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The etiology of preeclampsia

  • 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, US 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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  • 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, US 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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  • Lami Yeo
    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, US 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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  • Nardhy Gomez-Lopez
    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, US 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 Biochemistry, Microbiology and Immunology, 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, US 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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  • Adithep Jaovisidha
    Affiliations
    Faculty of Medicine, Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
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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, US 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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  • 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, US 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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      Preeclampsia is one of the “great obstetrical syndromes” in which multiple and sometimes overlapping pathologic processes activate a common pathway consisting of endothelial cell activation, intravascular inflammation, and syncytiotrophoblast stress. This article reviews the potential etiologies of preeclampsia. The role of uteroplacental ischemia is well-established on the basis of a solid body of clinical and experimental evidence. A causal role for microorganisms has gained recognition through the realization that periodontal disease and maternal gut dysbiosis are linked to atherosclerosis, thus possibly to a subset of patients with preeclampsia. The recent reports indicating that SARS-CoV-2 infection might be causally linked to preeclampsia are reviewed along with the potential mechanisms involved. Particular etiologic factors, such as the breakdown of maternal-fetal immune tolerance (thought to account for the excess of preeclampsia in primipaternity and egg donation), may operate, in part, through uteroplacental ischemia, whereas other factors such as placental aging may operate largely through syncytiotrophoblast stress. This article also examines the association between gestational diabetes mellitus and maternal obesity with preeclampsia. The role of autoimmunity, fetal diseases, and endocrine disorders is discussed. A greater understanding of the etiologic factors of preeclampsia is essential to improve treatment and prevention.

      Key words

      Introduction

      A fundamental task of medicine is establishing the causes of diseases. Preeclampsia, an enigmatic and elusive disorder of pregnancy, has been labeled the “disease of theories.” This condition is one of the “great obstetrical syndromes” in which multiple and sometimes overlapping pathologic processes activate a common pathway that leads to their clinical recognition. Just as the syndrome of preterm labor is recognized by the clinical manifestations of activation of the common pathway of parturition (ie, increased uterine contractility, cervical remodeling, and membrane and decidual activation), so is preeclampsia. The common pathway of preeclampsia consists of endothelial cell activation, intravascular inflammation, and syncytiotrophoblast stress. The diagnosis of preeclampsia has traditionally relied on the detection of hypertension and proteinuria, although professional organizations have recently suggested that, in the presence of multisystemic involvement, the diagnosis of preeclampsia can be made in the absence of proteinuria.
      A rich body of literature describes the risk factors for preeclampsia and eclampsia, thus providing insight on the conditions that increase the likelihood of these syndromes but which are not necessarily causal. However, the elucidation of etiologic factors is necessary to successfully treat and prevent disease. This article reviews the evidence linking such etiologic factors with preeclampsia and eclampsia, as summarized in Figure 1.
      Figure thumbnail gr1
      Figure 1The etiological explanations of preeclampsia
      Jung. The etiology of preeclampsia. Am J Obstet Gynecol 2022.

