{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T16:00:10Z","timestamp":1792425610159,"version":"4.5.0"},"reference-count":97,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Preeclampsia (PE) is clinically classified into early-onset (EOPE, &amp;lt;34 weeks) and late-onset (LOPE, \u226534 weeks) phenotypes that differ in epidemiology, angiogenic profiles, and outcomes. Although the 34-week cutoff is widely adopted, its biological rationale remains formally unarticulated in terms of placental developmental biology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To propose and evaluate the Placental Maturation Inflection Point (PMIP) \u2014 the transition from parenchymal expansion (Phase I) to functional optimization (Phase II) at approximately 34\u201336 weeks \u2014 as an integrative biological framework explaining the EOPE\/LOPE phenotype division. The PMIP is conceptualized as a distributed developmental transition zone (~30\u201336 weeks) rather than a discrete biological event at a single gestational age.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Narrative synthesis integrating evidence from placental morphometry, villous stereology, molecular trophoblast biology, endocrine and angiogenic biomarkers, imaging, and senescence biology, with structured engagement of competing frameworks.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Seven converging, partly interrelated lines of evidence may identify a placental developmental transition zone spanning ~34\u201336 weeks: (1) volumetric growth deceleration on MRI; (2) vasculosyncytial membrane attenuation and terminal villus predominance by stereology; (3) molecular regulators of syncytialization (p45 NF-E2, GCM1, Syncytin-1) showing trajectory shifts consistent with maturation; (4) human placental lactogen (hPL) near-plateau at ~34 weeks, reflecting maximal syncytiotrophoblast mass; (5) placental growth factor (PlGF) peak at ~30 weeks and subsequent soluble fms-like tyrosine kinase-1 (sFlt-1)\/PlGF ratio shift; (6) placental calcification accelerating after the 36-week Grannum threshold; and (7) differential senescence and stress-pathway activation in EOPE versus LOPE. Evidence strength varies across pillars and is graded explicitly. No prior framework has anchored the 34-week cutoff to a convergent multi-domain placental developmental transition.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The PMIP offers a biologically plausible framework for understanding why the 34-week cutoff has proven clinically productive. Within this hypothesis, EOPE reflects a pattern consistent with arrested Phase I, in which defective placentation may prevent functional maturity, whereas many LOPE cases may arise in the setting of a relatively mature placenta whose capacity is exceeded by maternal demand. Mixed phenotypes are expected; EOPE evidence is multi-stranded while LOPE evidence rests primarily on one molecular comparison and absence-of-pathology inference. This framework has implications for biomarker interpretation, therapeutic windows, and trial design.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2026.1899767","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T04:27:04Z","timestamp":1788236824000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["The placental maturation inflection point: an integrative biological framework for understanding early-onset versus late-onset preeclampsia"],"prefix":"10.3389","volume":"17","author":[{"given":"Ho Yen","family":"Chueh","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Medical Center","place":["Taoyuan, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia Lin","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Linkou Medical Center","place":["Taoyuan, Taiwan"]},{"name":"Chang Gung University College of Medicine","place":["Taoyuan, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1053\/j.semperi.2009.02.010","article-title":"The global impact of pre-eclampsia and eclampsia","volume":"33","author":"Duley","year":"2009","journal-title":"Semin Perinatol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejogrb.2013.05.005","article-title":"Global and regional estimates of preeclampsia and eclampsia","volume":"170","author":"Abalos","year":"2013","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1081\/PRG-120021060","article-title":"Subclassification of preeclampsia","volume":"22","author":"von Dadelszen","year":"2003","journal-title":"Hypertens Pregnancy"},{"key":"B4","doi-asserted-by":"publisher","first-page":"544.e1","DOI":"10.1016\/j.ajog.2013.08.019","article-title":"Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease","volume":"209","author":"Lisonkova","year":"2013","journal-title":"Am J Obstet