Uterine artery Doppler ultrasonograpy is a noninvasive tool that can be used to measure uteroplacental perfusion and thereby indirectly assess trophoblast development.16–18 Uterine artery Doppler has a better detection rate for preterm rather than term preeclampsia and is more sensitive in the second trimester compared with the first trimester.8–11 Cystatin C is an inhibitor of the cysteine proteases, which are thought to play an important role in the degradation of the extracellular matrix that occurs during normal trophoblast invasion. Recent evidence has demonstrated that cystatin C is not only increased in preeclampsia but also elevated in the first trimester in women destined to have preeclampsia develop compared with those having a normal pregnancy.19–21 β2-microglobulin, serum amyloid A, neopterin, and CRP are all markers of cellular or humoral immune activation. All of these markers have been implicated in the pathophysiology of preeclampsia.20,22–30
The current study assessed five early-pregnancy maternal serum markers and second-trimester uterine artery Doppler resistance index in the prediction of preeclampsia. Univariable regression analysis showed that women with preeclampsia do not have increased serum levels of serum amyloid A compared with women with a normal pregnancy outcome. Moreover, when applying multiple regression only cystatin C, CRP, and uterine artery RI remained significantly associated with the subsequent development of preeclampsia. β2-microglobulin and neopterin were too closely correlated with cystatin C to be used in combination. These results are consistent with the hypothesis that preeclampsia has a multifactorial cause and may result from the consequences of a persistent systemic inflammatory response and impaired placentation during early pregnancy. We confirm the hypothesis that by combining independent markers it is possible to improve the detection rate for preeclampsia. The receiver-operating characteristic curve analysis showed that, if we consider the combination of cystatin C, CRP, and mean RI, then the area under the curve is 0.825, which is higher than with each marker in isolation. At a fixed false-positive rate of 10%, prediction of preeclampsia is 38.5% by using uterine artery mean RI; however, if cystatin C and CRP are added, then the detection rate improves to 43.6%. The combined sensitivity of uterine artery RI, log cystatin C, and log CRP for preeclampsia was 69.2% when the screen-positive rate was set at 15%.
The findings of this study are that second-trimester uterine artery Doppler RI, cystatin C, and CRP are independent predictors of preeclampsia, and that combining the markers improves the detection of disease. We have also shown that careful analysis of multiple marker models is necessary because many exhibit a close correlation. Our data support the hypothesized etiological pathways related to preeclampsia, namely maternal systemic inflammation coupled with incomplete trophoblastic invasion and the dysregulation of placental proteases. Further prospective studies of larger populations are required to develop a panel of multiple predictors to cover all possible pathogenetic mechanisms. Combining independent markers gives the possibility of establishing a screening test with a high detection rate and low false-positive rate for the definitive prediction of preeclampsia.
1. Papageorghiou AT. Predicting and preventing preeclampsia-where to next? Ultrasound Obstet Gynecol 2008;31:367–70.
2. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365:785–99.
3. Villar J, Abdel-Aleem H, Merialdi M, Mathai M, Ali MM, Zavaleta N, et al. World health organization calcium supplementation for the prevention of preeclampsia. Am J Obstet Gynecol 2006;194:639–49.
4. Rumbold AR, Crowther CA, Haslam RR, Dekker GA, Robinson GA. ACTS Study Group. Vitamins C and E and the risks of preeclampsia and perinatal complications. N Engl J Med 2006;354:1796–806.
5. Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH. Vitamins in Pre-eclampsia (VIP) Trial Consortium. Vitamins in preeclampsia (VIP) Trial Consortium. Lancet 2006;367:1145–54.
6. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. PARIS Collaborative Group. Antiplatelet agents prevention for preeclampsia: a meta-analysis of individual patient data. Lancet 2007;369:1791–8.
7. Albaiges G, Missfelder-Lobos H, Lees C, Parra M, Nicolaides KH. One-stage screening for pregnancy complications by color Doppler assessment of the uterine arteries at 23 weeks' gestation. Obstet Gynecol 2000;96:559–64.
8. Papageorghiou AT, Yu CK, Bindra R, Pandis G, Nicolaides KH. Fetal Medicine Foundation Second Trimester Screening Group. Multicenter screening for preeclampsia and fetal growth restriction by transvaginal uterine artery Doppler at 23 weeks of gestation. Ultrasound Obstet Gynecol 2001;18:441–9.
9. Martin AM, Bindra R, Curcio P, Cicero S, Nicolaides KH. Screening for preeclampsia and fetal growth restriction by uterine artery Doppler at 11–14 weeks of gestation. Ultrasound Obstet Gynecol 2001;18:583–6.
10. Papageorghiou AT, Leslie K. Uterine artery Doppler in the prediction of adverse pregnancy outcome. Curr Opin Obstet Gynecol 2007;19:103–9.
11. Melchiorre K, Wormald B, Leslie K, Bhide A, Thilaganathan B. First-trimester uterine artery Doppler indices in term and pre-term preeclampsia. Ultrasound Obstet Gynecol 2008;32:133–7.
