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Preeclampsia and eclampsia: the conceptual evolution of a syndrome

  • Offer Erez
    Affiliations
    Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI

    Department of Obstetrics and Gynecology, HaEmek Medical Center, Afula, Israel
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  • Roberto Romero
    Correspondence
    Corresponding author: Roberto Romero, MD, DMedSci.
    Affiliations
    Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI

    Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI

    Detroit Medical Center, Detroit, MI
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  • Eunjung Jung
    Affiliations
    Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
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  • Piya Chaemsaithong
    Affiliations
    Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI

    Faculty of Medicine, Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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  • Mariachiara Bosco
    Affiliations
    Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
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  • Manaphat Suksai
    Affiliations
    Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
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  • Dahiana M. Gallo
    Affiliations
    Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
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  • Francesca Gotsch
    Affiliations
    Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services, Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
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      Preeclampsia, one of the most enigmatic complications of pregnancy, is considered a pregnancy-specific disorder caused by the placenta and cured only by delivery. This article traces the condition from its origins—once thought to be a disease of the central nervous system, recognized by the occurrence of seizures (ie, eclampsia)—to the present time when preeclampsia is conceptualized primarily as a vascular disorder. We review the epidemiologic data that led to the recommendation to use diastolic hypertension and proteinuria as diagnostic criteria, as their combined presence was associated with an increased risk of fetal death and the birth of small-for-gestational-age neonates. However, preeclampsia is a multisystemic disorder with protean manifestations, and the condition can be present even in the absence of hypertension and proteinuria. Toxins gaining access to the maternal circulation have been proposed to mediate the clinical manifestations—hence, the term “toxemia of pregnancy,” which was used for several decades. The search for putative toxins has challenged investigators for more than a century, and a growing body of evidence suggests that products of an ischemic or a stressed placenta are responsible for the vascular changes that characterize this syndrome. The discovery that the placenta can produce antiangiogenic factors, which regulate endothelial cell function and induce intravascular inflammation, has been a major step forward in the understanding of preeclampsia. We view the release of antiangiogenic factors by the placenta as an adaptive response to improve uterine perfusion by modulating endothelial function and maternal cardiovascular performance. However, this homeostatic response can become maladaptive and lead to damage of target organs during pregnancy or the postpartum period. Early-onset preeclampsia has many features in common with atherosclerosis, whereas late-onset preeclampsia seems to result from a mismatch of fetal demands and maternal supply, that is, a metabolic crisis. Preeclampsia, as it is understood today, is essentially vascular dysfunction unmasked or caused by pregnancy. A subset of patients diagnosed with preeclampsia are at greater risk of the subsequent development of hypertension, ischemic heart disease, heart failure, vascular dementia, and end-stage renal disease. However, these adverse events may be the result of a preexisting vascular pathologic process; it is not known if the occurrence of preeclampsia increases the baseline risk. Therefore, the understanding, prediction, prevention, and treatment of preeclampsia are healthcare priorities.

      Key words

      Introduction

      Preeclampsia is a syndrome considered unique to pregnant women; its causes, pathophysiology, prediction, management, and prevention present formidable challenges. This article reviews the conceptual evolution of this disorder.

      An Enigmatic Pregnancy-Specific Disorder

      Convulsions in pregnant women: epilepsy vs eclampsia

      For centuries, ancient texts from Egypt, China, India, and Europe have recorded that pregnant women were at greater risk for seizures (Figure 1).
      • Chesley L.C.
      History and epidemiology of preeclampsia-eclampsia.
      Convulsions were reported to occur more frequently in primigravidae, both antepartum and postpartum, and to have a poor prognosis. A fundamental issue was whether seizures represented epilepsy or a unique, specific complication of pregnancy. The term “eclampsia” (derived from the Greek eklampsis, meaning “a shining forth”
      • Chesley L.C.
      A short history of eclampsia.
      ,
      • Chesley L.C.
      Hypertensive disorders in pregnancy.
      ) is attributed to François Boissier de Sauvages de Lacroix, a French physician and botanist interested in the taxonomy of diseases.

      François Boissier de Sauvages de Lacroix F. Pathologia methodica. Montpellier, Martel; 1739.

      ,
      • Bell M.J.
      A historical overview of preeclampsia-eclampsia.
      He proposed that eclampsia differed from epilepsy because the latter was chronic and recurred throughout the life span while Eclampsia parturientium did not.
      • Chesley L.C.
      History and epidemiology of preeclampsia-eclampsia.
      Figure thumbnail gr1
      Figure 1The Kahun Gynaecological Papyrus
      A, The Kahun Gynaecological Papyrus was a medical text from the late Middle Kingdom (1850–1700 BC) addressing women’s health. The Papyrus was found near the modern-day Egyptian town of El Lahun in 1889 by Flinders Petrie. The Kahun Gynaecological Papyrus (UC 32057) is housed at University College London, London, United Kingdom. Pages 1, 2, and 3 of Plate VI are shown in the figure. Information was obtained from https://en.wikipedia.org/wiki/Kahun_Gynaecological_Papyrus. B, The Kahun Gynaecological Papyrus was translated in 1893 by Frederick Griffiths and published as “The Petrie Papyri: hieratic papyri from Kahun and Gurob (principally of the Middle Kingdom).” The figure shows the translation of Prescription No. XXXIII from page 3 of the Plate VI (Medical Papyrus). It describes a cure to prevent a woman from biting her tongue the day of birth. Some modifications were made from “The Petrie Papyri: hieratic papyri from Kahun and Gurob (principally of the Middle Kingdom).”
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

      Convulsions and albuminuria

      The association of convulsions, edema, and albuminuria was reported in 1843 by John C. W. Lever at Guy’s Hospital in London, England,
      • Lever J.C.
      Cases of puerperal convulsions, with remarks.
      and James Young Simpson at the University of Edinburgh, Scotland.
      • Simpson J.Y.
      Contributions to the pathology and treatment of diseases of the uterus (Part III).
      Lever was interested in the similarities between patients with eclampsia and those with glomerulonephritis, who were cared for by Richard Bright at Guy’s Hospital (glomerulonephritis was known as “Bright’s disease” at the time).
      • Lever J.C.
      Cases of puerperal convulsions, with remarks.
      Lever tested the urine of 10 women diagnosed with puerperal convulsions and found albumin in most cases (9/10) (Figure 2).
      • Lever J.C.
      Cases of puerperal convulsions, with remarks.
      The exception was a patient who died from meningitis. Lever proposed that eclampsia differed from glomerulonephritis because albuminuria disappeared after delivery.
      Figure thumbnail gr2
      Figure 2First description of albuminuria in eclampsia
      The title page of the “Cases of puerperal convulsions, with remarks,” in which Dr John C. W. Lever, a British obstetrical physician, reported the association between puerperal convulsions and albuminuria. Modified from Lever.
      • Lever J.C.
      Cases of puerperal convulsions, with remarks.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

      The triad: hypertension, albuminuria, and edema

      Hypertension was recognized as a feature of eclampsia in 1885 by John William Ballantyne at the University of Edinburgh, who reported abnormalities in sphygmographic tracings (Figure 3) in three cases of pregnant women with “Bright’s disease.”
      • Ballantyne J.W.
      Sphygmographic tracings in puerperal eclampsia.
      Tracings were obtained during pregnancy, labor, and the postpartum period. Glomerulonephritis had been suspected in these cases given the combination of edema and albuminuria. Others have credited Louis Henri Vaquez and Pierre Nobécourt in 1897 with the discovery of eclamptic hypertension.

      Vaquez N. De la pression artérielle dans 1‘eclampsie puerperale. Bull Mem Soc Méd Hôp Paris. 1897;14:117–119.

      Figure thumbnail gr3
      Figure 3First demonstration of hypertension in eclampsia
      The sphygmographic tracings record blood pressure from women with preeclampsia (A) during pregnancy and (B) in the postpartum period. Modified from Ballantyne.
      • Ballantyne J.W.
      Sphygmographic tracings in puerperal eclampsia.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

      The origin of the term “preeclampsia”

      The association of hypertension, proteinuria, and convulsions was subsequently confirmed by other investigators, and importantly, some noted that hypertension and proteinuria were present before seizures, hence the name “preeclampsia.”
      • Bell M.J.
      A historical overview of preeclampsia-eclampsia.
      Leon Chesley credited the introduction of this term to John Clarence Webster
      • Webster J.C.
      A text-book of obstetrics.
      in 1903 in the United States and to Bar
      • Lindheimer M.D.
      • Taylor R.N.
      • Roberts J.M.
      • Cunningham F.G.
      • Chesley L.
      Chapter 1. Introduction, history, controversies, and definitions.
      in France (eclampsisme, meaning eclampsia without convulsions).
      • Lindheimer M.D.
      • Taylor R.N.
      • Roberts J.M.
      • Cunningham F.G.
      • Chesley L.
      Chapter 1. Introduction, history, controversies, and definitions.
      The concept took hold and has since been a driving force in the organization of prenatal care, which is largely structured to detect preeclampsia by measuring blood pressure, proteinuria, and by increasing the frequency of prenatal visits as term approaches.

      “Toxemia of pregnancy”

      Eclampsia and preeclampsia were originally attributed to “toxins” or “poisons” believed to enter the maternal circulation—hence, the term toxemia of pregnancy,
      • Bell M.J.
      A historical overview of preeclampsia-eclampsia.
      ,
      • Lindheimer M.D.
      • Taylor R.N.
      • Roberts J.M.
      • Cunningham F.G.
      • Chesley L.
      Chapter 1. Introduction, history, controversies, and definitions.
      • Romero R.
      • Lockwood C.
      • Oyarzun E.
      • Hobbins J.C.
      Toxemia: new concepts in an old disease.
      • Robillard P.Y.
      • Dekker G.
      • Chaouat G.
      • Scioscia M.
      • Iacobelli S.
      • Hulsey T.C.
      Historical evolution of ideas on eclampsia/preeclampsia: a proposed optimistic view of preeclampsia.
      although there was debate
      • Dieckmann W.J.
      Toxemias of pregnancy.
      over whether the source of the toxins was exogenous or endogenous. One exogenous source was thought to be bacteria, and Gerdes proposed that eclampsia was caused by products of a bacillus, which he named Bacillus eclampsiae.
      • DeLee J.B.
      Theories of eclampsia.
      ,
      • Loudon I.
      Some historical aspects of toxaemia of pregnancy. A review.
      The endogenous sources (autotoxicity) were proposed to be metabolic products of the fetus, mother, or placenta.
      • Stander H.J.
      The toxemias of pregnancy.
      The term “toxemias of pregnancy” included eclampsia, hyperemesis gravidarum, acute yellow atrophy of the liver, pruritus gravidarum, and ptyalism.
      • MacGillivray I.
      Definitions and Classifications. In: Pre-eclampsia: the hypertensive disease of pregnancy.
      The search for the toxins responsible for preeclampsia and eclampsia has lasted for more than a century. In 1914, James Young reported an association between placental infarctions and eclampsia and showed that placental extracts administered to guinea pigs induced seizures and other pathologic abnormalities.
      • Young J.
      The etiology of eclampsia and albuminuria and their relation to accidental haemorrhage.
      Subsequently, Hunter and Howard
      • Hunter Jr., C.A.
      • Howard W.F.
      A pressor substance (hysterotonin) occurring in toxemia.
      ,
      • Hunter Jr CA
      • Howard W.F.
      Etiology of hypertension in toxemia of pregnancy.
      demonstrated the presence of a “pressor substance” in placental and decidual extracts as well as in the plasma of patients with preeclampsia: they named this substance “hysterotonin.” Later, Tatum and Mulé obtained whole blood from patients with severe preeclampsia and retransfused it into the same patients after delivery, resulting in a transient, but significant, increase in systolic and diastolic blood pressure.
      • Tatum H.J.
      • Mulé J.G.
      The hypertensive action of blood from patients with pre-eclampsia.
      Similar observations were made by Pirani and MacGillivray,
      • Pirani B.B.
      • MacGillivray I.
      The effect of plasma retransfusion on the blood pressure in the puerperium.
      who collected plasma from pregnant women and then retransfused aliquots on postpartum day 6 and at six weeks after delivery (Figure 4). Plasma from patients with preeclampsia—but not normal pregnancy—elicited a hypertensive response on postpartum day 6. This finding led to the conclusion that a soluble factor present in the plasma of patients with preeclampsia could induce hypertension—supporting the concept of a circulating “toxin.” However, when a similar aliquot of plasma was retransfused six weeks after delivery, hypertension did not occur. This was interpreted as indicating that the increased vascular activity of patients to the circulating pressor substances (toxins) had disappeared. This conclusion was strengthened by subsequent observations that women with preeclampsia and those destined to develop preeclampsia are more sensitive to the pressor effects of angiotensin II.
      • Gant N.F.
      • Daley G.L.
      • Chand S.
      • Whalley P.J.
      • MacDonald P.C.
      A study of angiotensin II pressor response throughout primigravid pregnancy.
      The search for the “toxins” has continued to date, but the use of the term “toxemia” has progressively been abandoned. The antiangiogenic factor (soluble fms-like tyrosine kinase-1 [sFlt-1]) has emerged as a major candidate for one of the “toxins” responsible for preeclampsia.
      Figure thumbnail gr4
      Figure 4Autotransfusion of maternal blood induces hypertension
      Changes in diastolic blood pressure in patients with preeclampsia and controls (A) on postpartum day 6 and (B) at 6 weeks postpartum after plasma autotransfusion. Modified from Pirani and MacGillivray.
      • Pirani B.B.
      • MacGillivray I.
      The effect of plasma retransfusion on the blood pressure in the puerperium.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