Gynecol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/ijms262211091","article-title":"Late vs. early preeclampsia","volume":"26","author":"Kariori","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.108.117358","article-title":"Early and late preeclampsia: two different maternal hemodynamic states","volume":"52","author":"Valensise","year":"2008","journal-title":"Hypertension"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1097\/01.AOG.0000264552.85436.a1","article-title":"Placental growth factor and soluble fms-like tyrosine kinase-1 in early-onset and late-onset preeclampsia","volume":"109","author":"Wikstr\u00f6m","year":"2007","journal-title":"Obstet Gynecol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.107.107607","article-title":"Placental origins of preeclampsia: challenging the current hypothesis","volume":"51","author":"Huppertz","year":"2008","journal-title":"Hypertension"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1515\/jpm.2011.098","article-title":"Placental lesions associated with maternal underperfusion are more frequent in early-onset than in late-onset preeclampsia","volume":"39","author":"Ogge","year":"2011","journal-title":"J Perinat Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1111\/aogs.13846","article-title":"Validation of the 34-week gestation as definition of late onset preeclampsia: testing different cutoffs from 30 to 37 weeks on a population-based cohort of 1700 preeclamptics","volume":"99","author":"Robillard","year":"2020","journal-title":"Acta Obstet Gynecol Scand"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gaag001","article-title":"Preeclampsia 2.0: limitations and challenges of the two-stage hypothesis, and beyond","volume":"32","author":"Huppertz","year":"2026","journal-title":"Mol Hum Reprod"},{"key":"B12","volume-title":"Pathology of the Human Placenta","author":"Benirschke","year":"2006"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-020-0372-6","article-title":"Tracking placental development in health and disease","volume":"16","author":"Aplin","year":"2020","journal-title":"Nat Rev Endocrinol"},{"key":"B14","doi-asserted-by":"crossref","DOI":"10.4199\/C00016ED1V01Y201008ISP009","volume-title":"Vascular Biology of the Placenta","author":"Wang","year":"2010"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/S0143-4004(02)90865-9","article-title":"Fetoplacental angiogenesis during gestation is biphasic, longitudinal and occurs by proliferation and remodelling of vascular endothelial cells","volume":"23","author":"Mayhew","year":"2002","journal-title":"Placenta"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/0143-4004(92)90060-7","article-title":"Quantitative description of the elaboration and maturation of villi from 10 weeks of gestation to term","volume":"13","author":"Jackson","year":"1992","journal-title":"Placenta"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7580.2006.00566.x","article-title":"Allometric studies on growth and development of the human placenta: growth of tissue compartments and diffusive conductances in relation to placental volume and fetal mass","volume":"208","author":"Mayhew","year":"2006","journal-title":"J Anat"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1159\/000452661","article-title":"Placental growth during normal pregnancy: a magnetic resonance imaging study","volume":"82","author":"Langhoff","year":"2017","journal-title":"Gynecol Obstet Invest"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s00247-018-4213-x","article-title":"A retrospective segmentation analysis of placental volume by magnetic resonance imaging from first trimester to term gestation","volume":"48","author":"Le\u00f3n","year":"2018","journal-title":"Pediatr Radiol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejogrb.2023.01.013","article-title":"Placental volume, thickness and transverse relaxation time (T2*) estimated by magnetic resonance imaging in relation to small for gestational age at birth","volume":"282","author":"Mydtskov","year":"2023","journal-title":"Eur J Obstet Gynecol Reprod Biol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.64898\/2026.01.16.26344259","article-title":"Normative volumetric growth modeling of the whole fetal body, placenta and amniotic fluid for 3-dimensional T2-weighted magnetic resonance imaging","author":"Uus","year":"2026","journal-title":"medRxiv"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.media.2021.102145","article-title":"APPLAUSE: Automatic prediction of PLAcental health via U-net segmentation and statistical evaluation","volume":"72","author":"Pietsch","year":"2021","journal-title":"Med Image Anal"},{"key":"B23","first-page":"94","article-title":"Placental growth and fetal\/placental weight