      Uteroplacental ischemia

      The principal mechanism of disease implicated in the etiology of preeclampsia and eclampsia is uteroplacental ischemia. In 1914, James Young
      • Young J.
      The etiology of eclampsia and albuminuria and their relation to accidental hæmorrhage.
      proposed that interference with the uterine blood supply to the placenta would lead to placental infarctions that, in turn, would release toxins into the maternal circulation, thus causing eclampsia. This theory was based on the observation of placental infarctions in patients with eclampsia and on animal studies showing that subcutaneous injections of autolyzed human placental extracts into guinea pigs elicited convulsions, hepatic focal necrosis, and renal lesions, similar to those observed in women who died of eclampsia.
      • Young J.
      The etiology of eclampsia and albuminuria and their relation to accidental hæmorrhage.
      Dixon and Taylor
      • Dixon W.E.
      • Taylor F.E.
      An epidiascopic demonstration on “the physiological action of the placenta.”.
      reported that intravenous injections of extracts of fresh human placenta induced an increase in blood pressure in cats, rabbits, and dogs, resembling the effects of adrenaline. Therefore, the search for the causes of preeclampsia and eclampsia and for the identity of the circulating “toxins” began more than a century ago.
      Additional evidence supporting a role for uteroplacental ischemia in preeclampsia or eclampsia came from Ogden et al,
      • Ogden E.
      • Hildebrand G.J.
      • Page E.W.
      Rise of blood pressure during ischemia of the gravid uterus.
      who reported that clamping of the abdominal aorta below the renal arteries in dogs led to maternal hypertension that resolved after the clamp was released. Since this hypertensive response was not observed in nonpregnant animals, the investigators concluded that the signals responsible for hypertension must have originated within the gravid uterus.
      • Ogden E.
      • Hildebrand G.J.
      • Page E.W.
      Rise of blood pressure during ischemia of the gravid uterus.
      This interpretation was buttressed by the observation that, after removal of the pregnant uterus, clamping of the aorta did not elicit hypertension (Figure 2).
      • Ogden E.
      • Hildebrand G.J.
      • Page E.W.
      Rise of blood pressure during ischemia of the gravid uterus.
      ,
      • Chaiworapongsa T.
      • Chaemsaithong P.
      • Yeo L.
      • Romero R.
      Pre-eclampsia part 1: current understanding of its pathophysiology.
      Subsequent studies reinforced this concept, demonstrating that placental ischemia, generated by placing silver clips on the uterine arteries of pregnant dogs, led to hypertension and proteinuria.
      • Kumar D.
      Chronic placental ischemia in relation to toxemias of pregnancy: a preliminary report.
      Figure thumbnail gr2
      Figure 2Experimental evidence that uterine ischemia during pregnancy causes hypertension
      A, In the Goldblatt model of renovascular hypertension, clamping the renal artery leads to development of hypertension through renal ischemia and the release of renin in nonpregnant animals. B, By contrast, clamping the aorta below the renal arteries does not induce hypertension in nonpregnant animals. C, Clamping of the aorta in pregnant animals below the renal arteries leads to hypertension. D, The hypertension disappears after a hysterectomy has been performed; this suggests that the source of the signals leading to maternal hypertension is the gravid uterus. Modified from Chaiworapongsa et al.
      • Chaiworapongsa T.
      • Chaemsaithong P.
      • Yeo L.
      • Romero R.
      Pre-eclampsia part 1: current understanding of its pathophysiology.
      Jung. The etiology of preeclampsia. Am J Obstet Gynecol 2022.
      Two lines of evidence support the view that placental ischemia rather than uterine ischemia is key. First, patients with an abdominal pregnancy can develop preeclampsia, even though the implantation site is outside of the uterus.
      • Piering W.F.
      • Garancis J.G.
      • Becker C.G.
      • Beres J.A.
      • Lemann Jr., J.
      Preeclampsia related to a functioning extrauterine placenta: report of a case and 25-year follow-up.
      Second, the placement of a Z-suture through the placenta to generate ischemia results in the development of hypertension and proteinuria (Figure 3, A–C),
      • Berger M.
      • Cavanagh D.
      Toxemia of pregnancy. The hypertensive effect of acute experimental placental ischemia.
      which can be attributed to the presence of a circulating “toxin.” Indeed, the transfusion of blood from a pregnant rabbit with experimental placental ischemia and hypertension (caused by the placement of a Z-suture) could induce hypertension in a non-pregnant rabbit (Figure 3, D).
      • Berger M.
      • Cavanagh D.
      Toxemia of pregnancy. The hypertensive effect of acute experimental placental ischemia.
      Figure thumbnail gr3
      Figure 3Experimental demonstration that placental ischemia causes maternal hypertension
      A, A Z-suture is placed in the uterus to generate placental ischemia. B, Gross evidence that the suture has caused a placental infarction. The pale portion of the placenta with the arrow represents a large infarction. C, Placental ischemia causes hypertension. Rabbit A had undergone a bilateral nephrectomy; therefore, the kidney is not a cause of the hypertension. After Z sutures were placed through several placentas, hypertension developed. D, Transfusion of blood from Rabbit A (a pregnant rabbit with placental ischemia) to a nonpregnant rabbit (Rabbit B) causes hypertension; this suggests that a circulating factor generated after placental ischemia is present in the maternal blood and that it can induce hypertension in a nonpregnant rabbit. Modified from Berger and Cavanagh.
      • Berger M.
      • Cavanagh D.
      Toxemia of pregnancy. The hypertensive effect of acute experimental placental ischemia.
      Jung. The etiology of preeclampsia. Am J Obstet Gynecol 2022.
      The first in vivo evidence indicating that women with preeclampsia had a decreased maternal placental blood flow was reported by Browne and Veall,
      • Browne J.C.
      • Veall N.
      The maternal placental blood flow in normotensive and hypertensive women.
      who described the injection of radioactive sodium into the choriodecidual space of women with a normal pregnancy and in those with preeclampsia. The investigators noted that the blood flow at term was 600 mL/min, but it was substantially lower in patients with preeclampsia. These observations have been confirmed in subsequent studies using different radioactive tracers.
      • Janisch H.
      • Leodolter S.
      Results of placental circulation measurements in hazard pregnancies.
      • Olkkonen H.S.
      • Suonio S.
      • Haring P.
      Determination of placental blood flow by external monitoring of 113In.