      A Shift in Focus: From Maternal Signs to Fetal and Neonatal Adverse Outcomes

      A major change in the conceptualization of preeclampsia and eclampsia occurred when investigators refocused the emphasis from maternal health outcomes (eg, seizures and death) to fetal and neonatal outcomes (eg, fetal death, fetal growth restriction, and small-for-gestational-age [SGA]). Two major studies conducted in the United States shaped the classification of hypertensive disorders and the importance of proteinuria.
      • Page E.W.
      • Christianson R.
      Influence of blood pressure changes with and without proteinuria upon outcome of pregnancy.
      ,
      • Friedman E.A.
      • Neff R.K.
      Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria.
      Page and Christianson
      • Page E.W.
      • Christianson R.
      Influence of blood pressure changes with and without proteinuria upon outcome of pregnancy.
      reported the results of a prospective study of nearly 13,000 pregnancies between 1959 and 1967, which were part of the Child and Health Development studies conducted in the United States. Patients were classified according to the mean arterial blood pressure measured in the second and third trimesters and to the presence or absence of proteinuria. Preeclampsia was defined as an elevated blood pressure in the third trimester with proteinuria. If the patient presented with an elevated blood pressure in the second trimester, the disorder was considered to represent chronic hypertension.
      • Page E.W.
      • Christianson R.
      Influence of blood pressure changes with and without proteinuria upon outcome of pregnancy.
      The major finding of the study indicated that the rate of fetal death was higher in patients diagnosed with preeclampsia or chronic hypertension, but not in those with gestational hypertension (Figure 5).
      • Page E.W.
      • Christianson R.
      Influence of blood pressure changes with and without proteinuria upon outcome of pregnancy.
      Of interest, proteinuria (defined as 2+ or greater) was also a risk factor for fetal death, regardless of the presence of hypertension.
      Figure thumbnail gr5
      Figure 5Risk of stillbirth in patients with normotensive, gestational hypertension, chronic hypertension, and proteinuria
      Modified from Page et al.
      • Page E.W.
      • Christianson R.
      Influence of blood pressure changes with and without proteinuria upon outcome of pregnancy.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
      A major epidemiologic effort to examine the relationship among blood pressure, proteinuria, and adverse pregnancy outcome was undertaken as part of the Collaborative Perinatal Project, sponsored by the National Institutes of Health, which began in 1958 and prospectively enrolled 58,806 pregnancies at 12 university centers in the United States.
      • Friedman E.A.
      • Neff R.K.
      Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria.
      The results of the systematic evaluation of blood pressure, proteinuria, and pregnancy outcome were published in the book “Pregnancy hypertension” by Friedman and Neff (Figure 6).
      • Friedman E.A.
      • Neff R.K.
      Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria.
      One of the conclusions of this study was that edema, whether diagnosed by history or by physical examination, had minimal influence on outcome. This observation strengthened the case to remove edema from the triad of hypertension, proteinuria, and edema, which had formerly been used to diagnose preeclampsia. Moreover, the study was key in generating important data about the relationships among hypertension, proteinuria, and adverse pregnancy outcome.
      Figure thumbnail gr6
      Figure 6The book cover of “Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria” authored by Emanuel A. Friedman and Raymond K. Neff and published in 1977
      In this book, the authors reported results from the Collaborative Perinatal Project conducted in the United States. Modified from Friedman and Neff
      • Friedman E.A.
      • Neff R.K.
      Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
      Table 1 shows the rate ratios of fetal mortality by diastolic blood pressure according to gestational age.
      • Friedman E.A.
      • Neff R.K.
      Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria.
      Before 36 weeks of gestation, fetal mortality was associated with values of ≥85 mm Hg (diastolic blood pressure).
      • Friedman E.A.
      • Neff R.K.
      Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria.
      After 36 completed weeks of gestation, fetal mortality was associated with a diastolic blood pressure of ≥95 mm Hg.
      • Friedman E.A.
      • Neff R.K.
      Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria.
      Moreover, fetal mortality was associated with proteinuria exceeding 1+, and the greater the proteinuria, the higher the risk of fetal mortality (Table 2). Importantly, a synergistic effect was noted between diastolic blood pressure and proteinuria (Figure 7). For example, fetal mortality was increased 9-fold (Table 3, red circle) if diastolic blood pressure (95–104 mm Hg) and proteinuria 2+ were present. The data from the Collaborative Perinatal Project indicated that an elevation in systolic blood pressure was associated with virtually the same fetal outcome as an elevation in diastolic blood pressure.
      • Friedman E.A.
      • Neff R.K.
      Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria.
      However, diastolic pressure was considered a better risk indicator than systolic pressure, given that low systolic pressure was not associated with a poor outcome but low diastolic pressure was.
      Table 1Rate ratios of fetal mortality by diastolic blood pressure according to gestational age
      Gestational ages, (wk)Diastolic blood pressure (mm Hg)
      n<6565–74 (reference)75–8485–9495–104>105
      28–3224,6400.71.01.02.35.910.2
      33–3419,3400.91.01.12.37.18.3
      35–3620,5930.81.01.32.08.87.8
      37–3820,2431.01.01.21.82.8-
      39–4115,7970.81.01.01.23.22.6
      Modified from Friedman and Neff.
      • Friedman E.A.
      • Neff R.K.
      Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
      Table 2Fetal mortality rate and rate ratios by proteinuria maxima
      ProteinuriaFetal mortality rate, %Fetal mortality rate ratio
      None (reference)0.91.0
      Trace0.91.0
      1+1.21.3
      2+2.32.6
      3+4.44.9
      4+5.76.3
      Modified from Friedman and Neff.
      • Friedman E.A.
      • Neff R.K.
      Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
      Figure thumbnail gr7
      Figure 7The synergistic effect of diastolic blood pressure and proteinuria on the risk of fetal death
      The synergistic effect of diastolic blood pressure and proteinuria is evident, and it determines a considerable increase in the risk of fetal mortality. Modified from Friedman and Neff.
      • Friedman E.A.
      • Neff R.K.
      Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
      Table 3Rate ratios for fetal mortality by diastolic blood pressure and proteinuria combination
      Diastolic pressure (mm Hg)Proteinuria
      NoneTrace1+2+3+4+
      <652.52.31.0
      65–741.51.30.85.57.0
      75–841.0
      Reference rate of fetal mortality: 0.6% or 6 per 1000 births.
      1.31.03.2
      85–941.51.54.03.7
      95–1043.22.84.59.319.223.8
      ≥1053.34.710.511.520.818.5
      Modified from Friedman and Neff.
      • Friedman E.A.
      • Neff R.K.
      Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
      a Reference rate of fetal mortality: 0.6% or 6 per 1000 births.
      The clinical implementation of these observations followed the recommendation of the World Health Organization and the American College of Obstetricians and Gynecologists (ACOG). The selection of 90 mm Hg as a cutoff value for diastolic blood pressure was made because it is a midpoint between 85 mm Hg and 95 mm Hg (85 mm Hg was associated with fetal mortality when combined with proteinuria, and 95 mm Hg was associated with fetal mortality regardless of proteinuria).
      • Friedman E.A.
      • Neff R.K.
      Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria.
      Recent recommendations of the American College of Cardiology and the American Heart Association to lower the threshold for the diagnosis of hypertension in nonpregnant subjects to 130/80 mm Hg
      • Whelton P.K.
      • Carey R.M.
      • Aronow W.S.
      • et al.
      2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines.
      have now stimulated a dialogue about whether the threshold should also be applied to the diagnosis of preeclampsia.
      • Sisti G.
      • Colombi I.
      New blood pressure cut off for preeclampsia definition: 130/80 mmHg.
      ,
      • Hurrell A.
      • Webster L.
      • Chappell L.C.
      • Shennan A.H.
      The assessment of blood pressure in pregnant women: pitfalls and novel approaches.
      Early evidence suggests that perinatal outcomes in pregnant women with stage 1 hypertension before 20 weeks of gestation are worse than those with normal blood pressure (stage 1 hypertension is defined as BP range 130-139/80-89 mm Hg).
      • Greenberg V.R.
      • Silasi M.
      • Lundsberg L.S.
      • et al.
      Perinatal outcomes in women with elevated blood pressure and stage 1 hypertension.
      However, more work is necessary to determine whether the diagnostic criteria should be modified.

      Preeclampsia: More than Pregnancy-Induced Hypertension

      The hallmark of the clinical diagnosis of preeclampsia has been hypertension. However, the involvement of other organs has been known for decades based on autopsy findings and clinical reports (Figure 8).
      • Sheehan H.L.
      • Lynch J.B.
      Pathology of toxaemia of pregnancy.
      ,
      • Hecht J.L.
      • Ordi J.
      • Carrilho C.
      • et al.
      The pathology of eclampsia: an autopsy series.
      The most frequent organs involved are the kidney (proteinuria),
      • Hecht J.L.
      • Ordi J.
      • Carrilho C.
      • et al.
      The pathology of eclampsia: an autopsy series.
      ,
      • Stillman I.E.
      • Karumanchi S.A.
      The glomerular injury of preeclampsia.
      liver (elevation of transaminases, liver hematoma, and rupture),
      • Hecht J.L.
      • Ordi J.
      • Carrilho C.
      • et al.
      The pathology of eclampsia: an autopsy series.
      ,
      • Antia F.P.
      • Bharadwaj T.P.
      • Watsa M.C.
      • Master J.
      Liver in normal pregnancy, pre-eclampsia, and eclampsia.
      • Arias F.
      • Mancilla-Jimenez R.
      Hepatic fibrinogen deposits in pre-eclampsia. Immunofluorescent evidence.
      • Greenstein D.
      • Henderson J.M.
      • Boyer T.D.
      Liver hemorrhage: recurrent episodes during pregnancy complicated by preeclampsia.
      • Rinehart B.K.
      • Terrone D.A.
      • Magann E.F.
      • Martin R.W.
      • May W.L.
      • Martin Jr., J.N.
      Preeclampsia-associated hepatic hemorrhage and rupture: mode of management related to maternal and perinatal outcome.
      hematopoietic system (hemolysis, leukocytosis, and thrombocytopenia),
      • Sibai B.M.
      • Taslimi M.M.
      • el-Nazer A.
      • Amon E.
      • Mabie B.C.
      • Ryan G.M.
      Maternal-perinatal outcome associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia-eclampsia.
      • Reubinoff B.E.
      • Schenker J.G.
      HELLP syndrome--a syndrome of hemolysis, elevated liver enzymes and low platelet count--complicating preeclampsia-eclampsia.
      • Haeger M.
      • Unander M.
      • Norder-Hansson B.
      • Tylman M.
      • Bengtsson A.
      Complement, neutrophil, and macrophage activation in women with severe preeclampsia and the syndrome of hemolysis, elevated liver enzymes, and low platelet count.
      • Von Dadelszen P.
      • Watson R.W.
      • Noorwali F.
      • et al.
      Maternal neutrophil apoptosis in normal pregnancy, preeclampsia, and normotensive intrauterine growth restriction.
      • Von Dadelszen P.
      • Wilkins T.
      • Redman C.W.
      Maternal peripheral blood leukocytes in normal and pre-eclamptic pregnancies.
      • Swinkels D.W.
      • de Kok J.B.
      • Hendriks J.C.
      • Wiegerinck E.
      • Zusterzeel P.L.
      • Steegers E.A.
      Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome as a complication of preeclampsia in pregnant women increases the amount of cell-free fetal and maternal DNA in maternal plasma and serum.
      • Burwick R.M.
      • Feinberg B.B.
      Complement activation and regulation in preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome.
      brain (seizures, cortical blindness, intracranial hemorrhage, and infarction),
      • Liman T.G.
      • Bohner G.
      • Heuschmann P.U.
      • Scheel M.
      • Endres M.
      • Siebert E.
      Clinical and radiological differences in posterior reversible encephalopathy syndrome between patients with preeclampsia-eclampsia and other predisposing diseases.
      • Siepmann T.
      • Boardman H.
      • Bilderbeck A.
      • et al.
      Long-term cerebral white and gray matter changes after preeclampsia.
      • Miller E.C.
      Preeclampsia and cerebrovascular disease.
      and uteroplacental circulation (fetal growth restriction, abruption, and fetal death).
      • Young J.
      The etiology of eclampsia and albuminuria and their relation to accidental haemorrhage.
      ,
      • Hertig A.
      Vascular pathology in hypertensive albuminuric toxemias of pregnancy.
      • Robertson W.B.
      • Brosens I.
      • Dixon H.G.
      The pathological response of the vessels of the placental bed to hypertensive pregnancy.
      • Brosens I.
      • Renaer M.
      On the pathogenesis of placental infarcts in pre-eclampsia.
      • Brosens I.A.
      • Robertson W.B.
      • Dixon H.G.
      The role of the spiral arteries in the pathogenesis of preeclampsia.
      • De Wolf F.
      • Robertson W.B.
      • Brosens I.
      The ultrastructure of acute atherosis in hypertensive pregnancy.
      • Lunell N.O.
      • Nylund L.E.
      • Lewander R.
      • Sarby B.
      Uteroplacental blood flow in pre-eclampsia measurements with indium-113m and a computer-linked gamma camera.
      • Khong T.Y.
      • De Wolf F.
      • Robertson W.B.
      • Brosens I.
      Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants.
      • Brosens I.
      • Pijnenborg R.
      • Vercruysse L.
      • Romero R.
      The “Great Obstetrical Syndromes” are associated with disorders of deep placentation.
      • Burton G.J.
      • Jauniaux E.
      Pathophysiology of placental-derived fetal growth restriction.
      Other organs and systems that may be involved include the lung (ventilation-perfusion mismatch and adult respiratory distress syndrome),
      • Sibai B.M.
      • Mabie B.C.
      • Harvey C.J.
      • Gonzalez A.R.
      Pulmonary edema in severe preeclampsia-eclampsia: analysis of thirty-seven consecutive cases.
      heart (systolic and diastolic dysfunction),
      • Szekely P.
      • Snaith L.
      The heart in toxaemia of pregnancy.
      • Desai D.K.
      • Moodley J.
      • Naidoo D.P.
      • Bhorat I.
      Cardiac abnormalities in pulmonary oedema associated with hypertensive crises in pregnancy.
      • De Paco C.
      • Kametas N.
      • Rencoret G.
      • Strobl I.
      • Nicolaides K.H.
      Maternal cardiac output between 11 and 13 weeks of gestation in the prediction of preeclampsia and small for gestational age.
      • Bamfo J.E.
      • Kametas N.A.
      • Chambers J.B.
      • Nicolaides K.H.
      Maternal cardiac function in normotensive and pre-eclamptic intrauterine growth restriction.
      • Bhorat I.
      • Naidoo D.P.
      • Moodley J.
      Maternal cardiac haemodynamics in severe pre-eclampsia complicated by acute pulmonary oedema: a review.
      • Orabona R.
      • Sciatti E.
      • Prefumo F.
      • et al.
      Pre-eclampsia and heart failure: a close relationship.
      pancreas (pancreatitis),
      • Sang C.
      • Wang S.
      • Zhang Z.
      • Lu J.
      Characteristics and outcome of severe preeclampsia/eclampsia concurrent with or complicated by acute pancreatitis: a report of five cases and literature review.
      eyes (retinal problems including detachment),
      • Auger N.
      • Fraser W.D.
      • Paradis G.
      • Healy-Profitós J.
      • Hsieh A.
      • Rhéaume M.A.
      Preeclampsia and long-term risk of maternal retinal disorders.
      ,
      • Lee C.S.
      • Choi E.Y.
      • Lee M.
      • Kim H.
      • Chung H.
      Serous retinal detachment in preeclampsia and malignant hypertension.
      small and large intestines (ischemia),
      • Barton J.R.
      • Sibai B.M.
      Gastrointestinal complications of pre-eclampsia.
      endocrine organs (adrenal glands, thyroid, and parathyroid),
      • Hultin H.
      • Hellman P.
      • Lundgren E.
      • et al.
      Association of parathyroid adenoma and pregnancy with preeclampsia.
      • Levine R.J.
      • Vatten L.J.
      • Horowitz G.L.
      • et al.
      Pre-eclampsia, soluble fms-like tyrosine kinase 1, and the risk of reduced thyroid function: nested case-control and population based study.
      • Siddiqui A.H.
      • Irani R.A.
      • Zhang W.
      • et al.
      Angiotensin receptor agonistic autoantibody-mediated soluble fms-like tyrosine kinase-1 induction contributes to impaired adrenal vasculature and decreased aldosterone production in preeclampsia.
      • Currie G.
      • Carty D.M.
      • Connell J.M.
      • Freel M.
      Endocrine aspects of pre-eclampsia.
      • Alharbi B.A.
      • Alqahtani M.A.
      • Hmoud M.
      • Alhejaili E.A.
      • Badros R.
      Preeclampsia: a possible complication of primary hyperparathyroidism.
      and immune system (exaggerated intravascular inflammation and changes in B and T cells as well as in T regulatory cells).
      • Dekker G.A.
      • Sibai B.M.
      The immunology of preeclampsia.
      • Gerard C.
      10 Workshops on immunology of preeclampsia.
      • Tsuda S.
      • Nakashima A.
      • Shima T.
      • Saito S.
      New paradigm in the role of regulatory T cells during pregnancy.
      • Miller D.
      • Motomura K.
      • Galaz J.
      • et al.
      Cellular immune responses in the pathophysiology of preeclampsia.
      Figure thumbnail gr8
      Figure 8Preeclampsia as a multisystemic disease that involves virtually every organ system
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

