Abstract
The focus on disease mechanisms underlying the hypertension and proteinuria defining preeclampsia has increased knowledge of the pathophysiology yet we lack both therapy and predictors. We propose this is in part due to the fact that diagnostic findings identify a “preeclampsia syndrome” but do not necessarily indicate the most important pathophysiology nor if organs are involved as cause or consequence. The increased risk for later life cardiovascular disease in women who develop preeclampsia suggests the stress test of pregnancy exposes pre-existing subclinical vascular disease. The dogma that inadequate trophoblast invasion and ischemia/reperfusion injury to the placenta is “the” cause of preeclampsia is more relevant to early onset preeclampsia (<34 weeks). There is much less evidence for defective placentation in late onset preeclampsia where maternal constitutive factors or susceptibility to vascular damage is more relevant. The contribution of differing disease phenotypes to the syndrome may explain the inability of biomarker studies to identify all preeclampsia. Identification of phenotypes will require large amounts of prospective clinical data and biospecimens, collected in a harmonized manner with analysis in an unbiased discovery approach.
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References
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Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol. 2009;33(3):130–7. doi:10.1053/j.semperi.2009.02.010.
Ghulmiyyah L, Sibai B. Maternal mortality from preeclampsia/eclampsia. Semin Perinatol. 2012;36(1):56–9. doi:10.1053/j.semperi.2011.09.011.
Myatt L, Webster RP. Vascular biology of preeclampsia. J Thromb Haemost. 2009;7(3):375–84. doi:10.1111/j.1538-7836.2008.03259.x.
Williams D. Pregnancy: a stress test for life. Curr Opin Obstet Gynecol. 2003;15(6):465–71. doi:10.1097/01.gco.0000103846.69273.ba.
Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E, et al. Low-dose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med. 1998;338(11):701–5.
Roberts JM, Hubel CA. Pregnancy: a screening test for later life cardiovascular disease. Womens Health Issues. 2010;20(5):304–7. doi:10.1016/j.whi.2010.05.004.
Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ. 2007;335(7627):974. doi:10.1136/bmj.39335.385301.BE.
Powe CE, Levine RJ, Karumanchi SA. Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease. Circulation. 2011;123(24):2856–69. doi:10.1161/CIRCULATIONAHA.109.853127.
Agatisa PK, Ness RB, Roberts JM, Costantino JP, Kuller LH, McLaughlin MK. Impairment of endothelial function in women with a history of preeclampsia: an indicator of cardiovascular risk. Am J Physiol Heart Circ Physiol. 2004;286(4):H1389–93.
Collen AC, Hellgren M, Gustafsson H, Johansson MC, Manhem K. Cardiovascular and metabolic characteristics 40 years after hypertensive pregnancies: a long-term follow-up study of mothers. J Hypertens. 2013;31(4):758–65.
Hubel CA, Wallukat G, Wolf M, Herse F, Rajakumar A, Roberts JM, et al. Agonistic angiotensin II type 1 receptor autoantibodies in postpartum women with a history of preeclampsia. Hypertension. 2007;49(3):612–7. doi:10.1161/01.HYP.0000256565.20983.d4.
Melchiorre K, Sutherland GR, Liberati M, Thilaganathan B. Preeclampsia is associated with persistent postpartum cardiovascular impairment. Hypertension. 2011;58(4):709–15.
Pouta A, Hartikainen A-L, Sovio U, Gissler M, Laitinen J, McCarthy MI, et al. Manifestations of metabolic syndrome after hypertensive pregnancy. Hypertension. 2004;43(4):825–31.
Wolf M, Hubel CA, Lam C, Sampson M, Ecker JL, Ness RB, et al. Preeclampsia and future cardiovascular disease: potential role of altered angiogenesis and insulin resistance. J Clin Endocrinol Metab. 2004;89(12):6239–43.
Catov JM, Parks WT, Roberts JM. Early pregnancy lipid and inflammatory markers in women with preterm premature rupture of membranes (PPROM) and preterm labor (PTL). Reprod Sci. 2010;17(3):389.
Catov JM, Wu CS, Olsen J, Sutton-Tyrrell K, Li J, Nohr EA. Early or recurrent preterm birth and maternal cardiovascular disease risk. Ann Epidemiol. 2010;20(8):604–9.
Germain AM, Romanik MC, Guerra I, Solari S, Reyes MS, Johnson RJ, et al. Endothelial dysfunction: a link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events?[see comment]. Hypertension. 2007;49(1):90–5.
Romundstad PR, Magnussen EB, Smith GD, Vatten LJ. Hypertension in pregnancy and later cardiovascular risk: common antecedents? Circulation. 2010;122(6):579–84. doi:10.1161/CIRCULATIONAHA.110.943407.