      Lippert TH, Cloeren SE, Fridrich R. Assessment of uteroplacental hemodynamics in complicated pregnancy. Int J Gynaecol Obstet 1978–1979;16:274–280.

      • Käär K.
      • Jouppila P.
      • Kuikka J.
      • Luotola H.
      • Toivanen J.
      • Rekonen A.
      Intervillous blood flow in normal and complicated late pregnancy measured by means of an intravenous 133Xe method.
      • 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.
      For example, Lunell et al
      • 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.
      reported that uteroplacental blood flow was reduced by 50% in patients with preeclampsia and that the reduction was greater in those with severe preeclampsia than in those with mild disease.
      The role of placental ischemia in the pathogenesis of preeclampsia is now well-established. Indeed, the most frequently used animal model of the syndrome is chronic reduction of uteroplacental perfusion in pregnant rats, generated by the placement of a constriction clip around the aorta below the renal arteries and before the origin of the uterine arteries at 14 days of gestation.
      • Alexander B.T.
      • Kassab S.E.
      • Miller M.T.
      • et al.
      Reduced uterine perfusion pressure during pregnancy in the rat is associated with increases in arterial pressure and changes in renal nitric oxide.
      This maneuver leads to a reduction in placental blood flow by approximately 40%, an increase in arterial blood pressure by 20 to 25 mm Hg by the 19th day of gestation, increased vascular resistance, decreased cardiac output and glomerular filtration rate, and the frequent appearance of proteinuria.
      • Alexander B.T.
      • Kassab S.E.
      • Miller M.T.
      • et al.
      Reduced uterine perfusion pressure during pregnancy in the rat is associated with increases in arterial pressure and changes in renal nitric oxide.
      This animal model recapitulates many of the findings of preeclampsia, including an increase in circulating concentrations of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1; also known as soluble fms-like tyrosine kinase-1 [sFlt-1]) and endoglin, as well as a rise in the concentrations of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-6. A similar nonhuman primate model of preeclampsia, developed in pregnant baboons by selective ligation of one uterine artery, led to the development of hypertension, proteinuria, and increased production of sFlt-1.
      • Makris A.
      • Thornton C.
      • Thompson J.
      • et al.
      Uteroplacental ischemia results in proteinuric hypertension and elevated sFLT-1.
      Importantly, the administration of short interfering RNAs, which silence three of the sFlt-1 messenger RNA (mRNA) isoforms, suppressed sFlt-1 overexpression and reduced hypertension and proteinuria.
      • Turanov A.A.
      • Lo A.
      • Hassler M.R.
      • et al.
      RNAi modulation of placental sFLT1 for the treatment of preeclampsia.
      These studies suggest that the soluble factor or “toxin” responsible for hypertension is, at least in part, sFlt-1. The reader is referred to the review by Bakrania et al
      • Bakrania B.A.
      • George E.M.
      • Granger J.P.
      Animal models of preeclampsia: investigating pathophysiology and therapeutic targets.
      in this Supplement for more details about the model and the pathophysiologic events caused by uteroplacental ischemia.
      What is the cause of placental ischemia in women with preeclampsia? The traditional explanation has been that a defect in placentation leads to ischemia,
      • Brosens I.
      [Spiraled arterioles of the decidua basalis in the hypertensive complications of pregnancy. Anatomoclinical study].
      ,
      • Brosens I.
      A study of the spiral arteries of the decidua basalis in normotensive and hypertensive pregnancies.
      but recently, a dysfunctional maternal cardiovascular system has been implicated.
      • Melchiorre K.
      • Giorgione V.
      • Thilaganathan B.
      The placenta and preeclampsia: villain or victim?.