ratios throughout gestation: their relationship to patterns of fetal growth","volume":"8","author":"Molteni","year":"1984","journal-title":"Semin Perinatol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"285.e1","DOI":"10.1016\/j.ajog.2018.05.016","article-title":"Fetal growth velocity: the NICHD fetal growth studies","volume":"219","author":"Grantz","year":"2018","journal-title":"Am J Obstet Gynecol"},{"key":"B25","article-title":"Placental development and early pregnancy pathology","volume-title":"GLOWM (Global Library of Women's Medicine)","author":"Salafia","year":"2009"},{"key":"B26","article-title":"Structure of the placenta","volume-title":"Vascular Biology of the Placenta","author":"Wang","year":"2010"},{"key":"B27","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-030-84725-8","volume-title":"Benirschke's Pathology of the Human Placenta","author":"Baergen","year":"2022"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/S0143-4004(85)80054-0","article-title":"Stereological studies on the true thickness of the villous membrane in human term placentae","volume":"6","author":"Jackson","year":"1985","journal-title":"Placenta"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/0143-4004(91)90017-A","article-title":"Villous composition and membrane thickness in the human placenta at term: a stereological study using unbiased estimators and optimal fixation techniques","volume":"12","author":"Feneley","year":"1991","journal-title":"Placenta"},{"key":"B30","first-page":"691","article-title":"Structure-function correlation in the human placenta: the morphometric diffusing capacity for oxygen at full term","volume":"139","author":"Mayhew","year":"1984","journal-title":"J Anat"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/apm.12858","article-title":"Re-view and view on maturation disorders in the placenta","volume":"126","author":"Turowski","year":"2018","journal-title":"APMIS"},{"key":"B32","doi-asserted-by":"publisher","first-page":"698","DOI":"10.5858\/arpa.2015-0225-CC","article-title":"Sampling and definitions of placental lesions: Amsterdam Placental Workshop Group Consensus Statement","volume":"140","author":"Khong","year":"2016","journal-title":"Arch Pathol Lab Med"},{"key":"B33","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.placenta.2024.09.020","article-title":"Characterising delayed villous maturation: a narrative literature review","volume":"156","author":"Soni","year":"2024","journal-title":"Placenta"},{"key":"B34","doi-asserted-by":"publisher","first-page":"231.e1","DOI":"10.1016\/j.ajog.2022.08.013","article-title":"Placental delayed villous maturation is associated with fetal congenital heart disease","volume":"228","author":"O'Hare","year":"2023","journal-title":"Am J Obstet Gynecol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/1471-0528.70125","article-title":"Risk factors and outcomes associated with delayed villous maturation in placenta: a systematic review and meta-analysis","volume":"133","author":"Mahindra","year":"2026","journal-title":"BJOG"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.placenta.2019.01.012","article-title":"Placental villous hypermaturation is associated with improved neonatal outcomes","volume":"76","author":"Christians","year":"2019","journal-title":"Placenta"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0194988","article-title":"Placental pathology predicts infantile physical development during first 18 months in Japanese population: Hamamatsu birth cohort for mothers and children (HBC Study)","volume":"13","author":"Yaguchi","year":"2018","journal-title":"PLoS One"},{"key":"B38","doi-asserted-by":"publisher","first-page":"2578","DOI":"10.1038\/s41598-022-06300-w","article-title":"Placental pathology predicts infantile neurodevelopment","volume":"12","author":"Ueda","year":"2022","journal-title":"Sci Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2203071119","article-title":"The multifaceted role of GCM1 during trophoblast differentiation in the human placenta","volume":"119","author":"Jeyarajah","year":"2022","journal-title":"Proc Natl Acad Sci USA"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1107182","article-title":"Regulators involved in trophoblast syncytialization in the placenta of intrauterine growth restriction","volume":"14","author":"Zhou","year":"2023","journal-title":"Front Endocrinol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2009.1","article-title":"Glial cell missing-1 transcription factor is required for the differentiation of the human trophoblast","volume":"16","author":"Baczyk","year":"2009","journal-title":"Cell Death Differ"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.127","article-title":"p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction","volume":"8","author":"Kohli","year":"2017","journal-title":"Cell