Screening for pre‐eclampsia at 11–13 weeks' gestation: use of pregnancy‐associated plasma <scp>protein‐A</scp>, placental growth factor or both

Lolos

et al. 2021

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Objectives To expand a new competing‐risks model for prediction of a small‐for‐gestational‐age (SGA) neonate, by the addition of pregnancy‐associated plasma protein‐A (PAPP‐A) and placental growth factor (PlGF), and to evaluate and compare PAPP‐A and PlGF in predicting SGA. Methods This was a prospective observational study of 60 875 women with singleton pregnancy undergoing routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation. We fitted a folded‐plane regression model for the PAPP‐A and PlGF likelihoods. A previously developed maternal history model and the likelihood models were combined, according to Bayes' theorem, to obtain individualized distributions for gestational age (GA) at delivery and birth‐weight Z‐score. We assessed the discrimination and calibration of the model. McNemar's test was used to compare the detection rates for SGA with, without or independently of pre‐eclampsia (PE) occurrence, of different combinations of maternal history, PAPP‐A and PlGF, for a fixed false‐positive rate. Results The distributions of PAPP‐A and PlGF depend on both GA at delivery and birth‐weight Z‐score, in the same continuous likelihood, according to a folded‐plane regression model. The new approach offers the capability for risk computation for any desired birth‐weight Z‐score and GA at delivery cut‐off. PlGF was consistently and significantly better than PAPP‐A in predicting SGA delivered before 37 weeks, especially in cases with co‐existence of PE. PAPP‐A had similar performance to PlGF for the prediction of SGA without PE. At a fixed false‐positive rate of 10%, the combination of maternal history, PlGF and PAPP‐A predicted 33.8%, 43.8% and 48.4% of all cases of a SGA neonate with birth weight < 10th percentile delivered at ≥ 37, < 37 and < 32 weeks' gestation, respectively. The respective values for birth weight < 3rd percentile were 38.6%, 48.7% and 51.0%. The new model performed well in terms of risk calibration. Conclusions The combination of PAPP‐A and PlGF values with maternal characteristics, according to Bayes' theorem, improves prediction of SGA. PlGF is a better predictor of SGA than PAPP‐A, especially when PE is present. The new competing‐risks model for SGA can be tailored to each pregnancy and to the relevant clinical requirements. © 2020 International Society of Ultrasound in Obstetrics and Gynecology

Section: Discussionmentioning

confidence: 65%

Section: Implications For Clinical Practicementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Competing‐risks model for prediction of small‐for‐gestational‐age neonate from maternal characteristics, serum pregnancy‐associated plasma protein‐A and placental growth factor at 11–13 weeks' gestation

Papastefanou

Lolos

et al. 2021

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“…First-trimester serum PlGF is also useful in screening for preterm pre-eclampsia (PE); screening by serum PlGF in combination with maternal factors, mean arterial pressure and uterine artery pulsatility index at 11-13 weeks' gestation identifies a high-risk group that benefits from the use of prophylactic aspirin [10][11][12][13][14][15] . Serum PAPP-A can also be used in screening for PE but the performance is lower than with the use of PlGF, and if PlGF is used in combination with maternal factors, mean arterial pressure and uterine artery pulsatility index, there is no additive value from the use of PAPP-A 16 .…”

Section: Introductionmentioning

confidence: 99%

Screening for trisomy at 11–13 weeks' gestation: use of pregnancy‐associated plasma protein‐A, placental growth factor or both

Zumaeta

Syngelaki

et al. 2020

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

“…In twin pregnancies, the rate of pre-eclampsia (PE) is about 9%, which is 3-times higher than in singleton pregnancies, but since twins are delivered at an earlier gestational age than singletons, comparison of the overall rates of PE between twin and singleton pregnancies underestimates the relative risk of preterm PE in twins, which is 9-times higher 1 . In singleton pregnancies, effective first-trimester screening for PE is provided by the combination of maternal characteristics and medical history with mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum pregnancy-associated plasma protein-A (PAPP-A) within the framework of a competing-risks model [2][3][4][5][6][7] . In the competing-risks approach, each woman has a personalized distribution of gestational age at delivery with PE; in pregnancies at low risk for PE, the mean gestational age at delivery with PE is increased, with the implication that in most pregnancies delivery from other causes occurs before development of PE; in high-risk pregnancies, the mean gestational age at delivery with PE is decreased so delivery with PE occurs more often 7 .…”

Section: Introductionmentioning

confidence: 99%

Prediction of pre‐eclampsia in twin pregnancy by maternal factors and biomarkers at 11–13 weeks' gestation: data from EVENTS trial

Benkő

Rehal

et al. 2021

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Objectives First, to validate a previously developed model for screening for pre‐eclampsia (PE) by maternal characteristics and medical history in twin pregnancies; second, to compare the distributions 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) in twin pregnancies that delivered with PE to those in singleton pregnancies and to develop new models based on these results; and, third, to examine the predictive performance of these models in screening for PE with delivery at < 32 and < 37 weeks' gestation. Methods Two datasets of prospective non‐intervention multicenter screening studies for PE in twin pregnancies at 11 + 0 to 13 + 6 weeks' gestation were used. The first dataset was from the EVENTS (Early vaginal progesterone for the preVention of spontaneous prEterm birth iN TwinS) trial and the second was from a previously reported study that examined the distributions of biomarkers in twin pregnancies. Maternal demographic characteristics and medical history from the EVENTS‐trial dataset were used to assess the validity of risks from our previously developed model. The combined data from the first and second datasets were used to compare the distributional properties of log10 multiples of the median (MoM) values of UtA‐PI, MAP, PlGF and PAPP‐A in twin pregnancies that delivered with PE to those in singleton pregnancies and develop new models based on these results. The competing‐risks model was used to estimate the individual patient‐specific risks of delivery with PE at < 32 and < 37 weeks' gestation. Screening performance was measured by detection rates (DR) and areas under the receiver‐operating‐characteristics curve. RESULTS The EVENTS‐trial dataset comprised 1798 pregnancies, including 168 (9.3%) that developed PE. In the validation of the prior model based on maternal characteristics and medical history, calibration plots demonstrated very good agreement between the predicted risks and the observed incidence of PE (calibration slope and intercept for PE < 32 weeks were 0.827 and 0.009, respectively, and for PE < 37 weeks they were 0.942 and −0.207, respectively). In the combined data, there were 3938 pregnancies, including 339 (8.6%) that developed PE and 253 (6.4%) that delivered with PE at < 37 weeks' gestation. In twin pregnancies that delivered with PE, MAP, UtA‐PI and PlGF were, at earlier gestational ages, more discriminative than in singleton pregnancies and at later gestational ages they were less so. For PAPP‐A, there was little difference between PE and unaffected pregnancies. The best performance of screening for PE was achieved by a combination of maternal factors, MAP, UtA‐PI and PlGF. In screening by maternal factors alone, the DR, at a 10% false‐positive rate, was 30.6% for delivery with PE at < 32 weeks' gestation and this increased to 86.4% when screening by the combined test; the respective values for PE < 37 weeks were 24.9% and 41.1%. Conclusions In the as...