      An Atypical Form of Preeclampsia: Hemolysis, Elevated Liver Enzymes, and Low Platelet Syndrome

      Clinicians and investigators realized that “toxemia of pregnancy” could occur without hypertension. For example, approximately 15% of patients with HELLP syndrome have normal diastolic blood pressure at admission,
      • Sibai B.M.
      • Taslimi M.M.
      • el-Nazer A.
      • Amon E.
      • Mabie B.C.
      • Ryan G.M.
      Maternal-perinatal outcome associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia-eclampsia.
      ,
      • Rath W.
      • Faridi A.
      • Dudenhausen J.W.
      HELLP syndrome.
      and 10% to 15% of patients with eclampsia
      • Mattar F.
      • Sibai B.M.
      Eclampsia. VIII. Risk factors for maternal morbidity.
      • Vollaard E.
      • Zeeman G.
      • Alexander J.A.
      • McIntire D.D.
      • Cunningham F.G.
      479: “Delta eclampsia”- a hypertensive encephalopathy of pregnancy in “normotensive” women.
      • Karumanchi S.A.
      • Lindheimer M.D.
      Advances in the understanding of eclampsia.
      do not develop hypertension. Goodlin
      • Goodlin R.C.
      Severe pre-eclampsia: another great imitator.
      emphasized this point with a case series of patients with atypical presentation and proposed that preeclampsia was another “great imitator” (others include syphilis, tuberculosis, and Lyme disease) (Figure 9). In 1982, Louis Weinstein coined the term “HELLP syndrome” to describe the combination of hemolysis, elevated liver enzymes, and low platelet count and proposed it to be a severe consequence of hypertension in pregnancy (Figure 10).
      • Weinstein L.
      Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy.
      However, this cluster of laboratory findings, often associated with abdominal pain, can occur in the absence of hypertension and proteinuria
      • Romero R.
      • Mazor M.
      • Lockwood C.J.
      • et al.
      Clinical significance, prevalence, and natural history of thrombocytopenia in pregnancy-induced hypertension.
      ,
      • Sibai B.M.
      Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count.
      : sometimes, thrombocytopenia and liver dysfunction can resolve before delivery.
      • Romero R.
      • Mazor M.
      • Lockwood C.J.
      • et al.
      Clinical significance, prevalence, and natural history of thrombocytopenia in pregnancy-induced hypertension.
      Thrombocytopenia and an elevated SGOT (serum glutamic-oxaloacetic transaminase) level are independent risk factors for adverse pregnancy outcomes after adjusting for hypertension and proteinuria. Patients may present with unusual clinical manifestations, such as visual disturbances,
      • Jaffe G.
      • Schatz H.
      Ocular manifestations of preeclampsia.
      • Abu Samra K.
      The eye and visual system in the preeclampsia/eclampsia syndrome: what to expect?.
      • Ghavidel L.A.
      • Mousavi F.
      • Bagheri M.
      • Asghari S.
      Preeclampsia induced ocular change.
      renal failure,
      • Stratta P.
      • Canavese C.
      • Colla L.
      • et al.
      Acute renal failure in preeclampsia-eclampsia.
      ,
      • Drakeley A.J.
      • Le Roux P.A.
      • Anthony J.
      • Penny J.
      Acute renal failure complicating severe preeclampsia requiring admission to an obstetric intensive care unit.
      congestive heart failure,
      • Orabona R.
      • Sciatti E.
      • Prefumo F.
      • et al.
      Pre-eclampsia and heart failure: a close relationship.
      abdominal pain,
      • Suarez B.
      • Alves K.
      • Senat M.V.
      • et al.
      Abdominal pain and preeclampsia: sonographic findings in the maternal liver.
      ,
      • Moore M.P.
      Don’t forget pre-eclampsia in the differential diagnosis of abdominal pain in pregnancy.
      and headaches.
      • Dangel A.R.
      • Atlas R.O.
      • Matsuo K.
      Headaches in pre-eclampsia: a clinical dilemma in diagnosing intracranial hemorrhage.
      ,
      • Marsál K.
      Association of cerebral perfusion pressure with headache in women with pre-eclampsia.
      .
      Figure thumbnail gr9
      Figure 9Atypical presentations of “toxemia of pregnancy”
      The abstract of the study “Severe pre-eclampsia: another great imitator” by Robert C. Goodlin is shown. Modified from Goodlin.
      • Goodlin R.C.
      Severe pre-eclampsia: another great imitator.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
      Figure thumbnail gr10
      Figure 10The origin of the term “HELLP syndrome”
      The term HELLP was coined from the original paper “Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy” by Weinstein. Adapted from Weinstein.
      • Weinstein L.
      Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy.
      HELLP, hemolysis, elevated liver enzymes, and low platelet count.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

      Preeclampsia Without Proteinuria?

      Proteinuria has been a requirement for the diagnosis of preeclampsia for decades, as it reflects renal involvement; however, in the 1990s, several groups of investigators began to question whether proteinuria should be a necessary criterion.
      • Brown M.A.
      • Buddie M.L.
      The importance of nonproteinuric hypertension in pregnancy.
      • Buchbinder A.
      • Sibai B.M.
      • Caritis S.
      • et al.
      Adverse perinatal outcomes are significantly higher in severe gestational hypertension than in mild preeclampsia.
      • Magee L.A.
      • von Dadelszen P.
      • Bohun C.M.
      • et al.
      Serious perinatal complications of non-proteinuric hypertension: an international, multicentre, retrospective cohort study.
      • Fishel Bartal M.
      • Lindheimer M.D.
      • Sibai B.M.
      Proteinuria during pregnancy: definition, pathophysiology, methodology, and clinical significance.
      Multiple studies reported that patients with severe gestational hypertension had a high rate of adverse pregnancy outcomes, despite the absence of proteinuria.
      • Brown M.A.
      • Buddie M.L.
      The importance of nonproteinuric hypertension in pregnancy.
      • Buchbinder A.
      • Sibai B.M.
      • Caritis S.
      • et al.
      Adverse perinatal outcomes are significantly higher in severe gestational hypertension than in mild preeclampsia.
      • Magee L.A.
      • von Dadelszen P.
      • Bohun C.M.
      • et al.
      Serious perinatal complications of non-proteinuric hypertension: an international, multicentre, retrospective cohort study.
      The frequency of preterm birth, SGA, placental abruption, neonatal respiratory distress syndrome, and perinatal death is higher among women with severe gestational hypertension than in those with mild preeclampsia.
      • Buchbinder A.
      • Sibai B.M.
      • Caritis S.
      • et al.
      Adverse perinatal outcomes are significantly higher in severe gestational hypertension than in mild preeclampsia.
      Additionally, approximately 50% of women with an initial diagnosis of gestational hypertension will subsequently develop proteinuria or end-organ damage.
      • Magee L.A.
      • von Dadelszen P.
      • Bohun C.M.
      • et al.
      Serious perinatal complications of non-proteinuric hypertension: an international, multicentre, retrospective cohort study.
      ,
      • Tochio A.
      • Obata S.
      • Saigusa Y.
      • Shindo R.
      • Miyagi E.
      • Aoki S.
      Does pre-eclampsia without proteinuria lead to different pregnancy outcomes than pre-eclampsia with proteinuria?.
      Two additional arguments favored abandoning the requirement of proteinuria for the diagnosis of preeclampsia: the standard definition (≥300 mg in a 24-hour urine collection or a ≥0.3 protein-to-creatinine ratio) is based on limited data,
      • Morris R.K.
      • Riley R.D.
      • Doug M.
      • Deeks J.J.
      • Kilby M.D.
      Diagnostic accuracy of spot urinary protein and albumin to creatinine ratios for detection of significant proteinuria or adverse pregnancy outcome in patients with suspected pre-eclampsia: systematic review and meta-analysis.
      ,
      • Verdonk K.
      • Niemeijer I.C.
      • Hop W.C.
      • et al.
      Variation of urinary protein to creatinine ratio during the day in women with suspected pre-eclampsia.
      and dipstick testing for proteinuria is unreliable.
      • Meyer N.L.
      • Mercer B.M.
      • Friedman S.A.
      • Sibai B.M.
      Urinary dipstick protein: a poor predictor of absent or severe proteinuria.
      ,
      • Lindheimer M.D.
      • Kanter D.
      Interpreting abnormal proteinuria in pregnancy: the need for a more pathophysiological approach.
      Collectively, this set of observations, coupled with the lack of difference in the clinical management of gestational hypertension and conventionally defined preeclampsia, led the ACOG Task Force on Hypertension in Pregnancy to modify the definition for preeclampsia in 2013 as follows
      Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy.
      : hypertension that develops after 20 weeks of gestation with proteinuria or evidence of end-organ damage, such as an abnormal renal function test, an elevation of liver enzymes, or thrombocytopenia without proteinuria. The modification reflected consensus that the crucial factor was blood pressure coupled with other manifestations of end-organ damage, one of which could be renal involvement. Although this recommendation was aimed at optimizing clinical management of patients, it has also led to an increase in the frequency of diagnoses of preeclampsia. It is unclear whether this change in diagnostic criteria will translate into improved maternal and perinatal outcomes because most of the newly diagnosed cases have a mild form of the disease.
      • Reddy M.
      • Fenn S.
      • Rolnik D.L.
      • et al.
      The impact of the definition of preeclampsia on disease diagnosis and outcomes: a retrospective cohort study.
      A more objective definition of preeclampsia is required to supersede the current approach of relying largely on blood pressure measurement. The identification of biomarkers for the early detection of the different forms of the syndrome is crucial for improved diagnosis, taxonomy, prediction, and prevention.