Death Dis"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1242\/dev.059105","article-title":"p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth","volume":"138","author":"Kashif","year":"2011","journal-title":"Development"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-010-0656-8","article-title":"Impaired cell fusion and differentiation in placentae from patients with intrauterine growth restriction correlate with reduced levels of HERV envelope genes","volume":"88","author":"Ruebner","year":"2010","journal-title":"J Mol Med (Berl)"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1515\/jpem.2000.13.4.343","article-title":"The roles of placental growth hormone and placental lactogen in the regulation of human fetal growth and development","volume":"13","author":"Handwerger","year":"2000","journal-title":"J Pediatr Endocrinol Metab"},{"key":"B46","article-title":"Human placental lactogen levels in multiple pregnancies","volume":"52","author":"Spellacy","year":"1978","journal-title":"Obstet Gynecol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232415621","article-title":"Human placental lactogen in relation to maternal metabolic health and fetal outcomes: a systematic review and meta-analysis","volume":"23","author":"Rassie","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa031884","article-title":"Circulating angiogenic factors and the risk of preeclampsia","volume":"350","author":"Levine","year":"2004","journal-title":"N Engl J Med"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/jhh.2017.61","article-title":"Placental growth factor and pre-eclampsia","volume":"31","author":"Chau","year":"2017","journal-title":"J Hum Hypertens"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.113.01787","article-title":"New gestational phase-specific cutoff values for the use of the soluble fms-like tyrosine kinase-1\/placental growth factor ratio as a diagnostic test for preeclampsia","volume":"63","author":"Verlohren","year":"2014","journal-title":"Hypertension"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.119.12760","article-title":"Short-term prediction of adverse outcomes using the sFlt-1 (soluble fms-like tyrosine kinase 1)\/PlGF (placental growth factor) ratio in Asian women with suspected preeclampsia","volume":"74","author":"Bian","year":"2019","journal-title":"Hypertension"},{"key":"B52","volume-title":"Diagnostic Guidance DG49: PlGF-based testing to help diagnose suspected preeclampsia","year":"2022"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1101\/2025.11.12.687933","article-title":"Late-onset preeclampsia is characterised by accelerated placental aging","author":"Arthurs","year":"2025","journal-title":"bioRxiv"},{"key":"B54","article-title":"Endocrinology of pregnancy","volume-title":"Endotext","author":"Tal","year":"2021"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(72)90185-8","article-title":"Plasma estrone, estradiol, estriol, progesterone, and 17-hydroxyprogesterone in human pregnancy. I. Normal pregnancy","volume":"112","author":"Tulchinsky","year":"1972","journal-title":"Am J Obstet Gynecol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3389\/fgwh.2024.1428494","article-title":"Estradiol and progesterone from pregnancy to postpartum: a longitudinal latent class analysis","volume":"5","author":"Dukic","year":"2024","journal-title":"Front Glob Womens Health"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(79)90312-0","article-title":"The ultrasonic changes in the maturing placenta and their relation to fetal pulmonic maturity","volume":"133","author":"Grannum","year":"1979","journal-title":"Am J Obstet Gynecol"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.3390\/healthcare13060601","article-title":"Impact of placental grading on pregnancy outcomes: a retrospective cohort study","volume":"13","author":"Siargkas","year":"2025","journal-title":"Healthcare (Basel)"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics15101264","article-title":"The association of placental grading with perinatal outcomes: a systematic review and meta-analysis","volume":"15","author":"Siargkas","year":"2025","journal-title":"Diagnostics (Basel)"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.18632\/aging.204445","article-title":"Placental telomere length shortening is not associated with severe preeclampsia but the gestational age","volume":"15","author":"Yang","year":"2022","journal-title":"Aging (Albany NY)"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1177\/1933719118811644","article-title":"Telomere homeostasis and senescence markers are differently expressed in placentas from