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

Objective:
To examine the performance of screening for early-, preterm- and term-preeclampsia (PE) at 11 13 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 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 – 13+6 weeks’ gestation in a combined total of 61,174 singleton pregnancies, including 1,770 (2.9%) that developed PE. Bayes theorem was used to combine the prior distribution of the gestational age at delivery with PE, obtained from maternal characteristics, with various combinations of biomarker multiple of the median (MoM) values to derive the p patient specific risks of delivery with PE at <37 weeks’ gestation. The performance of such screening was estimated.

Results In pregnancies that develop ed PE , compared to those without PE, the MoM values of UtA-PI and MAP were increased and 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 4 1 % of term PE, at 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; in screening by a combination of maternal factors, MAP, UtA-PI and PLGF and use of the risk cut off of 1 in 10 0 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.

1. Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, de Paco Matallana C,Akolekar R, Cicero S, Janga D, Singh M, Molina FS, Persico N, Jani JC, PlasenciaW, Papaioannou G, Tenenbaum-Gavish K, Meiri H, Gizurarson S, Maclagan K,Nicolaides KH. Aspirin versus placebo in pregnancies at high risk for pretermpreeclampsia. NEnglJMed2017; 377: 613–622.
2. Wright D, Poon LC, Rolnik DL, Syngelaki A, Delgado JL, Vojtassakova D, deAlvarado M, Kapeti E, Rehal A, Pazos A, Carbone IF, Dutemeyer V, Plasencia W,Papantoniou N, Nicolaides KH. Aspirin for Evidence-Based Preeclampsia Preventiontrial: influence of compliance on beneficial effect of aspirin in prevention of pretermpreeclampsia. Am J Obstet Gynecol 2017; 217: 685.e1–5.
3. Poon LC, Wright D, Rolnik DL, Syngelaki A, Delgado JL, Tsokaki T, LeipoldG, Akolekar R, Shearing S, De Stefani L, Jani JC, Plasencia W, EvangelinakisN, Gonzalez-Vanegas O, Persico N, Nicolaides KH. Aspirin for Evidence-BasedPreeclampsia Prevention trial: effect of aspirin in prevention of preterm preeclampsiain subgroups of women according to their characteristics and medical and obstetricalhistory. Am J Obstet Gynecol 2017; 217: 585.e1–5.
4. Wright D, Rolnik DL, Syngelaki A, de Paco Matallana C, Machuca M, de AlvaradoM, Mastrodima S, Yi Tan M, Shearing S, Persico N, Jani JC, Plasencia W,Papaioannou G, Molina FS, Poon LC, Nicolaides KH. Aspirin for Evidence-BasedPreeclampsia Prevention trial: effect of aspirin on length of stay in the neonatalintensive care unit. Am J Obstet Gynecol 2018; 218: 612.e1–6.
5. Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and termpreeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol 2017; 218:287–293.e1.
6. Roberge S, Bujold E, Nicolaides KH. Meta-analysis on the effect of aspirin use forprevention of preeclampsia on placental abruption and antepartum hemorrhage. AmJ Obstet Gynecol 2018; 218: 483–489.
7. National Collaborating Centre for Women’s and Children’s Health (UK).Hypertension in Pregnancy: The Management of Hypertensive Disorders DuringPregnancy. RCOG Press: London, 2010.
8. Wright D, Syngelaki A, Akolekar R, Poon LC, Nicolaides KH. Competing risksmodel in screening for preeclampsia by maternal characteristics and medical history.Am J Obstet Gynecol 2015; 213: 62.e1–10.
9. Tan MY, Wright D, Syngelaki A, Akolekar R, Cicero S, Janga D, Singh M, GrecoE, Wright A, Maclagan K, Poon LC, Nicolaides KH. Comparison of diagnosticaccuracy of early screening for pre-eclampsia by NICE guidelines and a methodcombining maternal factors and biomarkers: results of SPREE. Ultrasound ObstetGynecol 2018; 51: 743–750.
10. Wright D, Akolekar R, Syngelaki A, Poon L, Nicolaides KH. A competing risksmodel in early screening for preeclampsia. Fetal Diagn Ther 2012; 32: 171–178.
11. Akolekar R, Syngelaki A, Poon L, Wright D, Nicolaides KH. Competing risks modelin early screening for preeclampsia by biophysical and biochemical markers. FetalDiagn Ther 2013; 33: 8–15.