      Antiangiogenic factors in preeclampsia

      The discovery that the placenta from patients with preeclampsia overexpressed mRNA and protein for sFlt-1 was a breakthrough.
      • Luttun A.
      • Carmeliet P.
      Soluble VEGF receptor Flt1: the elusive preeclampsia factor discovered?.
      ,
      • Maynard S.E.
      • Min J.Y.
      • Merchan J.
      • et al.
      Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.
      The experiment consisted of a comparison of the transcriptomes of placentas from patients with and without preeclampsia. Karumanchi’s group found that two antiangiogenic factors—sFlt-1 and soluble endoglin (sEng)—were overexpressed in the placentas of women with preeclampsia.
      • Maynard S.E.
      • Min J.Y.
      • Merchan J.
      • et al.
      Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.
      • Bdolah Y.
      • Sukhatme V.P.
      • Karumanchi S.A.
      Angiogenic imbalance in the pathophysiology of preeclampsia: newer insights.
      • Levine R.J.
      • Lam C.
      • Qian C.
      • et al.
      Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.
      • Venkatesha S.
      • Toporsian M.
      • Lam C.
      • et al.
      Soluble endoglin contributes to the pathogenesis of preeclampsia.
      Around the same time, it became known that the blockade of angiogenesis with vascular endothelial growth factor (VEGF) antagonists (monoclonal antibodies against VEGF) in nonpregnant patients with cancer would lead to hypertension and proteinuria.
      • Yang J.C.
      • Haworth L.
      • Sherry R.M.
      • et al.
      A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.
      Encouraged by this finding, the investigators pursued a systematic series of studies that demonstrated that overproduction of sFlt-1 in pregnant animals recapitulated the features of preeclampsia and renal lesions associated with this condition (glomerular endotheliosis).
      • Maynard S.E.
      • Min J.Y.
      • Merchan J.
      • et al.
      Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.
      ,
      • Strevens H.
      • Wide-Swensson D.
      • Hansen A.
      • et al.
      Glomerular endotheliosis in normal pregnancy and pre-eclampsia.
      This information, coupled with previous observations in patients with a low maternal serum concentration of the angiogenic factor—placental growth factor (PlGF)—strengthened the case for a role of an antiangiogenic imbalance in preeclampsia (Figure 11).
      • Torry D.S.
      • Wang H.S.
      • Wang T.H.
      • Caudle M.R.
      • Torry R.J.
      Preeclampsia is associated with reduced serum levels of placenta growth factor.
      Figure thumbnail gr11
      Figure 11The role of sFlt-1 in preeclampsia
      A, Remodeling of the spiral arteries increases blood supply to the fetus. B, In preeclampsia, sFlt-1 is overexpressed in the placenta, leading to hypertension and proteinuria. Modified from Luttun et al.
      • Luttun A.
      • Carmeliet P.
      Soluble VEGF receptor Flt1: the elusive preeclampsia factor discovered?.
      PlGF, placental growth factor; sFlt-1, soluble fms-like tyrosine kinase-1; VEGF, vascular endothelial growth factor.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
      The realization that antiangiogenic factors are linked to preeclampsia has improved the understanding of the pathophysiology and has allowed classification according to the presence or absence of an abnormal antiangiogenic profile. Antiangiogenic factors meet the criteria to be one, if not the major, “toxin” responsible for preeclampsia and eclampsia. The scientific basis for this claim is provided in companion articles in this Supplement.
      • Rana S.
      • Burke S.D.
      • Karumanchi S.A.
      Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders.
      ,
      • Verlohren S.
      • Dröge L.A.
      The diagnostic value of angiogenic and antiangiogenic factors in differential diagnosis of preeclampsia.

      The syndromic nature of preeclampsia

      Obstetrical disorders, by contrast with diseases in the nonpregnant state, develop in the context of a unique biological situation—two individuals with different genomes coexisting, one inside the other. The common interest of the mother and her fetus is successful reproduction; however, conflict can occur when the interests of the mother and the fetus diverge, perhaps as the result of an insult (such as an infection or a compromised blood supply). The term “great obstetrical syndromes” was coined to describe the unique nature of obstetrical diseases. These features include (1) multiple etiologies, (2) a long subclinical phase, (3) fetal involvement, (4) the adaptive nature of clinical manifestations, and (5) complex gene-environment interactions.
      • Romero R.
      The child is the father of the man.
      • Romero R.
      Prenatal medicine: the child is the father of the man. 1996.
      • Di Renzo G.C.
      The great obstetrical syndromes.
      This section summarizes the evidence that preeclampsia has many of these features.

      Multiple etiologies

      Preeclampsia is not one disorder but rather different entities recognized by a common phenotype. Maternal, fetal, and placental causes of preeclampsia have been identified. The causative risk factors, or etiology, of preeclampsia are reviewed in detail by Jung et al.
      • Jung E.J.
      • Romero R.
      • Yeo L.
      • et al.
      The etiology of preeclampsia.

      Long subclinical phase

      Although preeclampsia is diagnosed typically in the late second or third trimester, there is evidence of a pathologic process weeks or months before the diagnosis. Some women have an abnormal pressor response to angiotensin II,
      • Gant N.F.
      • Chand S.
      • Whalley P.J.
      • MacDonald P.C.
      The nature of pressor responsiveness to angiotensin II in human pregnancy.
      an abnormal uterine artery Doppler velocimetry measurement, or abnormal angiogenic and antiangiogenic profiles well before the clinical diagnosis.
      • Levine R.J.
      • Lam C.
      • Qian C.
      • et al.
      Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.
      ,
      • Romero R.
      • Nien J.K.
      • Espinoza J.
      • et al.
      A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate.
      • Erez O.
      • Romero R.
      • Espinoza J.
      • et al.
      The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age.
      • Kusanovic J.P.
      • Romero R.
      • Chaiworapongsa T.
      • et al.
      A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia.
      • Gallo D.M.
      • Poon L.C.
      • Akolekar R.
      • Syngelaki A.
      • Nicolaides K.H.
      Prediction of preeclampsia by uterine artery Doppler at 20-24 weeks’ gestation.
      • Khalil A.
      • Garcia-Mandujano R.
      • Maiz N.
      • Elkhouli M.
      • Nicolaides K.H.
      Longitudinal changes in uterine artery Doppler and blood pressure and risk of pre-eclampsia.

      Fetal involvement

      The diagnosis of the syndrome depends exclusively on maternal signs. Nonetheless, fetal involvement, typically in the form of growth restriction, is present in a subset of patients, and sometimes fetal growth deceleration precedes the diagnosis of preeclampsia. Other subtle hematological abnormalities such as thrombocytopenia and neutropenia have also been reported.
      • Pittara T.
      • Vyrides A.
      • Lamnisos D.
      • Giannakou K.
      Pre-eclampsia and long-term health outcomes for mother and infant: an umbrella review.
      Remarkably, some neonates born to mothers with preeclampsia have been noted to have dilatation of the right coronary artery and to be at risk for developing long-term cardiovascular disease as well as attention deficit and hyperactivity disorders.
      • Pittara T.
      • Vyrides A.
      • Lamnisos D.
      • Giannakou K.
      Pre-eclampsia and long-term health outcomes for mother and infant: an umbrella review.
      ,
      • Lin I.C.
      • Hsu T.Y.
      • Tain Y.L.
      • et al.
      Coronary dilatation and endothelial inflammation in neonates born to mothers with preeclampsia.

      Clinical manifestations are adaptive

      Hypertension can be considered an adaptive response generated in an injured placenta, which signals to the mother the need to maintain perfusion; this is accomplished by increasing maternal cardiac output, by an elevation of maternal blood pressure, or, in some cases, by a combination of both. That hypertension is an adaptive response is supported by a set of clinical observations including the resolution of maternal hypertension following the death of a growth-restricted fetus in a twin pregnancy,
      • Heyborne K.D.
      • Chism D.M.
      Reversal of Ballantyne syndrome by selective second-trimester fetal termination. A case report.
      • Audibert F.
      • Salomon L.J.
      • Castaigne-Meary V.
      • Alves K.
      • Frydman R.
      Selective termination of a twin pregnancy as a treatment of severe pre-eclampsia.
      • Heyborne K.D.
      • Porreco R.P.
      Selective fetocide reverses preeclampsia in discordant twins.
      • Okby R.
      • Mazor M.
      • Erez O.
      • Beer-Weizel R.
      • Hershkovitz R.
      Reversal of mirror syndrome after selective feticide of a hydropic fetus in a dichorionic diamniotic twin pregnancy.
      after SARS-CoV-2 infection,
      • Mendoza M.
      • Garcia-Ruiz I.
      • Maiz N.
      • et al.
      Pre-eclampsia-like syndrome induced by severe COVID-19: a prospective observational study.
      or after transfusion to correct fetal anemia with fetal parvovirus infection.
      • Duthie S.J.
      • Walkinshaw S.A.
      Parvovirus associated fetal hydrops: reversal of pregnancy induced proteinuric hypertension by in utero fetal transfusion.
      Notably, pharmacologic treatment of maternal hypertension does not improve fetal outcomes. In some cases, the adaptive responses can become maladaptive, and a hypertensive crisis can result in cerebrovascular accidents and maternal death.

      Complex gene-environment interaction

      The occurrence of preeclampsia is likely influenced by a combination of genetic and environmental factors. A genetic predisposition has been suspected because preeclampsia clusters in families. Although most genetic association studies have focused on mothers,
      • Steinthorsdottir V.
      • McGinnis R.
      • Williams N.O.
      • et al.
      Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.
      ,
      • Hansen A.T.
      • Bernth Jensen J.M.
      • Hvas A.M.
      • Christiansen M.
      The genetic component of preeclampsia: a whole-exome sequencing study.
      an association between a fetal DNA variant and the syndrome has been recently reported.
      • Gray K.J.
      • Saxena R.
      • Karumanchi S.A.
      Genetic predisposition to preeclampsia is conferred by fetal DNA variants near FLT1, a gene involved in the regulation of angiogenesis.
      Indeed, a fetal genome DNA variant near FLT1 (the gene encoding sFlt-1) is associated with the risk of preeclampsia.
      • McGinnis R.
      • Steinthorsdottir V.
      • Williams N.O.
      • et al.
      Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.
      In addition to the potential contributions of fetal and maternal DNA variants to a particular obstetrical syndrome, the interaction and incompatibility of genotypes may also confer risk (e.g. specific combinations of major histocompatibility complex, class I, C (HLA-C) genotypes in the fetus and killer-cell immunoglobulin-like receptors by the mother and increased risk of other combinations of DNA variants in the genes encoding for the von Willebrand factor, alpha-2 chain of type IV collagen [COL4A2], and lymphotoxin alpha).
      • Hiby S.E.
      • Walker J.J.
      • O’shaughnessy K.M.
      • et al.
      Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success.
      • Hiby S.E.
      • Apps R.
      • Chazara O.
      • et al.
      Maternal KIR in combination with paternal HLA-C2 regulate human birth weight.
      • Nakimuli A.
      • Chazara O.
      • Hiby S.E.
      • et al.
      A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia.
      • Parimi N.
      • Tromp G.
      • Kuivaniemi H.
      • et al.
      Analytical approaches to detect maternal/fetal genotype incompatibilities that increase risk of pre-eclampsia.

      Implications

      Considering preeclampsia as one of the great obstetrical syndromes has several consequences. Given that preeclampsia has multiple etiologies, it is unlikely that there will be a single diagnostic or prognostic test, treatment, or preventive strategy.
      The long subclinical phase creates a window of opportunity for prediction and prevention, which have been accomplished with assessment in the first trimester and with the administration of aspirin. Early evidence suggests that prediction and prevention may also be possible for late-onset preeclampsia, but this may require different biomarkers, and serial testing and interventions (e.g. induction of labor).
      • Chaiworapongsa T.
      • Chaemsaithong P.
      • Korzeniewski S.J.
      • Yeo L.
      • Romero R.
      Pre-eclampsia part 2: prediction, prevention and management.
      ,
      • Orabona R.
      • Donzelli C.M.
      • Falchetti M.
      • Santoro A.
      • Valcamonico A.
      • Frusca T.
      Placental histological patterns and uterine artery Doppler velocimetry in pregnancies complicated by early or late pre-eclampsia.