      The developmental abnormalities include failure of physiologic transformation of the spiral arteries, which is characterized by a narrow diameter and retention of the muscle in the media of the vessel wall.
      • Brosens I.
      [Spiraled arterioles of the decidua basalis in the hypertensive complications of pregnancy. Anatomoclinical study].
      ,
      • Brosens I.
      A study of the spiral arteries of the decidua basalis in normotensive and hypertensive pregnancies.
      The persistence of the muscular coat is thought to make the vessels susceptible to the effect of vasoconstrictive agents. In addition, arteries affected by the failure of physiologic transformation are more likely to develop atherosis (Figure 4), which also narrows the vessel lumen and further compromises placental perfusion.
      • McMaster-Fay R.A.
      Uteroplacental vascular syndromes: theories, hypotheses and controversies.
      ,
      • Labarrere C.A.
      • DiCarlo H.L.
      • Bammerlin E.
      • et al.
      Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta.
      • Hertig A.
      Vascular pathology in hypertensive albuminuric toxemias of pregnancy.
      • De Wolf F.
      • Robertson W.B.
      • Brosens I.
      The ultrastructure of acute atherosis in hypertensive pregnancy.
      • Staff A.C.
      • Johnsen G.M.
      • Dechend R.
      • Redman C.W.G.
      Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
      • Kim Y.M.
      • Chaemsaithong P.
      • Romero R.
      • et al.
      Placental lesions associated with acute atherosis.
      Figure thumbnail gr4
      Figure 4Physiologic transformation of the spiral arteries, failure of physiologic transformation, and atherosis
      A, Diagram of the maternal blood supply to the placenta. The spiral arteries undergo physiologic changes in normal pregnancy (gray). In preeclampsia, the myometrial segment of the spiral artery fails to undergo physiologic transformation (blue), which is thought to explain the uteroplacental ischemia observed in preeclampsia. Nontransformed spiral arteries are prone to atherosis (yellow), characterized by the presence of lipid-laden macrophages within the lumen. Placental basal plate spiral arteries with hematoxylin-eosin stain (B, C, and D). B, Transformed spiral arteries are characterized by the presence of intramural trophoblasts (arrowheads) and fibrinoid degeneration (arrows) of the arterial wall. C, Nontransformed spiral arteries lack intramural trophoblasts and fibrinoid degeneration, and retain smooth muscle. Arrowheads indicate the presence of trophoblasts in myometrium, but not in the wall of the spiral artery. D, Acute atherosis in a decidual spiral artery. Many lipid-laden macrophages (arrows) are seen in the spiral artery with the lack of invasion of the trophoblast (arrowhead) into a myometrial segment of the spiral artery. Images (B, C, and D) stained with cytokeratin 7 (brown) and periodic acid–Schiff (pink), original magnification ×200. Immunohistochemistry of placental basal plate spiral arteries (E, F, and G). E, Endothelium (arrow, blue) in vessels with normal trophoblastic invasion, original magnification ×640. F, A non-transformed spiral artery with endothelium (blue, arrowhead) and smooth muscle cells (green, arrow), original magnification ×640. G, Atherosis lesions show numerous CD36-positive macrophages (red, blue arrow) and smooth muscle cells in the vessel wall (green, yellow arrow), original magnification ×400. Asterisk represents lumen of spiral artery. Modified from McMaster-Fay,
      • McMaster-Fay R.A.
      Uteroplacental vascular syndromes: theories, hypotheses and controversies.
      Espinoza et al,
      • Espinoza J.
      • Romero R.
      • Mee Kim Y.
      • et al.
      Normal and abnormal transformation of the spiral arteries during pregnancy.
      and Labarrere et al.
      • Labarrere C.A.
      • DiCarlo H.L.
      • Bammerlin E.
      • et al.
      Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta.
      Jung. The etiology of preeclampsia. Am J Obstet Gynecol 2022.