pregnancies with early- versus late-onset preeclampsia","volume":"26","author":"Farladansky-Gershnabel","year":"2019","journal-title":"Reprod Sci"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1002\/path.4394","article-title":"Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia","volume":"234","author":"Yung","year":"2014","journal-title":"J Pathol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/0143-4004(91)90339-h","article-title":"Current topic: pre-eclampsia and the placenta","volume":"12","author":"Redman","year":"1991","journal-title":"Placenta"},{"key":"B64","article-title":"The role of the spiral arteries in the pathogenesis of preeclampsia","volume":"1","author":"Brosens","year":"1972","journal-title":"Obstet Gynecol Annu"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2005.12.006","article-title":"The uterine spiral arteries in human pregnancy: facts and controversies","volume":"27","author":"Pijnenborg","year":"2006","journal-title":"Placenta"},{"key":"B66","doi-asserted-by":"publisher","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":"B67","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1159\/000341264","article-title":"Competing risks model in early screening for preeclampsia by biophysical and biochemical markers","volume":"33","author":"Akolekar","year":"2013","journal-title":"Fetal Diagn Ther"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1038\/ng1541","article-title":"Maternal segregation of the Dutch preeclampsia locus at 10q22 with a new member of the winged helix gene family","volume":"37","author":"van Dijk","year":"2005","journal-title":"Nat Genet"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.202994","article-title":"Preeclampsia-like symptoms induced in mice by fetoplacental expression of STOX1 are reversed by aspirin treatment","volume":"61","author":"Doridot","year":"2013","journal-title":"Hypertension"},{"key":"B70","article-title":"Late preterm birth","volume":"3","author":"Loftin","year":"2010","journal-title":"Rev Obstet Gynecol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1704559","article-title":"Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia","volume":"377","author":"Rolnik","year":"2017","journal-title":"N Engl J Med"},{"key":"B72","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1016\/j.ajog.2017.11.561","article-title":"Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis","volume":"218","author":"Roberge","year":"2018","journal-title":"Am J Obstet Gynecol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0b013e3181e9322a","article-title":"Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis","volume":"116","author":"Bujold","year":"2010","journal-title":"Obstet Gynecol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.5323","article-title":"Maternal sildenafil vs placebo in pregnant women with severe early-onset fetal growth restriction: a randomized clinical trial","volume":"3","author":"Pels","year":"2020","journal-title":"JAMA Netw Open"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.118.11191","article-title":"Cardiovascular system in preeclampsia and beyond","volume":"73","author":"Thilaganathan","year":"2019","journal-title":"Hypertension"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2026.156461","article-title":"Targeting the syncytiotrophoblast: a central player in the pathogenesis and therapy of preeclampsia","volume":"271","author":"Tong","year":"2026","journal-title":"Pathol Res Pract"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2021.11.1371","article-title":"The evolution of the diagnostic criteria of preeclampsia-eclampsia","volume":"226","author":"Tanner","year":"2022","journal-title":"Am J Obstet Gynecol"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/j.preghy.2021.09.008","article-title":"The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis & management recommendation for international practice","volume":"27","author":"Magee","year":"2022","journal-title":"Pregnancy Hypertens"},{"key":"B79","doi-asserted-by":"publisher","first-page":"517.e1","DOI":"10.1016\/j.ajog.2018.02.007","article-title":"Early and late preeclampsia are characterized by high cardiac output, but in the presence of fetal growth restriction, cardiac output is low: insights from a prospective study","volume":"218","author":"Tay","year":"2018","journal-title":"Am J Obstet Gynecol"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2020.10.052","article-title":"Preeclampsia has two phenotypes which require different treatment strategies","volume":"226","author":"Masini","year":"2022","journal-title":"Am J Obstet Gynecol"},{"key":"B81","doi-asserted-by":"publisher","first-page":"498","DOI":"10.3109\/14767058.2011.591461","article-title":"Late-onset