Brosens IA, Robertson WB, Dixon HG. The role of the spiral arteries in the pathogenesis of pre-eclampsia. J Pathol. 1970;101(4):Pvi.
Huppertz B. Placental origins of preeclampsia: challenging the current hypothesis. Hypertension. 2008;51(4):970–5. doi:10.1161/HYPERTENSIONAHA.107.107607.
Myatt L, Miodovnik M. Prediction of preeclampsia. Semin Perinatol. 1999;23(1):45–57.
Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350(7):672–83.
Roberts JM, Hubel CA. The two stage model of preeclampsia: variations on the theme. Placenta. 2009;30(Suppl A):S32–7. doi:10.1016/j.placenta.2008.11.009.
Chappell LC, Seed PT, Kelly FJ, Briley A, Hunt BJ, Charnock-Jones DS, et al. Vitamin C and E supplementation in women at risk of preeclampsia is associated with changes in indices of oxidative stress and placental function. Am J Obstet Gynecol. 2002;187(3):777–84.
Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC, Leveno KJ, et al. Vitamins C and E to prevent complications of pregnancy-associated hypertension. N Engl J Med. 2010;362:1282–91. doi:10.1056/NEJMoa0908056.
Kenny LC, Black MA, Poston L, Taylor R, Myers JE, Baker PN, et al. Early pregnancy prediction of preeclampsia in nulliparous women, combining clinical risk and biomarkers: the screening for pregnancy endpoints (SCOPE) international cohort study. Hypertension. 2014;64(3):644–52. doi:10.1161/HYPERTENSIONAHA.114.03578. The largest prospective study to date fails to reveal a panel of biomarkers and clinical factors that has clinical utility in prediction of preeclampsia.
Myatt L, Clifton RG, Roberts JM, Spong CY, Hauth JC, Varner MW, et al. First-trimester prediction of preeclampsia in nulliparous women at low risk. Obstet Gynecol. 2012;119(6):1234–42. doi:10.1097/AOG.0b013e3182571669.
Myatt L. Network. ftNM. Do women at high risk develop preeclampsia earlier in gestation than those at low risk? Am J Obstet Gynecol. 2001;184(Suppl):S81.
Myatt L. Network. ftNM. Differences in the time of diagnosis of mild vs severe preeclampsia between low and high risk patient groups. Hypertens Pregnancy. 2002;21 Suppl 1:63.
Roberts JM, Catov JM. Preeclampsia more than 1 disease: or is it? Hypertension. 2008;51(4):989–90. doi:10.1161/HYPERTENSIONAHA.107.100248.
Vatten LJ, Skjaerven R. Is pre-eclampsia more than one disease? BJOG. 2004;111(4):298–302.
Tranquilli AL, Brown MA, Zeeman GG, Dekker G, Sibai BM. The definition of severe and early-onset preeclampsia. Statements from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Pregnancy Hypertens. 2013;3(1):44–7. doi:10.1016/j.preghy.2012.11.001.
Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. Br Med J. 2001;323(7323):1213–7.
Mongraw-Chaffin ML, Cirillo PM, Cohn BA. Preeclampsia and cardiovascular disease death prospective evidence from the child health and development studies cohort. Hypertension. 2010;56(1):166–U264.
Nelson DB, Ziadie MS, McIntire DD, Rogers BB, Leveno KJ. Placental pathology suggesting that preeclampsia is more than one disease. Am J Obstet Gynecol. 2014;210(1):66 e1–7. doi:10.1016/j.ajog.2013.09.010.
Stark MW, Clark L, Craver RD. Histologic differences in placentas of preeclamptic/eclamptic gestations by birthweight, placental weight, and time of onset. Pediatr Dev Pathol. 2014;17(3):181–9. doi:10.2350/13-09-1378-OA.1.
Eskild A, Vatten LJ. Do pregnancies with pre-eclampsia have smaller placentas? A population study of 317 688 pregnancies with and without growth restriction in the offspring. BJOG. 2010;117(12):1521–6. doi:10.1111/j.1471-0528.2010.02701.x.
Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. First-trimester prediction of hypertensive disorders in pregnancy. Hypertension. 2009;53(5):812–8. doi:10.1161/HYPERTENSIONAHA.108.127977.
Roberts JM. Endothelial dysfunction in preeclampsia. Semin Reprod Endocrinol. 1998;16(1):5–15.
Khan F, Belch JJ, MacLeod M, Mires G. Changes in endothelial function precede the clinical disease in women in whom preeclampsia develops. Hypertension. 2005;46(5):1123–8. doi:10.1161/01.HYP.0000186328.90667.95.
Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989;161(5):1200–4.
Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111(5):649–58.