      Atherosis is a lesion specific to the spiral arteries, equivalent to the atherosclerotic lesions observed in the coronary arteries. Figure 5 illustrates the typical lesions of atherosis in the spiral arteries and shows lipid-laden macrophages with deposition of fat droplets detected with Oil Red O staining. A systematic review and meta-analysis showed that placental lesions consistent with maternal vascular malperfusion (eg, placental infarction, failure of physiologic transformation of the spiral arteries, acute atherosis) are 4- to 7-fold more frequent in patients with preeclampsia than in those with a normal pregnancy.
      • Falco M.L.
      • Sivanathan J.
      • Laoreti A.
      • Thilaganathan B.
      • Khalil A.
      Placental histopathology associated with pre-eclampsia: systematic review and meta-analysis.
      A comprehensive review of failure of physiologic transformation of the spiral arteries and atherosis by Staff et al
      • Staff A.C.
      • Fjeldstad H.E.
      • Fosheim I.K.
      • et al.
      Failure of physiological transformation and spiral artery atherosis: their roles in preeclampsia.
      is available as part of this Supplement. Atherosis is not specific to preeclampsia, and this type of lesion has been reported in other pregnancy-related conditions, such as spontaneous abortion,
      • 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.
      preterm labor,
      • Kim Y.M.
      • Bujold E.
      • Chaiworapongsa T.
      • et al.
      Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes.
      preterm prelabor rupture of membranes,
      • Kim Y.M.
      • Chaiworapongsa T.
      • Gomez R.
      • et al.
      Failure of physiologic transformation of the spiral arteries in the placental bed in preterm premature rupture of membranes.
      fetal growth restriction,
      • Labarrere C.
      • Alonso J.
      • Manni J.
      • Domenichini E.
      • Althabe O.
      Immunohistochemical findings in acute atherosis associated with intrauterine growth retardation.
      ,
      • Khong T.Y.
      Acute atherosis in pregnancies complicated by hypertension, small-for-gestational-age infants, and diabetes mellitus.
      and fetal death.
      • McMaster-Fay R.A.
      Uteroplacental vascular syndromes: theories, hypotheses and controversies.
      ,
      • Labarrere C.A.
      • DiCarlo H.L.
      • Bammerlin E.
      • et al.
      Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta.
      ,
      • Falco M.L.
      • Sivanathan J.
      • Laoreti A.
      • Thilaganathan B.
      • Khalil A.
      Placental histopathology associated with pre-eclampsia: systematic review and meta-analysis.
      ,
      • 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.
      We have proposed that placental ischemia is a major mechanism of disease in various obstetrical syndromes and that the timing, severity, and duration of the process may explain the clinical occurrence of different obstetrical syndromes.
      • Romero R.
      • Kusanovic J.P.
      • Chaiworapongsa T.
      • Hassan S.S.
      Placental bed disorders in preterm labor, preterm PROM, spontaneous abortion and abruptio placentae.
      Figure thumbnail gr5
      Figure 5Acute atherosis with lipid deposition within a spiral artery
      Fat droplets (arrows) in the nontransformed spiral artery are stained red. Asterisk represents lumen of spiral artery. Am J Obstet Gynecol. 2014 Nov; 14:cover. Photo by Yeon Mee Kim and Roberto Romero.
      Jung. The etiology of preeclampsia. Am J Obstet Gynecol 2022.
      In summary, the following evidence supports a causal link between placental ischemia and preeclampsia: (1) experimentally induced ischemia in several animal models leads to hypertension and proteinuria
      • Ogden E.
      • Hildebrand G.J.
      • Page E.W.
      Rise of blood pressure during ischemia of the gravid uterus.
      ,
      • Kumar D.
      Chronic placental ischemia in relation to toxemias of pregnancy: a preliminary report.
      ,
      • Berger M.
      • Cavanagh D.
      Toxemia of pregnancy. The hypertensive effect of acute experimental placental ischemia.
      ; (2) uterine blood flow is lower in patients with preeclampsia than in women with a normal pregnancy
      • Browne J.C.
      • Veall N.
      The maternal placental blood flow in normotensive and hypertensive women.
      ,