preeclampsia is associated with an imbalance of angiogenic and anti-angiogenic factors in patients with and without placental lesions consistent with maternal underperfusion","volume":"25","author":"Soto","year":"2012","journal-title":"J Matern Fetal Neonatal Med"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.111.054361","article-title":"Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia","volume":"125","author":"Rana","year":"2012","journal-title":"Circulation"},{"key":"B83","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/j.medj.2023.07.005","article-title":"Two distinct molecular faces of preeclampsia revealed by single-cell transcriptomics","volume":"4","author":"Admati","year":"2023","journal-title":"Med (NY)"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2007-2952","article-title":"\"Late-preterm\" infants: a population at risk","volume":"120","author":"Engle","year":"2007","journal-title":"Pediatrics"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1113\/JP273330","article-title":"Placental phenotype and the insulin-like growth factors: resource allocation to fetal growth","volume":"595","author":"Sferruzzi-Perri","year":"2017","journal-title":"J Physiol"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2013-1210","article-title":"Hyperinsulinemia stimulates angiogenesis of human fetoplacental endothelial cells: a possible role of insulin in placental hypervascularization in diabetes mellitus","volume":"98","author":"Lassance","year":"2013","journal-title":"J Clin Endocrinol Metab"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2011.04.015","article-title":"Stereology of the placenta in type 1 and type 2 diabetes","volume":"32","author":"Higgins","year":"2011","journal-title":"Placenta"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.2337\/dc07-s203","article-title":"The human placenta in gestational diabetes mellitus: the insulin and cytokine network","volume":"30","author":"Desoye","year":"2007","journal-title":"Diabetes Care"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(82)90579-8","article-title":"Human fetal serum cortisol levels related to gestational age: evidence of a midgestational fall and a steep late gestational rise, independent of sex or mode of delivery","volume":"144","author":"Murphy","year":"1982","journal-title":"Am J Obstet Gynecol"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(19)31963-4","article-title":"Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial","volume":"394","author":"Chappell","year":"2019","journal-title":"Lancet"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1111\/1471-0528.70077","article-title":"Timing of delivery in preeclampsia: time to reconsider","author":"Horgan","year":"","journal-title":"BJOG"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0698-6","article-title":"Single-cell reconstruction of the early maternal-fetal interface in humans","volume":"563","author":"Vento-Tormo","year":"2018","journal-title":"Nature"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2026.04.014","article-title":"In women with chronic hypertension, does fetal growth restriction increase progression to maternal preeclampsia","author":"Magee","year":"","journal-title":"Am J Obstet Gynecol"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2026.04.004","article-title":"Evaluation of functional spiral artery count and jet dispersion index using power Doppler ultrasound: in vivo insights into the vascular pathology of placental dysfunction","author":"Mathewlynn","year":"","journal-title":"Placenta"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2026.04.014","article-title":"Maternal serum SPARCL-1 levels in preeclampsia: diagnostic performance by onset subtype","volume":"179","author":"Shirinova","year":"2026","journal-title":"Placenta"},{"key":"B96","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1056\/NEJMoa1414838","article-title":"Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia","volume":"374","author":"Zeisler","year":"2016","journal-title":"N Engl J Med"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25116136","article-title":"First trimester placental biomarkers for pregnancy outcomes","volume":"25","author":"Cristodoro","year":"2024","journal-title":"Int J Mol Sci"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1899767\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T04:27:07Z","timestamp":1788236827000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1899767\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":97,"alternative-id":["10.3389\/fendo.2026.1899767"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1899767","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]},"article-number":"1899767"}}