      Classification: Early vs Late, Mild vs Severe Disease

      Preeclampsia has been classified according to gestational age at the time of diagnosis or delivery as early onset (<34 weeks) or late onset (≥34 weeks). Although other gestational-age cutoff values have been proposed, 34 weeks remains the most commonly used, likely because the rate of neonatal morbidities declines considerably after this gestational age.
      • von Dadelszen P.
      • Magee L.A.
      • Roberts J.M.
      Subclassification of preeclampsia.
      ,
      • Roberts J.M.
      • Rich-Edwards J.W.
      • McElrath T.F.
      • Garmire L.
      • Myatt L.
      Global Pregnancy Collaboration
      Subtypes of preeclampsia: recognition and determining clinical usefulness.
      Specifically, in women with severe preeclampsia, expectant management is not considered, and induction of labor is recommended after 34 weeks of gestation. In addition, preeclampsia can be classified according to its severity (Table 4).
      Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy.
      ,
      • Brown M.A.
      • Magee L.A.
      • Kenny L.C.
      • et al.
      Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice.
      Table 4Severe features of preeclampsia (≥1 finding)
      • Systolic blood pressure of ≥160 mm Hg or diastolic blood pressure of ≥110 mm Hg on 2 occasions at least 4 hours apart while the patient is on bed rest (unless antihypertensive therapy is initiated before this time)
      • Thrombocytopenia (platelet count<100,000/μL)
      • Impaired liver function as indicated by abnormally elevated blood concentrations of liver enzymes (twice the normal concentration), severe persistent right upper quadrant or epigastric pain unresponsive to medication and not accounted for by alternative diagnoses, or both
      • Progressive renal insufficiency (serum creatinine concentration>1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal diseases)
      • Pulmonary edema
      • New-onset cerebral or visual disturbances
      Adapted from the American College of Obstetricians and Gynecologists.
      Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
      Multiple lines of evidence have now coalesced, proposing that early and late preeclampsia are different conditions (Table 5). Early-onset preeclampsia is characterized by a higher frequency of HELLP syndrome,
      • Orabona R.
      • Donzelli C.M.
      • Falchetti M.
      • Santoro A.
      • Valcamonico A.
      • Frusca T.
      Placental histological patterns and uterine artery Doppler velocimetry in pregnancies complicated by early or late pre-eclampsia.
      ,
      • von Dadelszen P.
      • Payne B.
      • Li J.
      • et al.
      Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model.
      abnormal uterine artery Doppler waveforms,
      • Orabona R.
      • Donzelli C.M.
      • Falchetti M.
      • Santoro A.
      • Valcamonico A.
      • Frusca T.
      Placental histological patterns and uterine artery Doppler velocimetry in pregnancies complicated by early or late pre-eclampsia.
      atherosis,
      • Kim Y.M.
      • Chaemsaithong P.
      • Romero R.
      • et al.
      The frequency of acute atherosis in normal pregnancy and preterm labor, preeclampsia, small-for-gestational age, fetal death and midtrimester spontaneous abortion.
      ,
      • Lekva T.
      • Sugulle M.
      • Moe K.
      • Redman C.
      • Dechend R.
      • Staff A.C.
      Multiplex analysis of circulating maternal cardiovascular biomarkers comparing preeclampsia subtypes.
      placental lesions consistent with maternal vascular malperfusion,
      • Orabona R.
      • Donzelli C.M.
      • Falchetti M.
      • Santoro A.
      • Valcamonico A.
      • Frusca T.
      Placental histological patterns and uterine artery Doppler velocimetry in pregnancies complicated by early or late pre-eclampsia.
      ,
      • Ogge G.
      • Chaiworapongsa T.
      • Romero R.
      • et al.
      Placental lesions associated with maternal underperfusion are more frequent in early-onset than in late-onset preeclampsia.
      SGA,
      • Chaiworapongsa T.
      • Chaemsaithong P.
      • Korzeniewski S.J.
      • Yeo L.
      • Romero R.
      Pre-eclampsia part 2: prediction, prevention and management.
      ,
      • Orabona R.
      • Donzelli C.M.
      • Falchetti M.
      • Santoro A.
      • Valcamonico A.
      • Frusca T.
      Placental histological patterns and uterine artery Doppler velocimetry in pregnancies complicated by early or late pre-eclampsia.
      and fetal growth restriction.
      • Orabona R.
      • Donzelli C.M.
      • Falchetti M.
      • Santoro A.
      • Valcamonico A.
      • Frusca T.
      Placental histological patterns and uterine artery Doppler velocimetry in pregnancies complicated by early or late pre-eclampsia.
      Moreover, abnormal maternal plasma ratios of PlGF-to-sFLT-1 or PlGF-to-sEng are present in 80% to 90% of patients with early-onset preeclampsia, but in only 40% to 50% of patients with late-onset preeclampsia.
      • Chaiworapongsa T.
      • Chaemsaithong P.
      • Korzeniewski S.J.
      • Yeo L.
      • Romero R.
      Pre-eclampsia part 2: prediction, prevention and management.
      ,
      • Powers R.W.
      • Roberts J.M.
      • Plymire D.A.
      • et al.
      Low placental growth factor across pregnancy identifies a subset of women with preterm preeclampsia: type 1 versus type 2 preeclampsia?.
      ,
      • Rana S.
      • Schnettler W.T.
      • Powe C.
      • et al.
      Clinical characterization and outcomes of preeclampsia with normal angiogenic profile.
      Early-onset preeclampsia can be considered a clinical manifestation of atherosclerosis in pregnancy while late-onset disease is a metabolic crisis emerging from a mismatch between fetal demands and maternal supply.
      Table 5Early-onset vs late-onset preeclampsia
      VariableEarlyLate
       Gestational age at onset
      Gestational age at diagnosis or delivery
      <34 wk≥34 wk
       Prevalence
      • Lisonkova S.
      • Joseph K.S.
      Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease.
      0.38% (12% of all preeclampsia)2.72% (88% of all preeclampsia)
       HELLP syndrome
      • Orabona R.
      • Donzelli C.M.
      • Falchetti M.
      • Santoro A.
      • Valcamonico A.
      • Frusca T.
      Placental histological patterns and uterine artery Doppler velocimetry in pregnancies complicated by early or late pre-eclampsia.
      40.0%11.1%
       Fetal growth restriction
      • Orabona R.
      • Donzelli C.M.
      • Falchetti M.
      • Santoro A.
      • Valcamonico A.
      • Frusca T.
      Placental histological patterns and uterine artery Doppler velocimetry in pregnancies complicated by early or late pre-eclampsia.
      60.0%25.0%
       Small for gestational age
      birthweight <5th percentile
      ,
      • Orabona R.
      • Donzelli C.M.
      • Falchetti M.
      • Santoro A.
      • Valcamonico A.
      • Frusca T.
      Placental histological patterns and uterine artery Doppler velocimetry in pregnancies complicated by early or late pre-eclampsia.
      66.7%31.9%
       Neonatal death or severe neonatal morbidity
      • Lisonkova S.
      • Joseph K.S.
      Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease.
      21.8%2.3%
       Combined adverse maternal outcomes
      combined adverse maternal outcome includes maternal mortality or one or more serious central nervous system, cardiorespiratory, hepatic, renal, or hematological morbidity.
      ,
      • von Dadelszen P.
      • Payne B.
      • Li J.
      • et al.
      Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model.
      20.9%9.2%
       Uterine artery Doppler PI > 95th percentile
      • Orabona R.
      • Donzelli C.M.
      • Falchetti M.
      • Santoro A.
      • Valcamonico A.
      • Frusca T.
      Placental histological patterns and uterine artery Doppler velocimetry in pregnancies complicated by early or late pre-eclampsia.
      88.6%48.6%
       Abnormal maternal plasma PlGF/sFlt-1 ratio
      • Chaiworapongsa T.
      • Chaemsaithong P.
      • Korzeniewski S.J.
      • Yeo L.
      • Romero R.
      Pre-eclampsia part 2: prediction, prevention and management.
      ∼80.0%–90.0%∼40.0%–50.0%
      HELLP, hemolysis, elevated liver enzymes, and low platelet count; PI, pulsatility index; PlGF, placental growth factor; sFlt-1, soluble fms-like tyrosine kinase.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
      a Gestational age at diagnosis or delivery
      b birthweight <5th percentile
      c combined adverse maternal outcome includes maternal mortality or one or more serious central nervous system, cardiorespiratory, hepatic, renal, or hematological morbidity.

      Postpartum Preeclampsia

      This condition is an enigma as delivery of the placenta is considered to be the cure of preeclampsia. Retained fragments of the placenta have been implicated in postpartum preeclampsia and eclampsia for decades.
      • Endler M.
      • Saltvedt S.
      • Cnattingius S.
      • Stephansson O.
      • Wikström A.K.
      Retained placenta is associated with pre-eclampsia, stillbirth, giving birth to a small-for-gestational-age infant, and spontaneous preterm birth: a national register-based study.
      In 1960, while investigating the etiology of hypertension in “toxemia of pregnancy,” Hunter and Howard
      • Hunter Jr., C.A.
      • Howard W.F.
      A pressor substance (hysterotonin) occurring in toxemia.
      reported that the decidua of patients with toxemia and molar pregnancy produced a pressor substance: “hysterotonin.” Although the molecule responsible for this pressor response was never characterized, Hunter et al
      • Hunter Jr., C.A.
      • Howard W.F.
      • McCormick Jr., C.O.
      Amelioration of the hypertension of toxemia by postpartum curettage.
      proposed that postpartum curettage of the decidua could improve the condition. Indeed, curettage was reported to ameliorate hypertension in 69 patients. In one patient with postpartum eclampsia, convulsions did not recur after curettage (Figure 12).
      • Hunter Jr., C.A.
      • Howard W.F.
      • McCormick Jr., C.O.
      Amelioration of the hypertension of toxemia by postpartum curettage.
      Approximately 30 years later, Magann et al
      • Magann E.F.
      • Martin Jr., J.N.
      • Isaacs J.D.
      • Perry Jr., K.G.
      • Martin R.W.
      • Meydrech E.F.
      Immediate postpartum curettage: accelerated recovery from severe preeclampsia.
      reported the results of a randomized clinical trial of immediate postpartum curettage in 32 patients with severe preeclampsia and observed that patients who had undergone curettage had significantly lower blood pressure (Figure 13, A) as well as a significantly higher urinary output and platelet count (Figure 13, B) than those who did not undergo a curettage. Collectively, these observations suggest that material present in the uterus after the delivery of the placenta can still have biological properties. Although Hunter et al
      • Hunter Jr., C.A.
      • Howard W.F.
      • McCormick Jr., C.O.
      Amelioration of the hypertension of toxemia by postpartum curettage.
      attributed this to the decidua, trophoblasts are also present in the uterus after delivery of the placenta and are consistently observed in histologic examinations of hysterectomy specimens. Therefore, it is possible that trophoblasts may continue to be a source of bioactive material. Why some patients develop hypertension and proteinuria only after delivery remains an unanswered question.
      Figure thumbnail gr12
      Figure 12Effect of uterine curettage on blood pressure in a woman with postpartum eclampsia
      In one patient with postpartum eclampsia and three episodes of convulsions, curettage was performed, maternal hypertension improved, and convulsions did not recur. Modified from Hunter et al.
      • Hunter Jr., C.A.
      • Howard W.F.
      • McCormick Jr., C.O.
      Amelioration of the hypertension of toxemia by postpartum curettage.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
      Figure thumbnail gr13
      Figure 13Effects of uterine curettage in patients with preeclampsia
      Postpartum uterine curettage has an effect not only on blood pressure (A) but also on platelet count (B) in patients with preeclampsia. Modified from Magann et al.
      • Magann E.F.
      • Martin Jr., J.N.
      • Isaacs J.D.
      • Perry Jr., K.G.
      • Martin R.W.
      • Meydrech E.F.
      Immediate postpartum curettage: accelerated recovery from severe preeclampsia.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
      Postpartum preeclampsia belongs to a group of conditions of unknown etiology diagnosed after delivery that include cardiomyopathy, renal failure, uremic hemolytic syndrome, and acute fatty liver. Insights into the pathophysiology of these conditions can be gleaned by recent progress made in the understanding of peripartum cardiomyopathy, which is now recognized as the result of the antiangiogenic factor, sFlt-1, in a two-hit model.
      • Patten I.S.
      • Rana S.
      • Shahul S.
      • et al.
      Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.
      The first is an increased concentration of sFlt-1 in the maternal circulation, which can impair cardiac function, and the second is a lack of local proangiogenic defenses in the maternal heart. Peripartum cardiomyopathy can be experimentally induced in pregnant mice by the combination of increased sFlt-1 (through an adenovirus vector) and gene deletion of a regulator of angiogenesis called “peroxisome proliferator-activated receptor-gamma coactivator” (PGC-1α).
      • Patten I.S.
      • Rana S.
      • Shahul S.
      • et al.
      Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.
      Similarly, pregnant women with peripartum cardiomyopathy have an increased concentration of sFlt-1 in the postpartum period, which has been detected four to six weeks after delivery (elevated sFlt-1 typically returns to normal range within three days of delivery).
      • Patten I.S.
      • Rana S.
      • Shahul S.
      • et al.
      Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.
      A similar pathophysiological process can be responsible for other postpartum syndromes, including postpartum renal failure. VEGF is essential for the maintenance of glomerular health, and its blockade damages the fenestrated endothelium, causing proteinuria.
      • Esser S.
      • Wolburg K.
      • Wolburg H.
      • Breier G.
      • Kurzchalia T.
      • Risau W.
      Vascular endothelial growth factor induces endothelial fenestrations in vitro.
      ,
      • Eremina V.
      • Jefferson J.A.
      • Kowalewska J.
      • et al.
      VEGF inhibition and renal thrombotic microangiopathy.
      It is now recognized that a subset of patients with preeclampsia have impaired subclinical renal function and proteinuria after delivery, which may persist for months. The antepartum sFlt-1 concentration correlates with a lower glomerular filtration rate, and a high concentration is a risk factor for renal impairment at six and 12 months postpartum.
      • Kaleta T.
      • Stock A.
      • Panayotopoulos D.
      • et al.
      Predictors of impaired postpartum renal function in women after preeclampsia: results of a prospective single center study.
      Recent observations suggest that the pathophysiology of acute fatty liver of pregnancy may also be related to an excessive concentration of sFlt-1 (Figure 14).
      • Neuman R.I.
      • Hesselink E.R.M.
      • Saleh L.
      • van den Meiracker A.H.
      • Danser A.H.J.
      • Visser W.
      Angiogenic markers are elevated in women with acute fatty liver of pregnancy.
      ,
      • Neuman R.I.
      • Saleh L.
      • Verdonk K.
      • et al.
      Accurate prediction of total PlGF (placental growth factor) from free PlGF and sFlt-1 (soluble Fms-like tyrosine Kinase-1): evidence for markedly elevated PlGF levels in women with acute fatty liver of pregnancy.
      Why and how an excess of sFlt-1 or other antiangiogenic factors may target the heart, kidney, liver, or brain (in some cases of postpartum eclampsia) are unknown. We envision that several enigmatic postpartum syndromes represent the clinical manifestations of vascular dysfunction in the peripartum period.
      Figure thumbnail gr14
      Figure 14Plasma concentration of sFlt-1 in women with normal pregnancy, preeclampsia, HELLP syndrome, and acute fatty liver of pregnancy
      Women with acute fatty liver of pregnancy have a higher plasma concentration of sFlt-1 than women with other conditions. Data are presented as individual values (dot) and median (bar). Modified from Neuman et al.
      • Neuman R.I.
      • Saleh L.
      • Verdonk K.
      • et al.
      Accurate prediction of total PlGF (placental growth factor) from free PlGF and sFlt-1 (soluble Fms-like tyrosine Kinase-1): evidence for markedly elevated PlGF levels in women with acute fatty liver of pregnancy.
      HELLP, hemolysis, elevated liver enzymes, and low platelet count; sFlt-1, soluble fms-like tyrosine kinase-1.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