      Lippert TH, Cloeren SE, Fridrich R. Assessment of uteroplacental hemodynamics in complicated pregnancy. Int J Gynaecol Obstet 1978–1979;16:274–280.

      ,
      • 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.
      ; (3) placental histopathologic lesions indicative of ischemia (often referred to as maternal vascular malperfusion) are frequent and consistent findings in preeclampsia and eclampsia
      • Falco M.L.
      • Sivanathan J.
      • Laoreti A.
      • Thilaganathan B.
      • Khalil A.
      Placental histopathology associated with pre-eclampsia: systematic review and meta-analysis.
      ; (4) failure of physiologic transformation of the spiral arteries and atherosis are typical features of preeclampsia
      • Espinoza J.
      • Romero R.
      • Mee Kim Y.
      • et al.
      Normal and abnormal transformation of the spiral arteries during pregnancy.
      ,
      • Staff A.C.
      • Fjeldstad H.E.
      • Fosheim I.K.
      • et al.
      Failure of physiological transformation and spiral artery atherosis: their roles in preeclampsia.
      ,
      • Romero R.
      • Kusanovic J.P.
      • Chaiworapongsa T.
      • Hassan S.S.
      Placental bed disorders in preterm labor, preterm PROM, spontaneous abortion and abruptio placentae.
      ; (5) the pulsatility index of the uterine artery (a parameter to assess resistance to flow) is higher in patients with preeclampsia than in women with a normal pregnancy; this can be observed during the midtrimester of pregnancy, weeks or even months before the development of disease
      • 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.
      ; (6) the maternal plasma placental growth factor (PlGF) to sFlt-1 ratio, a noninvasive marker of lesions of maternal vascular malperfusion, is elevated at the time of disease onset and before the development of preeclampsia
      • 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.
      • Chaiworapongsa T.
      • Romero R.
      • Savasan Z.A.
      • et al.
      Maternal plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in patients presenting to the obstetrical triage area with the suspicion of preeclampsia.
      • Vaisbuch E.
      • Whitty J.E.
      • Hassan S.S.
      • et al.
      Circulating angiogenic and antiangiogenic factors in women with eclampsia.
      • Chaiworapongsa T.
      • Romero R.
      • Korzeniewski S.J.
      • et al.
      Plasma concentrations of angiogenic/anti-angiogenic factors have prognostic value in women presenting with suspected preeclampsia to the obstetrical triage area: a prospective study.
      ; and (7) a blockage of sFlt-1 mRNA reduces hypertension and proteinuria.
      • Turanov A.A.
      • Lo A.
      • Hassler M.R.
      • et al.
      RNAi modulation of placental sFLT1 for the treatment of preeclampsia.
      The frequency of placental lesions of maternal vascular malperfusion, of abnormalities in the uterine artery Doppler, and of alterations in biomarkers (eg, PlGF/sFlt-1) is higher in preterm preeclampsia than in term preeclampsia, suggesting that ischemia plays a different role in early-onset vs late-onset preeclampsia.
      • Espinoza J.
      • Romero R.
      • Nien J.K.
      • et al.
      Identification of patients at risk for early onset and/or severe preeclampsia with the use of uterine artery Doppler velocimetry and placental growth factor.
      • 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.
      • Rana S.
      • Schnettler W.T.
      • Powe C.
      • et al.
      Clinical characterization and outcomes of preeclampsia with normal angiogenic profile.
      • 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.
      • Rolnik D.L.
      • Wright D.
      • Poon L.C.
      • et al.
      Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia.
      The case for ischemia as an etiologic factor in preeclampsia could be even more persuasive if the treatment of ischemia could prevent the occurrence of preeclampsia. This evidence is difficult to obtain in humans. Some have argued that the efficacy of aspirin in reducing the rate of preterm preeclampsia may be due to the prevention of arterial thrombosis in the spiral arteries and intervillous space, given that this is the proposed mechanism of aspirin in the prevention of myocardial infarction in atherosclerosis.
      • Relman A.S.
      Aspirin for the primary prevention of myocardial infarction.
      This interpretation would also explain the lack of efficacy of aspirin in preventing preeclampsia at term, given that ischemia plays a lesser role in such cases.