12. O’Gorman N, Wright D, Syngelaki A, Akolekar R, Wright A, Poon LC, NicolaidesKH. Competing risks model in screening for preeclampsia by maternal factors
and biomarkers at 11-13 weeks’ gestation. Am J Obstet Gynecol 2016; 214:103.e1–12.
13. Conde-Agudelo A, Villar J, Lindheimer M. World Health Organization systematicreview of screening tests for preeclampsia. Obstet Gynecol 2004; 104: 1367–1391.
14. Akolekar R, Syngelaki A, Sarquis R, Zvanca M, Nicolaides KH. Prediction ofearly, intermediate and late pre-eclampsia from maternal factors, biophysical andbiochemical markers at 11-13 weeks. Prenat Diagn 2011; 31: 66–74.
15. O’Gorman N, Wright D, Poon LC, Rolnik DL, Syngelaki A, Wright A, Akolekar R,Cicero S, Janga D, Jani J, Molina FS, de Paco Matallana C, Papantoniou N, PersicoN, Plasencia W, Singh M, Nicolaides KH. Accuracy of competing-risks model inscreening for pre-eclampsia by maternal factors and biomarkers at 11– 13 weeks’gestation. Ultrasound Obstet Gynecol 2017; 49: 751–755.
16. Plasencia W, Maiz N, Bonino S, Kaihura C, Nicolaides KH. Uterine artery Dopplerat 11 + 0to13+ 6 weeks in the prediction of pre-eclampsia. Ultrasound ObstetGynecol 2007; 30: 742–749.
17. Poon LC, Zymeri NA, Zamprakou A, Syngelaki A, Nicolaides KH. Protocol formeasurement of mean arterial pressure at 11-13 weeks’ gestation. Fetal Diagn Ther2012; 31: 42–48.
18. Robinson HP, Fleming JE. A critical evaluation of sonar crown rump lengthmeasurements. BrJObstetGynaecol1975; 82: 702–710.
19. Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM. Theclassification and diagnosis of the hypertensive disorders of pregnancy: Statementfrom the international society for the study of hypertension in pregnancy (ISSHP).Hypertens Pregnancy 2001; 20:IX–XIV.
20. Wright A, Wright D, Ispas A, Poon LC, Nicolaides KH. Mean arterial pressure in thethree trimesters of pregnancy: effects of maternal characteristics and medical history.Ultrasound Obstet Gynecol 2015; 45: 698–706.
21. Tayyar A, Guerra L, Wright A, Wright D, Nicolaides KH. Uterine arterypulsatility index in the three trimesters of pregnancy: effects of maternalcharacteristics and medical history. Ultrasound Obstet Gynecol 2015; 45:689–697.
22. Tsiakkas A, Duvdevani N, Wright A, Wright D, Nicolaides KH. Serum placentalgrowth factor in the three trimesters of pregnancy: effects of maternal characteristicsand medical history. Ultrasound Obstet Gynecol 2015; 45: 591–598.
23. Wright D, Silva M, Papadopoulos S, Wright A, Nicolaides KH. Serumpregnancy-associated plasma protein-A in the three trimesters of pregnancy: effectsof maternal characteristics and medical history. Ultrasound Obstet Gynecol 2015;46: 42–50.
24. R Development Core Team. R. A language and environment for statistical computing.R Foundation for Statistical Computing, Vienna, Austria, 2011.
25. Robin X, Turck N, Hainard A, Tiberti N, Lisacek F, Sanchez J, M¨uller M. pROC:an open-source package for R and S+ to analyze and compare ROC curves. BMCBioinformatics 2011; 12: 77–84.
26. ACOG. Committee Opinion No. 638: First-trimester risk assessment for early-onsetpreeclampsia. Obstet Gynecol 2015; 126: e25–27.
27. Panaitescu A, Ciobanu A, Syngelaki A, Wright A, Wright D, Nicolaides KH. Screeningfor pre-eclampsia at 35 –37 weeks’ gestation. Ultrasound Obstet Gynecol 2018. DOI:10.1002/uog.19111.
28. Poon LC, Rolnik DL, Tan MY, Delgado JL, Tsokaki T, Akolekar R, Singh M,Andrade W, Efeturk T, Jani JC, Plasencia W, Papaioannou G, Blazquez AR, CarboneIF, Wright D, Nicolaides KH. ASPRE trial: incidence of preterm preeclampsia inpatients fulfilling ACOG and NICE criteria according to risk by the FMF algorithm.Ultrasound Obstet Gynecol 2018; 51: 738–742.
29. Wright D, Gallo DM, Gil Pugliese S, Casanova C, Nicolaides KH. Contingentscreening for preterm pre-eclampsia. Ultrasound Obstet Gynecol 2016; 47:554–559.
30. Panaitescu AM, Syngelaki A, Prodan N, Akolekar R, Nicolaides KH. Chronichypertension and adverse pregnancy outcomes: a cohort study. Ultrasound ObstetGynecol 2017; 50: 228–235.
31. Panaitescu AM, Akolekar R, Kametas N, Syngelaki A, Nicolaides KH. Impairedplacentation in women with chronic hypertension who develop pre-eclampsia.Ultrasound Obstet Gynecol 2017; 50: 496–500.