw data of biomarkers into MoM. This study aimed to investigate whether this model can be used across populations without specific adaptations.
Methods
Previously, a machine‐learning model derived with the use of a fully connected neural network for first‐trimester prediction of early (< 34 weeks), preterm (< 37 weeks) and all PE was developed and tested in a cohort of pregnant women in the UK. The model was based on maternal risk factors and mean arterial blood pressure (MAP), uterine artery pulsatility index (UtA‐PI), placental growth factor (PlGF) and pregnancy‐associated plasma protein‐A (PAPP‐A). In this study, the model was applied to a dataset of 10 110 singleton pregnancies examined in Spain who participated in the first‐trimester PE validation (PREVAL) study, in which first‐trimester screening for PE was carried out using the Fetal Medicine Foundation (FMF) competing‐risks model. The performance of screening was assessed by examining the area under the receiver‐operating‐characteristics curve (AUC) and detection rate (DR) at a 10% screen‐positive rate (SPR). These indices were compared with those derived from the application of the FMF competing‐risks model. The performance of screening was poor if no adjustment was made for the analyzer used to measure PlGF, which was different in the UK and Spain. Therefore, adjustment for the analyzer used was performed using simple linear regression.
Results
The DRs at 10% SPR for early, preterm and all PE with the machine‐learning model were 84.4% (95% CI, 67.2–94.7%), 77.8% (95% CI, 66.4–86.7%) and 55.7% (95% CI, 49.0–62.2%), respectively, with the corresponding AUCs of 0.920 (95% CI, 0.864–0.975), 0.913 (95% CI, 0.882–0.944) and 0.846 (95% CI, 0.820–0.872). This performance was achieved with the use of three of the biomarkers (MAP, UtA‐PI and PlGF); inclusion of PAPP‐A did not provide significant improvement in DR. The machine‐learning model had similar performance to that achieved by the FMF competing‐risks model (DR at 10% SPR, 82.7% (95% CI, 69.6–95.8%) for early PE, 72.7% (95% CI, 62.9–82.6%) for preterm PE and 55.1% (95% CI, 48.8–61.4%) for all PE) without requiring specific adaptations to the population.
Conclusions
A machine‐learning model for first‐trimester prediction of PE based on a neural network provides effective screening for PE that can be applied in different populations. However, before doing so, it is essential to make adjustments for the analyzer used for biochemical testing. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
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Comparison of different methods of first‐trimester screening for preterm pre‐eclampsia: cohort study
Cuenca‐Gómez, D.; De Paco Matallana, C.; Rolle, V. ...
Ultrasound in obstetrics & gynecology,
July 2024, 2024-07-00, 20240701, Letnik:
64, Številka:
1
Journal Article
Recenzirano
ABSTRACT
Objective
To compare the predictive performance of three different mathematical models for first‐trimester screening of pre‐eclampsia (PE), which combine maternal risk factors with mean ...
arterial pressure (MAP), uterine artery pulsatility index (UtA‐PI) and serum placental growth factor (PlGF), and two risk‐scoring systems.
Methods
This was a prospective cohort study performed in eight fetal medicine units in five different regions of Spain between September 2017 and December 2019. All pregnant women with singleton pregnancy and a non‐malformed live fetus attending their routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation were invited to participate in the study. Maternal characteristics and medical history were recorded and measurements of MAP, UtA‐PI, serum PlGF and pregnancy‐associated plasma protein‐A (PAPP‐A) were converted into multiples of the median (MoM). Risks for term PE, preterm PE (< 37 weeks' gestation) and early PE (< 34 weeks' gestation) were calculated according to the FMF competing‐risks model, the Crovetto et al. logistic regression model and the Serra et al. Gaussian model. PE classification was also performed based on the recommendations of the National Institute for Health and Care Excellence (NICE) and the American College of Obstetricians and Gynecologists (ACOG). We estimated detection rates (DR) with their 95% CIs at a fixed 10% screen‐positive rate (SPR), as well as the area under the receiver‐operating‐characteristics curve (AUC) for preterm PE, early PE and all PE for the three mathematical models. For the scoring systems, we calculated DR and SPR. Risk calibration was also assessed.