      Vascular Dysfunction of Pregnancy: Unmasked, Induced, Protean

      The most important adaptation for a successful pregnancy is the establishment and development of an adequate blood supply to the placenta and conceptus. The clinical consequences of suboptimal perfusion range from fetal growth restriction, SGA, preeclampsia, abruptio placenta, and fetal death (Figure 15). A fundamental question is: why does maternal malperfusion lead to one particular syndrome rather than to others? The timing and magnitude of the insult and the genetic makeup of the mother, fetus, and placenta probably determine the clinical presentation. Extreme compromise of the blood supply results in fetal death. Lesser degrees of maternal malperfusion could be compensated by a reduction in fetal growth, maternal hypertension, or a combination of both. In some cases, the adaptive response may be spontaneous preterm birth. Why some cases of fetal growth restriction attributable to placental malperfusion are associated with preeclampsia and others are not is unknown.
      Figure thumbnail gr15
      Figure 15Vascular dysfunction of pregnancy
      Vascular dysfunction during pregnancy may result in one of several obstetrical syndromes. The timing and magnitude of the insult may determine the clinical syndromes.
      PROM, premature rupture of membranes.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.
      It is now clear that a subset of women who develop preeclampsia have preexisting vascular dysfunction, which manifests clinically during pregnancy and remains operative in the postpartum period. This realization offers unique opportunities to improve the healthcare of women by implementing strategies to prevent cardiovascular disease. Figure 16 illustrates the long-term adverse events associated with preeclampsia. These include not only maternal hypertension and coronary artery disease but also vascular dementia and end-stage renal disease.
      • Ramlakhan K.P.
      • Johnson M.R.
      • Roos-Hesselink J.W.
      Pregnancy and cardiovascular disease.
      This article has focused on preeclampsia. However, patients with other complications of pregnancy, such as fetal death, are also at risk of subsequent cardiovascular diseases. Therefore, vascular dysfunction during pregnancy diagnosed through preeclampsia or other great obstetrical syndromes has important implications for women’s health.
      • Ray J.G.
      • Vermeulen M.J.
      • Schull M.J.
      • Redelmeier D.A.
      Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
      Figure thumbnail gr16
      Figure 16Relative risk of cardiometabolic disease in women with a history of preeclampsia
      Modified from Ramlakhan et al.
      • Ramlakhan K.P.
      • Johnson M.R.
      • Roos-Hesselink J.W.
      Pregnancy and cardiovascular disease.
      Erez. Conceptual evolution of preeclampsia and eclampsia as a syndrome. Am J Obstet Gynecol 2022.

      Conclusion

      The implications of preeclampsia in maternal and infant health have been a major determinant in the organization of prenatal care for more than a century. Initially thought to be a disorder of the central nervous system, and then to involve the kidneys, it is now considered fundamentally a cardiovascular disorder. The view that preeclampsia is a pregnancy-specific condition caused by the placenta and cured only by delivery, has been the accepted dogma. We now know that vascular dysfunction, clinically recognized by the combination of hypertension and proteinuria, is not specific to pregnancy; it can occur in non-pregnant subjects after a viral infection such as SARS-CoV-2,
      • Xiong S.
      • Liu L.
      • Lin F.
      • et al.
      Clinical characteristics of 116 hospitalized patients with COVID-19 in Wuhan, China: a single-centered, retrospective, observational study.
      • Huang C.
      • Huang L.
      • Wang Y.
      • et al.
      6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.
      • Nadim M.K.
      • Forni L.G.
      • Mehta R.L.
      • et al.
      COVID-19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup.
      • Zahid U.
      • Ramachandran P.
      • Spitalewitz S.
      • et al.
      Acute kidney injury in COVID-19 patients: an inner City Hospital experience and policy implications.
      the administration of VEGF inhibitors,
      • Yang J.C.
      • Haworth L.
      • Sherry R.M.
      • et al.
      A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.
      or in the context of other disorders such as diabetes. What makes pregnant women particularly prone to develop vascular dysfunction is the placenta, an organ that produces antiangiogenic factors in response to insults. However, it is not clear if all cases of preeclampsia require placental involvement. The notion that preeclampsia can be cured only by delivery also needs to be revisited. Indeed, hypertension and proteinuria in pregnant women with SARS-CoV-2 infection can disappear after the viral infection is cleared.
      • Mendoza M.
      • Garcia-Ruiz I.
      • Maiz N.
      • et al.
      Pre-eclampsia-like syndrome induced by severe COVID-19: a prospective observational study.
      Moreover, preeclampsia can resolve in twin gestations with selective fetal growth restriction after the affected twin dies
      • Audibert F.
      • Salomon L.J.
      • Castaigne-Meary V.
      • Alves K.
      • Frydman R.
      Selective termination of a twin pregnancy as a treatment of severe pre-eclampsia.
      ,
      • Heyborne K.D.
      • Porreco R.P.
      Selective fetocide reverses preeclampsia in discordant twins.
      or after treatment of fetal anemia caused by parvovirus B19 infection.
      • Duthie S.J.
      • Walkinshaw S.A.
      Parvovirus associated fetal hydrops: reversal of pregnancy induced proteinuric hypertension by in utero fetal transfusion.
      These clinical observations about the reversibility of preeclampsia are buttressed by experimental evidence that the molecular abnormalities of trophoblasts obtained from patients with preeclampsia can resolve in vitro.
      • Romero R.
      • Chaiworapongsa T.
      Preeclampsia: a link between trophoblast dysregulation and an antiangiogenic state.
      ,
      • Zhou Y.
      • Gormley M.J.
      • Hunkapiller N.M.
      • et al.
      Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia.
      Perhaps, it is time to reframe our conceptualization of preeclampsia. Has too much weight been given to the results of a sphygmomanometer to identify this complex syndrome? The identification of biological markers that detect the pathophysiologic derangements of this syndrome in early phases is necessary to the diagnosis, classification, treatment, prediction, and prevention of this elusive disorder.

      References

        • Chesley L.C.
        History and epidemiology of preeclampsia-eclampsia.
        Clin Obstet Gynecol. 1984; 27: 801-820
        • Chesley L.C.
        A short history of eclampsia.
        Obstet Gynecol. 1974; 43: 559-820
        • Chesley L.C.
        Hypertensive disorders in pregnancy.
        Appleton-Century-Crofts, New York, NY1978: 17-34
      1. François Boissier de Sauvages de Lacroix F. Pathologia methodica. Montpellier, Martel; 1739.

        • Bell M.J.
        A historical overview of preeclampsia-eclampsia.
        J Obstet Gynecol Neonatal Nurs. 2010; 39: 510-518
        • Lever J.C.
        Cases of puerperal convulsions, with remarks.
        Palmer & Clayton, London1843
        • Simpson J.Y.
        Contributions to the pathology and treatment of diseases of the uterus (Part III).
        London and Edinburgh Monthly Journal of Medical Science. 1843; 3: 1009-1027
        • Ballantyne J.W.
        Sphygmographic tracings in puerperal eclampsia.
        Edinburgh Med J. 1885; 30: 1007-1020
      2. Vaquez N. De la pression artérielle dans 1‘eclampsie puerperale. Bull Mem Soc Méd Hôp Paris. 1897;14:117–119.

