{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T04:39:14Z","timestamp":1791261554815,"version":"4.1.0"},"reference-count":59,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T00:00:00Z","timestamp":1767744000000},"content-version":"vor","delay-in-days":6,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The pregnancy-specific syndrome preeclampsia remains the syndrome of hypotheses. Still, there is not a single hypothesis explaining the etiology of the full spectrum of preeclampsia. This has direct consequences for the clinical management of the syndrome. So far, no single early biomarker has been identified to predict all women who will develop preeclampsia later in pregnancy. Similarly, no preventive treatment for all types of preeclampsia has been integrated into clinical routine. Interestingly, the last decade has not seen much progress in the quest of identifying the pathophysiological processes resulting in the clinical syndrome preeclampsia. This could be due to the following: (i) the preeclampsia definition has been immensely altered and widened to include a large variety of clinical subgroups; and\/or (ii) scientists and clinicians still adhere to the already challenged two-stage hypothesis and give only little room for new hypotheses. These two reasons could have thwarted the deciphering of the etiology of preeclampsia. This review will describe the limitations and challenges of the two-stage hypothesis. It will also highlight some of the new ideas and theories that have been put forward. In conclusion, there is an urgent need for new concepts that allow a better explanation of the diversity of preeclampsia regarding symptoms and time of occurrence. This in turn will result in more options to develop specific predictive biomarkers and personalized treatment options.<\/jats:p>","DOI":"10.1093\/molehr\/gaag001","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T12:22:58Z","timestamp":1767615778000},"source":"Crossref","is-referenced-by-count":7,"title":["Preeclampsia 2.0: limitations and challenges of the two-stage hypothesis, and beyond"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4814-2158","authenticated-orcid":false,"given":"Berthold","family":"Huppertz","sequence":"first","affiliation":[{"name":"Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Center, Medical University of Graz , Graz,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"key":"2026012107560225200_gaag001-B1","doi-asserted-by":"crossref","first-page":"2837","DOI":"10.3390\/ijms20112837","article-title":"The role of epigenetics in placental development and the etiology of preeclampsia","volume":"20","author":"Apicella","year":"2019","journal-title":"Int J Mol Sci"},{"key":"2026012107560225200_gaag001-B2","doi-asserted-by":"crossref","first-page":"604.e1","DOI":"10.1016\/j.ajog.2018.09.036","article-title":"The clinical heterogeneity of preeclampsia is related to both placental gene expression and placental histopathology","volume":"219","author":"Benton","year":"2018","journal-title":"Am J Obstet Gynecol"},{"key":"2026012107560225200_gaag001-B3","first-page":"2014","article-title":"The 9-month stress test: pregnancy and exercise-similarities and interactions","volume":"37","author":"Brislane","year":"2021","journal-title":"Can J Cardiol"},{"key":"2026012107560225200_gaag001-B4","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1186\/s12916-022-02610-y","article-title":"Maternal blood pressure associates with placental DNA methylation both directly and through alterations in cell-type composition","volume":"20","author":"Bros\u00e9us","year":"2022","journal-title":"BMC Med"},{"key":"2026012107560225200_gaag001-B5","doi-asserted-by":"crossref","first-page":"l2381","DOI":"10.1136\/bmj.l2381","article-title":"Pre-eclampsia: pathophysiology and clinical implications","volume":"366","author":"Burton","year":"2019","journal-title":"BMJ"},{"key":"2026012107560225200_gaag001-B6","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.placenta.2009.02.009","article-title":"Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy","volume":"30","author":"Burton","year":"2009","journal-title":"Placenta"},{"key":"2026012107560225200_gaag001-B7","doi-asserted-by":"crossref","first-page":"S1071","DOI":"10.1016\/j.ajog.2020.07.020","article-title":"First trimester preeclampsia screening and prediction","volume":"226","author":"Chaemsaithong","year":"2022","journal-title":"Am J Obstet Gynecol"},{"key":"2026012107560225200_gaag001-B8","doi-asserted-by":"crossref","first-page":"6439","DOI":"10.3390\/ijms26136439","article-title":"The role of mitochondrial dysfunction and oxidative stress in women\u2019s reproductive disorders: implications for polycystic ovary syndrome and preeclampsia","volume":"26","author":"Deer","year":"2025","journal-title":"Int J Mol Sci"},{"key":"2026012107560225200_gaag001-B9","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.jri.2010.12.010","article-title":"The etiology of preeclampsia: the role of the father","volume":"89","author":"Dekker","year":"2011","journal-title":"J Reprod Immunol"},{"key":"2026012107560225200_gaag001-B10","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/00006254-199806000-00023","article-title":"Immune maladaptation in the etiology of preeclampsia: a review of corroborative epidemiologic studies","volume":"53","author":"Dekker","year":"1998","journal-title":"Obstet Gynecol Surv"},{"key":"2026012107560225200_gaag001-B11","volume-title":"Statistical Brief #222. 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