Results
The study population comprised 10 110 singleton pregnancies, including 32 (0.3%) that developed early PE, 72 (0.7%) that developed preterm PE and 230 (2.3%) with any PE. At a fixed 10% SPR, the FMF, Crovetto et al. and Serra et al. models detected 82.7% (95% CI, 69.6–95.8%), 73.8% (95% CI, 58.7–88.9%) and 79.8% (95% CI, 66.1–93.5%) of early PE; 72.7% (95% CI, 62.9–82.6%), 69.2% (95% CI, 58.8–79.6%) and 74.1% (95% CI, 64.2–83.9%) of preterm PE; and 55.1% (95% CI, 48.8–61.4%), 47.1% (95% CI, 40.6–53.5%) and 53.9% (95% CI, 47.4–60.4%) of all PE, respectively. The best correlation between predicted and observed cases was achieved by the FMF model, with an AUC of 0.911 (95% CI, 0.879–0.943), a slope of 0.983 (95% CI, 0.846–1.120) and an intercept of 0.154 (95% CI, –0.091 to 0.397). The NICE criteria identified 46.7% (95% CI, 35.3–58.0%) of preterm PE at 11% SPR and ACOG criteria identified 65.9% (95% CI, 55.4–76.4%) of preterm PE at 33.8% SPR.
Conclusions
The best performance of screening for preterm PE is achieved by mathematical models that combine maternal factors with MAP, UtA‐PI and PlGF, as compared to risk‐scoring systems such as those of NICE and ACOG. While all three algorithms show similar results in terms of overall prediction, the FMF model showed the best performance at an individual level. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.
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Performance of first‐trimester combined screening for preterm pre‐eclampsia: findings from cohort of 10 110 pregnancies in Spain
Cuenca‐Gómez, D.; De Paco Matallana, C.; Rolle, V. ...
Ultrasound in obstetrics & gynecology,
October 2023, 2023-10-00, 20231001, Letnik:
62, Številka:
4
Journal Article
Recenzirano
Odprti dostop
ABSTRACT
Objective
To evaluate the diagnostic accuracy of the Fetal Medicine Foundation (FMF) competing‐risks model, incorporating maternal characteristics, mean arterial pressure (MAP), uterine ...
artery pulsatility index (UtA‐PI) and placental growth factor (PlGF) (the ‘triple test’), for the prediction at 11–13 weeks' gestation of preterm pre‐eclampsia (PE) in a Spanish population.
Methods
This was a prospective cohort study performed in eight fetal medicine units in five different regions of Spain between September 2017 and December 2019. All pregnant women with a singleton pregnancy and a non‐malformed live fetus attending a routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation were invited to participate. Maternal demographic characteristics and medical history were recorded and MAP, UtA‐PI, serum PlGF and pregnancy‐associated plasma protein‐A (PAPP‐A) were measured following standardized protocols. Treatment with aspirin during pregnancy was also recorded. Raw values of biomarkers were converted into multiples of the median (MoM), and audits were performed periodically to provide regular feedback to operators and laboratories. Patient‐specific risks for term and preterm PE were calculated according to the FMF competing‐risks model, blinded to pregnancy outcome. The performance of screening for PE, taking into account aspirin use, was assessed by calculating the area under the receiver‐operating‐characteristics curve (AUC) and detection rate (DR) at a 10% fixed screen‐positive rate (SPR). Risk calibration of the model was assessed.
Results
The study population comprised 10 110 singleton pregnancies, including 72 (0.7%) that developed preterm PE. In the preterm PE group, compared to those without PE, median MAP MoM and UtA‐PI MoM were significantly higher, and median serum PlGF MoM and PAPP‐A MoM were significantly lower. In women with PE, the deviation from normal in all biomarkers was inversely related to gestational age at delivery. Screening for preterm PE by a combination of maternal characteristics and medical history with MAP, UtA‐PI and PlGF had a DR, at 10% SPR, of 72.7% (95% CI, 62.9–82.6%). An alternative strategy of replacing PlGF with PAPP‐A in the triple test was associated with poorer screening performance for preterm PE, giving a DR of 66.5% (95% CI, 55.8–77.2%). The calibration plot showed good agreement between predicted risk and observed incidence of preterm PE, with a slope of 0.983 (95% CI, 0.846–1.120) and an intercept of 0.154 (95% CI, −0.091 to 0.397).
Conclusions
The FMF model is effective in predicting preterm PE in the Spanish population at 11–13 weeks' gestation. This method of screening is feasible to implement in routine clinical practice, but it should be accompanied by a robust audit and monitoring system, in order to maintain high‐quality screening. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
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