      Maternal infection

      Maternal infection has been implicated in the etiology of preeclampsia and eclampsia since the beginning of the 20th century. Albert

      Albert, Gynaekologie Afür.Ixiii, vol. 488; 1901.

      proposed that the “toxins” responsible for eclampsia were the product of putrefactive changes in the uterine cavity caused by the action of bacteria (“a latent microbic endometritis”). Indeed, the microorganism “Bacillus eclampsiae” was proposed to be the cause.
      • Loudon I.
      Some historical aspects of toxaemia of pregnancy. A review.
      ,
      • DeLee J.
      Theories of eclampsia.
      This view progressively fell out of favor because preeclampsia and eclampsia do not present the typical features of an infectious disease (eg, fever). Nonetheless, the idea that microorganisms may be involved in the genesis of preeclampsia and eclampsia recurs in the literature every few years, and it has recently reemerged on the basis of research on the relationship between preeclampsia and periodontal disease, urinary tract infection, SARS-CoV-2 infection, or maternal gut dysbiosis.

      Periodontal disease

      The best evidence to support a relationship between microorganisms and preeclampsia is derived from studies of periodontal disease, a condition that increases the risk of developing preeclampsia (odds ratio [OR], 1.76; 95% confidence interval [CI], 1.43–2.18).
      • Conde-Agudelo A.
      • Villar J.
      • Lindheimer M.
      Maternal infection and risk of preeclampsia: systematic review and metaanalysis.
      The term periodontal disease refers to an inflammatory condition caused by immune dysfunction initiated by bacteria within the oral cavity.
      • Williams R.C.
      Periodontal disease.
      The spectrum of disease ranges from gingivitis (inflammation of the soft tissues only) to the destruction of the connective tissue attachment and alveolar bone, which can eventually lead to tooth loss.
      • Williams R.C.
      Periodontal disease.
      Bacteria in the periodontal space can be released during dental procedures or in the course of severe disease, leading to a systemic inflammatory response that can cause damage as well as seeding sites in the cardiovascular system.
      • Sanz M.
      • Del Castillo A.M.
      • Jepsen S.
      • et al.
      Periodontitis and cardiovascular diseases. Consensus Report.
      Indeed, strong evidence indicates that periodontal disease is a risk factor for atherosclerotic cardiovascular diseases, including atherosclerosis, coronary artery disease, stroke, and atrial fibrillation.
      • Herrera D.
      • Molina A.
      • Buhlin K.
      • Klinge B.
      Periodontal diseases and association with atherosclerotic disease.
      ,
      • Sen S.
      • Redd K.
      • Trivedi T.
      • et al.
      Periodontal disease, atrial fibrillation and stroke.
      In brief, such evidence includes the following: (1) microorganisms found in the periodontal space can cause bacteremia
      • Hajishengallis G.
      • Chavakis T.
      Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities.
      ; (2) bacteria from the oral cavity are found in atheromatous plaques
      • Velsko I.M.
      • Chukkapalli S.S.
      • Rivera M.F.
      • et al.
      Active invasion of oral and aortic tissues by Porphyromonas gingivalis in mice causally links periodontitis and atherosclerosis.
      ; and (3) periodontal infections can induce vascular lesions in the aorta and coronary arteries.
      • Herrera D.
      • Molina A.
      • Buhlin K.
      • Klinge B.
      Periodontal diseases and association with atherosclerotic disease.
      ,
      • Lalla E.
      • Lamster I.B.
      • Hofmann M.A.
      • et al.