        • Webster J.C.
        A text-book of obstetrics.
        Saunders, Philadelphia1903: 375-376
        • Lindheimer M.D.
        • Taylor R.N.
        • Roberts J.M.
        • Cunningham F.G.
        • Chesley L.
        Chapter 1. Introduction, history, controversies, and definitions.
        in: Taylor R.N. Roberts J.M. Cunningham F.G. Lindheimer M.D. Chesley’s hypertensive disorders in pregnancy. Elsevier, 2014: 1-24
        • Romero R.
        • Lockwood C.
        • Oyarzun E.
        • Hobbins J.C.
        Toxemia: new concepts in an old disease.
        Semin Perinatol. 1988; 12: 302-323
        • Robillard P.Y.
        • Dekker G.
        • Chaouat G.
        • Scioscia M.
        • Iacobelli S.
        • Hulsey T.C.
        Historical evolution of ideas on eclampsia/preeclampsia: a proposed optimistic view of preeclampsia.
        J Reprod Immunol. 2017; 123: 72-77
        • Dieckmann W.J.
        Toxemias of pregnancy.
        Henry Kimpton, London1952
        • DeLee J.B.
        Theories of eclampsia.
        Am J Obstet. 1905; 51: 325-330
        • Loudon I.
        Some historical aspects of toxaemia of pregnancy. A review.
        Br J Obstet Gynaecol. 1991; 98: 853-858
        • Stander H.J.
        The toxemias of pregnancy.
        The Williams & Wilkins Company, Baltimore1929
        • MacGillivray I.
        Definitions and Classifications. In: Pre-eclampsia: the hypertensive disease of pregnancy.
        W.B. Saunders Company, 1983: 1-12
        • Young J.
        The etiology of eclampsia and albuminuria and their relation to accidental haemorrhage.
        Trans Edinb Obstet Soc. 1914; 39: 153-202
        • Hunter Jr., C.A.
        • Howard W.F.
        A pressor substance (hysterotonin) occurring in toxemia.
        Am J Obstet Gynecol. 1960; 79: 838-846
        • Hunter Jr CA
        • Howard W.F.
        Etiology of hypertension in toxemia of pregnancy.
        Am J Obstet Gynecol. 1961; 81: 441-450
        • Tatum H.J.
        • Mulé J.G.
        The hypertensive action of blood from patients with pre-eclampsia.
        Am J Obstet Gynecol. 1962; 83: 1028-1035
        • Pirani B.B.
        • MacGillivray I.
        The effect of plasma retransfusion on the blood pressure in the puerperium.
        Am J Obstet Gynecol. 1975; 121: 221-226
        • Gant N.F.
        • Daley G.L.
        • Chand S.
        • Whalley P.J.
        • MacDonald P.C.
        A study of angiotensin II pressor response throughout primigravid pregnancy.
        J Clin Invest. 1973; 52: 2682-2689
        • Page E.W.
        • Christianson R.
        Influence of blood pressure changes with and without proteinuria upon outcome of pregnancy.
        Am J Obstet Gynecol. 1976; 126: 821-833
        • Friedman E.A.
        • Neff R.K.
        Pregnancy hypertension: a systematic evaluation of clinical diagnostic criteria.
        PSG Publishing Company, Inc, Littleton, MA1977
        • Whelton P.K.
        • Carey R.M.
        • Aronow W.S.
        • et al.
        2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice guidelines.
        J Am Coll Cardiol. 2018; 71: e127-e248
        • Sisti G.
        • Colombi I.
        New blood pressure cut off for preeclampsia definition: 130/80 mmHg.
        Eur J Obstet Gynecol Reprod Biol. 2019; 240: 322-324
        • Hurrell A.
        • Webster L.
        • Chappell L.C.
        • Shennan A.H.
        The assessment of blood pressure in pregnant women: pitfalls and novel approaches.
        Am J Obstet Gynecol. 2020; ([Epub ahead of print])
        • Greenberg V.R.
        • Silasi M.
        • Lundsberg L.S.
        • et al.
        Perinatal outcomes in women with elevated blood pressure and stage 1 hypertension.
        Am J Obstet Gynecol. 2021; 224: 521.e1-521.e11
        • Sheehan H.L.
        • Lynch J.B.
        Pathology of toxaemia of pregnancy.
        Churchill Livingstone, New York1973
        • Hecht J.L.
        • Ordi J.
        • Carrilho C.
        • et al.
        The pathology of eclampsia: an autopsy series.
        Hypertens Pregnancy. 2017; 36: 259-268
        • Stillman I.E.
        • Karumanchi S.A.
        The glomerular injury of preeclampsia.
        J Am Soc Nephrol. 2007; 18: 2281-2284
        • Antia F.P.
        • Bharadwaj T.P.
        • Watsa M.C.
        • Master J.
        Liver in normal pregnancy, pre-eclampsia, and eclampsia.
        Lancet. 1958; 2: 776-778
        • Arias F.
        • Mancilla-Jimenez R.
        Hepatic fibrinogen deposits in pre-eclampsia. Immunofluorescent evidence.
        N Engl J Med. 1976; 295: 578-582
        • Greenstein D.
        • Henderson J.M.
        • Boyer T.D.
        Liver hemorrhage: recurrent episodes during pregnancy complicated by preeclampsia.
        Gastroenterology. 1994; 106: 1668-1671
        • Rinehart B.K.
        • Terrone D.A.
        • Magann E.F.
        • Martin R.W.
        • May W.L.
        • Martin Jr., J.N.
        Preeclampsia-associated hepatic hemorrhage and rupture: mode of management related to maternal and perinatal outcome.
        Obstet Gynecol Surv. 1999; 54: 196-202
        • Sibai B.M.
        • Taslimi M.M.
        • el-Nazer A.
        • Amon E.
        • Mabie B.C.
        • Ryan G.M.
        Maternal-perinatal outcome associated with the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia-eclampsia.
        Am J Obstet Gynecol. 1986; 155: 501-509
        • Reubinoff B.E.
        • Schenker J.G.
        HELLP syndrome--a syndrome of hemolysis, elevated liver enzymes and low platelet count--complicating preeclampsia-eclampsia.
        Int J Gynaecol Obstet. 1991; 36: 95-102
        • Haeger M.
        • Unander M.
        • Norder-Hansson B.
        • Tylman M.
        • Bengtsson A.
        Complement, neutrophil, and macrophage activation in women with severe preeclampsia and the syndrome of hemolysis, elevated liver enzymes, and low platelet count.
        Obstet Gynecol. 1992; 79: 19-26
        • Von Dadelszen P.
        • Watson R.W.
        • Noorwali F.
        • et al.
        Maternal neutrophil apoptosis in normal pregnancy, preeclampsia, and normotensive intrauterine growth restriction.
        Am J Obstet Gynecol. 1999; 181: 408-414
        • Von Dadelszen P.
        • Wilkins T.
        • Redman C.W.
        Maternal peripheral blood leukocytes in normal and pre-eclamptic pregnancies.
        Br J Obstet Gynaecol. 1999; 106: 576-581
        • Swinkels D.W.
        • de Kok J.B.
        • Hendriks J.C.
        • Wiegerinck E.
        • Zusterzeel P.L.
        • Steegers E.A.
        Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome as a complication of preeclampsia in pregnant women increases the amount of cell-free fetal and maternal DNA in maternal plasma and serum.
        Clin Chem. 2002; 48: 650-653
        • Burwick R.M.
        • Feinberg B.B.
        Complement activation and regulation in preeclampsia and hemolysis, elevated liver enzymes, and low platelet count syndrome.
        Am J Obstet Gynecol. 2020; ([Epub ahead of print])
        • Liman T.G.
        • Bohner G.
        • Heuschmann P.U.
        • Scheel M.
        • Endres M.
        • Siebert E.
        Clinical and radiological differences in posterior reversible encephalopathy syndrome between patients with preeclampsia-eclampsia and other predisposing diseases.
        Eur J Neurol. 2012; 19: 935-943
        • Siepmann T.
        • Boardman H.
        • Bilderbeck A.
        • et al.
        Long-term cerebral white and gray matter changes after preeclampsia.
        Neurology. 2017; 88: 1256-1264
        • Miller E.C.
        Preeclampsia and cerebrovascular disease.
        Hypertension. 2019; 74: 5-13
        • Hertig A.
        Vascular pathology in hypertensive albuminuric toxemias of pregnancy.
        Clinics. 1945; 4: 602
        • Robertson W.B.
        • Brosens I.
        • Dixon H.G.
        The pathological response of the vessels of the placental bed to hypertensive pregnancy.
        J Pathol Bacteriol. 1967; 93: 581-592
        • Brosens I.
        • Renaer M.
        On the pathogenesis of placental infarcts in pre-eclampsia.
        J Obstet Gynaecol Br Commonw. 1972; 79: 794-799
        • Brosens I.A.
        • Robertson W.B.
        • Dixon H.G.
        The role of the spiral arteries in the pathogenesis of preeclampsia.
        Obstet Gynecol Annu. 1972; 1: 177-191
        • De Wolf F.
        • Robertson W.B.
        • Brosens I.
        The ultrastructure of acute atherosis in hypertensive pregnancy.
        Am J Obstet Gynecol. 1975; 123: 164-174
        • Lunell N.O.
        • Nylund L.E.
        • Lewander R.
        • Sarby B.
        Uteroplacental blood flow in pre-eclampsia measurements with indium-113m and a computer-linked gamma camera.
        Clin Exp Hypertens B. 1982; 1: 105-117
        • Khong T.Y.
        • De Wolf F.
        • Robertson W.B.
        • Brosens I.
        Inadequate maternal vascular response to placentation in pregnancies complicated by pre-eclampsia and by small-for-gestational age infants.
        Br J Obstet Gynaecol. 1986; 93: 1049-1059
        • Brosens I.
        • Pijnenborg R.
        • Vercruysse L.
        • Romero R.
        The “Great Obstetrical Syndromes” are associated with disorders of deep placentation.
        Am J Obstet Gynecol. 2011; 204: 193-201
        • Burton G.J.
        • Jauniaux E.
        Pathophysiology of placental-derived fetal growth restriction.
        Am J Obstet Gynecol. 2018; 218: S745-S761
        • Sibai B.M.
        • Mabie B.C.
        • Harvey C.J.
        • Gonzalez A.R.
        Pulmonary edema in severe preeclampsia-eclampsia: analysis of thirty-seven consecutive cases.
        Am J Obstet Gynecol. 1987; 156: 1174-1179
        • Szekely P.
        • Snaith L.
        The heart in toxaemia of pregnancy.
        Br Heart J. 1947; 9: 128-137
        • Desai D.K.
        • Moodley J.
        • Naidoo D.P.
        • Bhorat I.
        Cardiac abnormalities in pulmonary oedema associated with hypertensive crises in pregnancy.
        Br J Obstet Gynaecol. 1996; 103: 523-528
        • De Paco C.
        • Kametas N.
        • Rencoret G.
        • Strobl I.
        • Nicolaides K.H.
        Maternal cardiac output between 11 and 13 weeks of gestation in the prediction of preeclampsia and small for gestational age.
        Obstet Gynecol. 2008; 111: 292-300
        • Bamfo J.E.
        • Kametas N.A.
        • Chambers J.B.
        • Nicolaides K.H.
        Maternal cardiac function in normotensive and pre-eclamptic intrauterine growth restriction.
        Ultrasound Obstet Gynecol. 2008; 32: 682-686
        • Bhorat I.
        • Naidoo D.P.
        • Moodley J.
        Maternal cardiac haemodynamics in severe pre-eclampsia complicated by acute pulmonary oedema: a review.
        J Matern Fetal Neonatal Med. 2017; 30: 2769-2777
        • Orabona R.
        • Sciatti E.
        • Prefumo F.
        • et al.
        Pre-eclampsia and heart failure: a close relationship.
        Ultrasound Obstet Gynecol. 2018; 52: 297-301
        • Sang C.
        • Wang S.
        • Zhang Z.
        • Lu J.
        Characteristics and outcome of severe preeclampsia/eclampsia concurrent with or complicated by acute pancreatitis: a report of five cases and literature review.
        J Matern Fetal Neonatal Med. 2019; 32: 633-640
        • Auger N.
        • Fraser W.D.
        • Paradis G.
        • Healy-Profitós J.
        • Hsieh A.
        • Rhéaume M.A.
        Preeclampsia and long-term risk of maternal retinal disorders.
        Obstet Gynecol. 2017; 129: 42-49
        • Lee C.S.
        • Choi E.Y.
        • Lee M.
        • Kim H.
        • Chung H.
        Serous retinal detachment in preeclampsia and malignant hypertension.
        Eye (Lond). 2019; 33: 1707-1714
        • Barton J.R.
        • Sibai B.M.
        Gastrointestinal complications of pre-eclampsia.
        Semin Perinatol. 2009; 33: 179-188
        • Hultin H.
        • Hellman P.
        • Lundgren E.
        • et al.
        Association of parathyroid adenoma and pregnancy with preeclampsia.
        J Clin Endocrinol Metab. 2009; 94: 3394-3399
        • Levine R.J.
        • Vatten L.J.
        • Horowitz G.L.
        • et al.
        Pre-eclampsia, soluble fms-like tyrosine kinase 1, and the risk of reduced thyroid function: nested case-control and population based study.
        BMJ. 2009; 339: b4336
        • Siddiqui A.H.
        • Irani R.A.
        • Zhang W.
        • et al.
        Angiotensin receptor agonistic autoantibody-mediated soluble fms-like tyrosine kinase-1 induction contributes to impaired adrenal vasculature and decreased aldosterone production in preeclampsia.
        Hypertension. 2013; 61: 472-479
        • Currie G.
        • Carty D.M.
        • Connell J.M.
        • Freel M.
        Endocrine aspects of pre-eclampsia.
        Cardiovasc Endocrinol Metab. 2015; 4: 1-10
        • Alharbi B.A.
        • Alqahtani M.A.
        • Hmoud M.
        • Alhejaili E.A.
        • Badros R.
        Preeclampsia: a possible complication of primary hyperparathyroidism.
        Case Rep Obstet Gynecol. 2016; 2016: 7501263
        • Dekker G.A.
        • Sibai B.M.
        The immunology of preeclampsia.
        Semin Perinatol. 1999; 23: 24-33
        • Gerard C.
        10 Workshops on immunology of preeclampsia.
        J Reprod Immunol. 2017; 123: 94-99
        • Tsuda S.
        • Nakashima A.
        • Shima T.
        • Saito S.
        New paradigm in the role of regulatory T cells during pregnancy.
        Front Immunol. 2019; 10: 573
        • Miller D.
        • Motomura K.
        • Galaz J.
        • et al.
        Cellular immune responses in the pathophysiology of preeclampsia.
        J Leukoc Biol. 2021; ([Epub ahead of print])
        • Rath W.
        • Faridi A.
        • Dudenhausen J.W.
        HELLP syndrome.
        J Perinat Med. 2000; 28: 249-260
        • Mattar F.
        • Sibai B.M.
        Eclampsia. VIII. Risk factors for maternal morbidity.
        Am J Obstet Gynecol. 2000; 182: 307-312
        • Vollaard E.
        • Zeeman G.
        • Alexander J.A.
        • McIntire D.D.
        • Cunningham F.G.
        479: “Delta eclampsia”- a hypertensive encephalopathy of pregnancy in “normotensive” women.
        Am J Obstet Gynecol. 2007; 197: S140
        • Karumanchi S.A.
        • Lindheimer M.D.
        Advances in the understanding of eclampsia.
        Curr Hypertens Rep. 2008; 10: 305-312
        • Goodlin R.C.
        Severe pre-eclampsia: another great imitator.
        Am J Obstet Gynecol. 1976; 125: 747-753
        • Weinstein L.
        Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy.
        Am J Obstet Gynecol. 1982; 142: 159-167
        • Romero R.
        • Mazor M.
        • Lockwood C.J.
        • et al.
        Clinical significance, prevalence, and natural history of thrombocytopenia in pregnancy-induced hypertension.
        Am J Perinatol. 1989; 6: 32-38
        • Sibai B.M.
        Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count.
        Obstet Gynecol. 2004; 103: 981-991
        • Jaffe G.
        • Schatz H.
        Ocular manifestations of preeclampsia.
        Am J Ophthalmol. 1987; 103: 309-315
        • Abu Samra K.
        The eye and visual system in the preeclampsia/eclampsia syndrome: what to expect?.
        Saudi J Ophthalmol. 2013; 27: 51-53
        • Ghavidel L.A.
        • Mousavi F.
        • Bagheri M.
        • Asghari S.
        Preeclampsia induced ocular change.
        Int J Womens Health Reprod Sci. 2018; 6: 123-126
        • Stratta P.
        • Canavese C.
        • Colla L.
        • et al.
        Acute renal failure in preeclampsia-eclampsia.
        Gynecol Obstet Invest. 1987; 24: 225-231
        • Drakeley A.J.
        • Le Roux P.A.
        • Anthony J.
        • Penny J.
        Acute renal failure complicating severe preeclampsia requiring admission to an obstetric intensive care unit.
        Am J Obstet Gynecol. 2002; 186: 253-256
        • Suarez B.
        • Alves K.
        • Senat M.V.
        • et al.
        Abdominal pain and preeclampsia: sonographic findings in the maternal liver.
        J Ultrasound Med. 2002; 21: 1077-1086
        • Moore M.P.
        Don’t forget pre-eclampsia in the differential diagnosis of abdominal pain in pregnancy.
        BMJ. 2013; 346: f1056
        • Dangel A.R.
        • Atlas R.O.
        • Matsuo K.
        Headaches in pre-eclampsia: a clinical dilemma in diagnosing intracranial hemorrhage.
        Eur J Obstet Gynecol Reprod Biol. 2009; 146: 232-233
        • Marsál K.