Karumanchi SA, Bdolah Y. Hypoxia and sFlt-1 in preeclampsia: the “chicken-and-egg” question. Endocrinology. 2004;145(11):4835–7.
Powers RW, Roberts JM, Plymire DA, Pucci D, Datwyler SA, Laird DM, et al. Low placental growth factor across pregnancy identifies a subset of women with preterm preeclampsia: type 1 versus type 2 preeclampsia? Hypertension. 2012;60(1):239–46. doi:10.1161/HYPERTENSIONAHA.112.191213. This paper shows that low PlGF is not common to all pregnancies with preeclampsia and reveals different phenotypes based on PLGF levels.
Wallner W, Sengenberger R, Strick R, Strissel PL, Meurer B, Beckmann MW, et al. Angiogenic growth factors in maternal and fetal serum in pregnancies complicated by intrauterine growth restriction. Clin Sci (Lond). 2007;112(1):51–7. doi:10.1042/CS20060161.
Dekker GA, Sibai BM. The immunology of preeclampsia. Semin Perinatol. 1999;23(1):24–33.
Redman CW, Sacks GP, Sargent IL. Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol. 1999;180(2 Pt 1):499–506.
Seely EW, Solomon CG. Insulin resistance and its potential role in pregnancy-induced hypertension. J Clin Endocrinol Metab. 2003;88(6):2393–8.
Founds SA, Catov JM, Gallaher MJ, Harger GF, Markovic N, Roberts JM. Is there evidence of separate inflammatory or metabolic forms of preeclampsia? Hypertens Pregnancy. 2011;30(1):1–10. doi:10.3109/10641950903322907.
Leijnse J, de Heus R, Peeters L, Oudijk M, Franx A, Eijkelkamp N. Poor placental vascularization at 12 weeks of pregnancy is associated with a specific cluster of serum proteins. Reprod Sci. 2015;22(S1):69A.
Johnson MP, Brennecke SP, East CE, Goring HH, Kent Jr JW, Dyer TD, et al. Genome-wide association scan identifies a risk locus for preeclampsia on 2q14, near the inhibin, beta B gene. PLoS One. 2012;7(3), e33666. doi:10.1371/journal.pone.0033666.
Laivuori H, Lahermo P, Ollikainen V, Widen E, Haiva-Mallinen L, Sundstrom H, et al. Susceptibility loci for preeclampsia on chromosomes 2p25 and 9p13 in Finnish families. Am J Hum Genet. 2003;72(1):168–77.
Founds SA, Conley YP, Lyons-Weiler JF, Jeyabalan A, Hogge WA, Conrad KP. Altered global gene expression in first trimester placentas of women destined to develop preeclampsia. Placenta. 2009;30(1):15–24. doi:10.1016/j.placenta.2008.09.015.
Kleinrouweler CE, van Uitert M, Moerland PD, Ris-Stalpers C, van der Post JA, Afink GB. Differentially expressed genes in the pre-eclamptic placenta: a systematic review and meta-analysis. PLoS One. 2013;8(7), e68991. doi:10.1371/journal.pone.0068991.
Loset M, Mundal SB, Johnson MP, Fenstad MH, Freed KA, Lian IA, et al. A transcriptional profile of the decidua in preeclampsia. Am J Obstet Gynecol. 2011;204(1):84 e1–27. doi:10.1016/j.ajog.2010.08.043.
Winn VD, Gormley M, Paquet AC, Kjaer-Sorensen K, Kramer A, Rumer KK, et al. Severe preeclampsia-related changes in gene expression at the maternal-fetal interface include sialic acid-binding immunoglobulin-like lectin-6 and pappalysin-2. Endocrinology. 2009;150(1):452–62. doi:10.1210/en.2008-0990.
Yong HE, Melton PE, Johnson MP, Freed KA, Kalionis B, Murthi P, et al. [81-OR]: genome-wide transcriptome directed pathway analysis of maternal preeclampsia susceptibility genes. Hypertens Pregnancy. 2015;5(1):43–4. doi:10.1016/j.preghy.2014.10.085.
Leavey K, Bainbridge SA, Cox BJ. Large scale aggregate microarray analysis reveals three distinct molecular subclasses of human preeclampsia. PLoS One. ;10(2):e0116508. doi:10.1371/journal.pone.0116508. An analysis of 7 placental microarray datasets revealed 3 distinct phenotypes of preeclampsia defined by differences in placental gene expression.
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Myatt, L., Roberts, J.M. Preeclampsia: Syndrome or Disease?. Curr Hypertens Rep 17, 83 (2015). https://doi.org/10.1007/s11906-015-0595-4
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DOI: https://doi.org/10.1007/s11906-015-0595-4