12. Aquilina J, Thompson O, Thilaganathan B, Harrington K. Improved early prediction of pre-eclampsia by combining second-trimester maternal serum inhibin-A and uterine artery Doppler. Ultrasound Obstet Gynecol 2001;17:477–84.
13. Spencer K, Yu CK, Savvidou M, Papageorghiou AT, Nicolaides KH. Prediction of preeclampsia by uterine artery Doppler ultrasonography and maternal serum pregnancy-associated plasma protein A, free beta-human chorionic gonadotropin, activin A and inhibin A at 22+0 to 24+6 weeks' gestation. Ultrasound Obstet Gynecol 2006;27:658–63.
14. Prefumo F, Canini S, Casagrande V, Pastorino D, Venturini PL, De Biasio P. Correlation between first-trimester uterine artery Doppler indices and maternal serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A. Fertil Steril 2006;86:977–80.
15. Cnossen JS, ter Riet G, Mol BW, van der Post JA, Leeflang MM, Meads CA, et al. Are tests for predicting pre-eclampsia good enough to make screening viable? A review of reviews and critical appraisal. Acta Obstet Gynecol Scand. 2009;88:758–65.
16. Prefumo F, Sebire NJ, Thilaganathan B. Decreased endovascular trophoblast invasion in first trimester pregnancies with high-resistance uterine artery Doppler indices. Hum Reprod 2004;19:206–9.
17. Lin S, Shimizu I, Suehara N, Nakayama M, Aono T. Uterine artery Doppler velocimetry in relation to trophoblast migration into the myometrium of the placental bed. Obstet Gynecol 1995;85(5 Pt 1):760–5.
18. Aardema MW, Oosterhof H, Timmer A, van Rooy I, Aarnoudse JG. Uterine artery Doppler flow and uteroplacental vascular pathology in normal pregnancies and pregnancies complicated by pre-eclampsia and small for gestational age fetuses. Placenta 2001;22:405–11.
19. Kristensen K, Larsson I, Hansson SR. Increased cystatin C expression in the pre-eclamptic placenta. Mol Hum Reprod 2007;13:189–95.
20. Kristensen K, Wide-Swensson D, Schmidt C, Blirup-Jensen S, Lindström V, Strevens H, et al. Cystatin C, beta-2-microglobulin and beta-trace protein in preeclampsia. Acta Obstet Gynecol Scand 2007;86:921–6.
21. Thilaganathan B, Ralph E, Papageorghiou AT, Melchiorre K, Sheldon J. Raised maternal serum cystatin C: an early pregnancy marker for preeclampsia. Reprod Sci 2009;16:788–93.
22. Haddad B, Desvaux D, Livingston JC, Barranger E, Paniel BJ, Sibai BM. Failure of serum beta2-microglobulin levels as an early marker of preeclampsia. Am J Obstet Gynecol 2000;182:595–8.
23. Engin-Ustün Y, Ustün Y, Karabulut AB, Ozkaplan E, Meydanli MM, Kafkasli A. Serum amyloid A levels are increased in preeclampsia. Gynecol Obstet Invest 2007;64:117–20.
24. Kronborg CS, Knudsen UB, Moestrup SK, Allen J, Vittinghus E, Møller HJ. Serum markers of macrophage activation in preeclampsia: no predictive value of soluble CD163 and neopterin. Acta Obstet Gynecol Scand 2007;86:1041–6.
25. Kaleli I, Kaleli B, Demir M, Yildirim B, Cevahir N, Demir S. Serum Levels of Neopterin and Interleukin-2 Receptor in Women With Severe Preeclampsia. J Clin Lab Anal 2005;19:36–9.
26. Ustün Y, Engin-Ustün Y, Kamaci M. Association of fibrinogen and C-reactive protein with severity of preeclampsia. Eur J Obstet Gynecol Reprod Biol 2005;121:154–8.
27. Djurovic S, Clausen T, Wergeland R, Brosstad F, Berg K, Henriksen T. Absence of enhanced systemic inflammatory response at 18 weeks of gestation in women with subsequent preeclampsia. BJOG 2002;109:759–64.
28. Qiu C, Luthy DA, Zhang C, Walsh SW, Leisenring WM, Williams MA. A prospective study of maternal serum C-reactive protein concentrations and risk of preeclampsia. Am J Hypertension 2004;17:154–60.
29. Tjoa ML, Van Vugt JM, Go AT, Blankenstein MA, Oudejans CB, van Wijk IJ. Elevated C-reactive protein levels during first trimester of pregnancy are indicative of preeclampsia and intrauterine growth restriction. J Reprod Immunol 2003;59:29–37.
30. Garcia RG, Celedon J, Sierra-Laquado J, Alarcon MA, Luengas C, Silva F, et al. Raised C-reactive protein and impaired flow-mediated vasodilatation precede the development of preeclampsia. Am J Hypert 2007;20:98–103.