        Association of cerebral perfusion pressure with headache in women with pre-eclampsia.
        BJOG. 2001; 108: 126-127
        • Brown M.A.
        • Buddie M.L.
        The importance of nonproteinuric hypertension in pregnancy.
        Hypertens Pregnancy. 1995; 14: 57-65
        • Buchbinder A.
        • Sibai B.M.
        • Caritis S.
        • et al.
        Adverse perinatal outcomes are significantly higher in severe gestational hypertension than in mild preeclampsia.
        Am J Obstet Gynecol. 2002; 186: 66-71
        • Magee L.A.
        • von Dadelszen P.
        • Bohun C.M.
        • et al.
        Serious perinatal complications of non-proteinuric hypertension: an international, multicentre, retrospective cohort study.
        J Obstet Gynaecol Can. 2003; 25: 372-382
        • Fishel Bartal M.
        • Lindheimer M.D.
        • Sibai B.M.
        Proteinuria during pregnancy: definition, pathophysiology, methodology, and clinical significance.
        Am J Obstet Gynecol. 2020; ([Epub ahead of print])
        • Tochio A.
        • Obata S.
        • Saigusa Y.
        • Shindo R.
        • Miyagi E.
        • Aoki S.
        Does pre-eclampsia without proteinuria lead to different pregnancy outcomes than pre-eclampsia with proteinuria?.
        J Obstet Gynaecol Res. 2019; 45: 1576-1583
        • Morris R.K.
        • Riley R.D.
        • Doug M.
        • Deeks J.J.
        • Kilby M.D.
        Diagnostic accuracy of spot urinary protein and albumin to creatinine ratios for detection of significant proteinuria or adverse pregnancy outcome in patients with suspected pre-eclampsia: systematic review and meta-analysis.
        BMJ. 2012; 345: e4342
        • Verdonk K.
        • Niemeijer I.C.
        • Hop W.C.
        • et al.
        Variation of urinary protein to creatinine ratio during the day in women with suspected pre-eclampsia.
        BJOG. 2014; 121: 1660-1665
        • Meyer N.L.
        • Mercer B.M.
        • Friedman S.A.
        • Sibai B.M.
        Urinary dipstick protein: a poor predictor of absent or severe proteinuria.
        Am J Obstet Gynecol. 1994; 170: 137-141
        • Lindheimer M.D.
        • Kanter D.
        Interpreting abnormal proteinuria in pregnancy: the need for a more pathophysiological approach.
        Obstet Gynecol. 2010; 115: 365-375
      3. Hypertension in pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy.
        Obstet Gynecol. 2013; 122: 1122-1131
        • Reddy M.
        • Fenn S.
        • Rolnik D.L.
        • et al.
        The impact of the definition of preeclampsia on disease diagnosis and outcomes: a retrospective cohort study.
        Am J Obstet Gynecol. 2021; 224: 217.e1-217.e11
        • Luttun A.
        • Carmeliet P.
        Soluble VEGF receptor Flt1: the elusive preeclampsia factor discovered?.
        J Clin Invest. 2003; 111: 600-602
        • Maynard S.E.
        • Min J.Y.
        • Merchan J.
        • 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: 649-658
        • Bdolah Y.
        • Sukhatme V.P.
        • Karumanchi S.A.
        Angiogenic imbalance in the pathophysiology of preeclampsia: newer insights.
        Semin Nephrol. 2004; 24: 548-556
        • Levine R.J.
        • Lam C.
        • Qian C.
        • et al.
        Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.
        N Engl J Med. 2006; 355: 992-1005
        • Venkatesha S.
        • Toporsian M.
        • Lam C.
        • et al.
        Soluble endoglin contributes to the pathogenesis of preeclampsia.
        Nat Med. 2006; 12: 642-649
        • Yang J.C.
        • Haworth L.
        • Sherry R.M.
        • et al.
        A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer.
        N Engl J Med. 2003; 349: 427-434
        • Strevens H.
        • Wide-Swensson D.
        • Hansen A.
        • et al.
        Glomerular endotheliosis in normal pregnancy and pre-eclampsia.
        BJOG. 2003; 110: 831-836
        • Torry D.S.
        • Wang H.S.
        • Wang T.H.
        • Caudle M.R.
        • Torry R.J.
        Preeclampsia is associated with reduced serum levels of placenta growth factor.
        Am J Obstet Gynecol. 1998; 179: 1539-1544
        • Rana S.
        • Burke S.D.
        • Karumanchi S.A.
        Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders.
        Am J Obstet Gynecol. 2020; ([Epub ahead of print])
        • Verlohren S.
        • Dröge L.A.
        The diagnostic value of angiogenic and antiangiogenic factors in differential diagnosis of preeclampsia.
        Am J Obstet Gynecol. 2020; ([Epub ahead of print])
        • Romero R.
        The child is the father of the man.
        Prenat Neonat Med. 1996; 1: 8-11
        • Romero R.
        Prenatal medicine: the child is the father of the man. 1996.
        J Matern Fetal Neonatal Med. 2009; 22: 636-639
        • Di Renzo G.C.
        The great obstetrical syndromes.
        J Matern Fetal Neonatal Med. 2009; 22: 633-635
        • Jung E.J.
        • Romero R.
        • Yeo L.
        • et al.
        The etiology of preeclampsia.
        Am J Obstet Gynecol. 2022; ([Epub ahead of print])
        • Gant N.F.
        • Chand S.
        • Whalley P.J.
        • MacDonald P.C.
        The nature of pressor responsiveness to angiotensin II in human pregnancy.
        Obstet Gynecol. 1974; 43: 854
        • Romero R.
        • Nien J.K.
        • Espinoza J.
        • et al.
        A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate.
        J Matern Fetal Neonatal Med. 2008; 21: 9-23
        • Erez O.
        • Romero R.
        • Espinoza J.
        • et al.
        The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age.
        J Matern Fetal Neonatal Med. 2008; 21: 279-287
        • Kusanovic J.P.
        • Romero R.
        • Chaiworapongsa T.
        • et al.
        A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia.
        J Matern Fetal Neonatal Med. 2009; 22: 1021-1038
        • Gallo D.M.
        • Poon L.C.
        • Akolekar R.
        • Syngelaki A.
        • Nicolaides K.H.
        Prediction of preeclampsia by uterine artery Doppler at 20-24 weeks’ gestation.
        Fetal Diagn Ther. 2013; 34: 241-247
        • Khalil A.
        • Garcia-Mandujano R.
        • Maiz N.
        • Elkhouli M.
        • Nicolaides K.H.
        Longitudinal changes in uterine artery Doppler and blood pressure and risk of pre-eclampsia.
        Ultrasound Obstet Gynecol. 2014; 43: 541-547
        • Pittara T.
        • Vyrides A.
        • Lamnisos D.
        • Giannakou K.
        Pre-eclampsia and long-term health outcomes for mother and infant: an umbrella review.
        BJOG. 2021; 128: 1421-1430
        • Lin I.C.
        • Hsu T.Y.
        • Tain Y.L.
        • et al.
        Coronary dilatation and endothelial inflammation in neonates born to mothers with preeclampsia.
        J Pediatr. 2021; 228: 58-65.e3
        • Heyborne K.D.
        • Chism D.M.
        Reversal of Ballantyne syndrome by selective second-trimester fetal termination. A case report.
        J Reprod Med. 2000; 45: 360-362
        • Audibert F.
        • Salomon L.J.
        • Castaigne-Meary V.
        • Alves K.
        • Frydman R.
        Selective termination of a twin pregnancy as a treatment of severe pre-eclampsia.
        BJOG. 2003; 110: 68-69
        • Heyborne K.D.
        • Porreco R.P.
        Selective fetocide reverses preeclampsia in discordant twins.
        Am J Obstet Gynecol. 2004; 191: 477-480
        • Okby R.
        • Mazor M.
        • Erez O.
        • Beer-Weizel R.
        • Hershkovitz R.
        Reversal of mirror syndrome after selective feticide of a hydropic fetus in a dichorionic diamniotic twin pregnancy.
        J Ultrasound Med. 2015; 34: 351-353
        • Mendoza M.
        • Garcia-Ruiz I.
        • Maiz N.
        • et al.
        Pre-eclampsia-like syndrome induced by severe COVID-19: a prospective observational study.
        BJOG. 2020; 127: 1374-1380
        • Duthie S.J.
        • Walkinshaw S.A.
        Parvovirus associated fetal hydrops: reversal of pregnancy induced proteinuric hypertension by in utero fetal transfusion.
        Br J Obstet Gynaecol. 1995; 102: 1011-1013
        • Steinthorsdottir V.
        • McGinnis R.
        • Williams N.O.
        • et al.
        Genetic predisposition to hypertension is associated with preeclampsia in European and Central Asian women.
        Nat Commun. 2020; 11: 5976
        • Hansen A.T.
        • Bernth Jensen J.M.
        • Hvas A.M.
        • Christiansen M.
        The genetic component of preeclampsia: a whole-exome sequencing study.
        PLoS One. 2018; 13e0197217
        • Gray K.J.
        • Saxena R.
        • Karumanchi S.A.
        Genetic predisposition to preeclampsia is conferred by fetal DNA variants near FLT1, a gene involved in the regulation of angiogenesis.
        Am J Obstet Gynecol. 2018; 218: 211-218
        • McGinnis R.
        • Steinthorsdottir V.
        • Williams N.O.
        • et al.
        Variants in the fetal genome near FLT1 are associated with risk of preeclampsia.
        Nat Genet. 2017; 49: 1255-1260
        • Hiby S.E.
        • Walker J.J.
        • O’shaughnessy K.M.
        • et al.
        Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success.
        J Exp Med. 2004; 200: 957-965
        • Hiby S.E.
        • Apps R.
        • Chazara O.
        • et al.
        Maternal KIR in combination with paternal HLA-C2 regulate human birth weight.
        J Immunol. 2014; 192: 5069-5073
        • Nakimuli A.
        • Chazara O.
        • Hiby S.E.
        • et al.
        A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia.
        Proc Natl Acad Sci U S A. 2015; 112: 845-850
        • Parimi N.
        • Tromp G.
        • Kuivaniemi H.
        • et al.
        Analytical approaches to detect maternal/fetal genotype incompatibilities that increase risk of pre-eclampsia.
        BMC Med Genet. 2008; 9: 60
        • Chaiworapongsa T.
        • Chaemsaithong P.
        • Korzeniewski S.J.
        • Yeo L.
        • Romero R.
        Pre-eclampsia part 2: prediction, prevention and management.
        Nat Rev Nephrol. 2014; 10: 531-540
        • Orabona R.
        • Donzelli C.M.
        • Falchetti M.
        • Santoro A.
        • Valcamonico A.
        • Frusca T.
        Placental histological patterns and uterine artery Doppler velocimetry in pregnancies complicated by early or late pre-eclampsia.
        Ultrasound Obstet Gynecol. 2016; 47: 580-585
        • von Dadelszen P.
        • Magee L.A.
        • Roberts J.M.
        Subclassification of preeclampsia.
        Hypertens Pregnancy. 2003; 22: 143-148
        • Roberts J.M.
        • Rich-Edwards J.W.
        • McElrath T.F.
        • Garmire L.
        • Myatt L.
        • Global Pregnancy Collaboration
        Subtypes of preeclampsia: recognition and determining clinical usefulness.
        Hypertension. 2021; 77: 1430-1441
        • Brown M.A.
        • Magee L.A.
        • Kenny L.C.
        • et al.
        Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice.
        Hypertension. 2018; 72: 24-43
        • Lisonkova S.
        • Joseph K.S.
        Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease.
        Am J Obstet Gynecol. 2013; 209: 544.e1-544.e12
        • von Dadelszen P.
        • Payne B.
        • Li J.
        • et al.
        Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model.
        Lancet. 2011; 377: 219-227
        • Kim Y.M.
        • Chaemsaithong P.
        • Romero R.
        • et al.
        The frequency of acute atherosis in normal pregnancy and preterm labor, preeclampsia, small-for-gestational age, fetal death and midtrimester spontaneous abortion.
        J Matern Fetal Neonatal Med. 2015; 28: 2001-2009
        • Lekva T.
        • Sugulle M.
        • Moe K.
        • Redman C.
        • Dechend R.
        • Staff A.C.
        Multiplex analysis of circulating maternal cardiovascular biomarkers comparing preeclampsia subtypes.
        Hypertension. 2020; 75: 1513-1522
        • Ogge G.
        • Chaiworapongsa T.
        • Romero R.
        • et al.
        Placental lesions associated with maternal underperfusion are more frequent in early-onset than in late-onset preeclampsia.
        J Perinat Med. 2011; 39: 641-652
        • Powers R.W.
        • Roberts J.M.
        • Plymire D.A.
        • 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: 239-246
        • Rana S.
        • Schnettler W.T.
        • Powe C.
        • et al.
        Clinical characterization and outcomes of preeclampsia with normal angiogenic profile.
        Hypertens Pregnancy. 2013; 32: 189-201
        • Endler M.
        • Saltvedt S.
        • Cnattingius S.
        • Stephansson O.
        • Wikström A.K.
        Retained placenta is associated with pre-eclampsia, stillbirth, giving birth to a small-for-gestational-age infant, and spontaneous preterm birth: a national register-based study.
        BJOG. 2014; 121: 1462-1470
        • Hunter Jr., C.A.
        • Howard W.F.
        • McCormick Jr., C.O.
        Amelioration of the hypertension of toxemia by postpartum curettage.
        Am J Obstet Gynecol. 1961; 81: 884-889
        • Magann E.F.
        • Martin Jr., J.N.
        • Isaacs J.D.
        • Perry Jr., K.G.
        • Martin R.W.
        • Meydrech E.F.
        Immediate postpartum curettage: accelerated recovery from severe preeclampsia.
        Obstet Gynecol. 1993; 81: 502-506
        • Patten I.S.
        • Rana S.
        • Shahul S.
        • et al.
        Cardiac angiogenic imbalance leads to peripartum cardiomyopathy.
        Nature. 2012; 485: 333-338
        • Esser S.
        • Wolburg K.
        • Wolburg H.
        • Breier G.
        • Kurzchalia T.
        • Risau W.
        Vascular endothelial growth factor induces endothelial fenestrations in vitro.
        J Cell Biol. 1998; 140: 947-959
        • Eremina V.
        • Jefferson J.A.
        • Kowalewska J.
        • et al.
        VEGF inhibition and renal thrombotic microangiopathy.
        N Engl J Med. 2008; 358: 1129-1136
        • Kaleta T.
        • Stock A.
        • Panayotopoulos D.
        • et al.
        Predictors of impaired postpartum renal function in women after preeclampsia: results of a prospective single center study.
        Dis Markers. 2016; 2016: 7861919
        • Neuman R.I.
        • Hesselink E.R.M.
        • Saleh L.
        • van den Meiracker A.H.
        • Danser A.H.J.
        • Visser W.
        Angiogenic markers are elevated in women with acute fatty liver of pregnancy.
        Ultrasound Obstet Gynecol. 2020; 56: 465-466
        • Neuman R.I.
        • Saleh L.
        • Verdonk K.
        • et al.
        Accurate prediction of total PlGF (placental growth factor) from free PlGF and sFlt-1 (soluble Fms-like tyrosine Kinase-1): evidence for markedly elevated PlGF levels in women with acute fatty liver of pregnancy.
        Hypertension. 2021; 78: 489-498
        • Ramlakhan K.P.
        • Johnson M.R.
        • Roos-Hesselink J.W.
        Pregnancy and cardiovascular disease.
        Nat Rev Cardiol. 2020; 17: 718-731
        • Ray J.G.
        • Vermeulen M.J.
        • Schull M.J.
        • Redelmeier D.A.
        Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study.
        Lancet. 2005; 366: 1797-1803
        • Xiong S.
        • Liu L.
        • Lin F.
        • et al.
        Clinical characteristics of 116 hospitalized patients with COVID-19 in Wuhan, China: a single-centered, retrospective, observational study.
        BMC Infect Dis. 2020; 20: 787
        • Huang C.
        • Huang L.
        • Wang Y.
        • et al.
        6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.
        Lancet. 2021; 397: 220-232
        • Nadim M.K.
        • Forni L.G.
        • Mehta R.L.
        • et al.
        COVID-19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup.
        Nat Rev Nephrol. 2020; 16: 747-764
        • Zahid U.
        • Ramachandran P.
        • Spitalewitz S.
        • et al.
        Acute kidney injury in COVID-19 patients: an inner City Hospital experience and policy implications.
        Am J Nephrol. 2020; 51: 786-796
        • Romero R.
        • Chaiworapongsa T.
        Preeclampsia: a link between trophoblast dysregulation and an antiangiogenic state.
        J Clin Invest. 2013; 123: 2775-2777
        • Zhou Y.
        • Gormley M.J.
        • Hunkapiller N.M.
        • et al.
        Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia.
        J Clin Invest. 2013; 123: 2862-2872