      Oral infection with a periodontal pathogen accelerates early atherosclerosis in apolipoprotein E-null mice.
      In an animal model of hyperlipidemia (apolipoprotein E-null mice), an oral infection with Porphyromonas gingivalis led to plaque in the aorta (Figure 6).
      • Lalla E.
      • Lamster I.B.
      • Hofmann M.A.
      • et al.
      Oral infection with a periodontal pathogen accelerates early atherosclerosis in apolipoprotein E-null mice.
      Similar findings have been reported in an integrin β6-null mice model with polymicrobial infection with periodontal pathogens.
      • Velsko I.M.
      • Chukkapalli S.S.
      • Rivera-Kweh M.F.
      • et al.
      Periodontal pathogens invade gingiva and aortic adventitia and elicit inflammasome activation in αvβ6 integrin-deficient mice.
      The etiologic role of periodontal disease in preeclampsia is predicated on the same mechanisms linking periodontal disease and atherosclerosis.
      Figure thumbnail gr6
      Figure 6Periodontal disease can lead to atherosclerosis
      A, Bacteria found in the periodontal space can enter the bloodstream (bacteremia) and eventually the cardiovascular system, resulting in atherosclerotic plaques in the blood vessels. Compared with uninfected control (B), periodontal infection with Porphyromonas gingivalis causes atherosclerotic aortic arch plaques (C, arrow) in apoE-null mice. Scale bar=1 mm. Oil Red O staining of cryosections at the aortic sinus shows few small fatty streaks (control, D), whereas atherosclerotic lesions were greater in number and size (arrow) in infected animals (E). Scale bar=50 μm. Modified from Hajishengallis and Chavakis.
      • Hajishengallis G.
      • Chavakis T.
      Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities.
      Jung. The etiology of preeclampsia. Am J Obstet Gynecol 2022.
      Ruma et al
      • Ruma M.
      • Boggess K.
      • Moss K.
      • et al.
      Maternal periodontal disease, systemic inflammation, and risk for preeclampsia.
      have provided clinical, epidemiologic, and experimental evidence that periodontal disease is causally linked to preeclampsia. For example, women with periodontal disease who have an elevated C-reactive protein concentration are at higher risk for the development of preeclampsia than women without periodontal disease (adjusted relative risk [aRR], 5.8; 95% CI, 1.2–26.9).
      • Ruma M.
      • Boggess K.
      • Moss K.
      • et al.
      Maternal periodontal disease, systemic inflammation, and risk for preeclampsia.
      An elevated C-reactive protein can provide a link between periodontal disease and preeclampsia by indicating that periodontal disease has led to a systemic inflammatory process.

      Urinary tract infection

      The relationship between microbial colonization of the maternal urinary tract and preeclampsia has also been reported. A systematic review noted that urinary tract infections are associated with preeclampsia (OR, 1.57; 95% CI, 1.45–1.70).
      • Conde-Agudelo A.
      • Villar J.
      • Lindheimer M.
      Maternal infection and risk of preeclampsia: systematic review and metaanalysis.
      However, the case definitions have been broad and have included pyelonephritis, lower urinary tract infections, and asymptomatic bacteriuria as a group.
      • Easter S.R.
      • Cantonwine D.E.
      • Zera C.A.
      • Lim K.H.
      • Parry S.I.
      • McElrath T.F.
      Urinary tract infection during pregnancy, angiogenic factor profiles, and risk of preeclampsia.
      ,
      • Yan L.
      • Jin Y.
      • Hang H.
      • Yan B.
      The association between urinary tract infection during pregnancy and preeclampsia: a meta-analysis.
      When subgroup analysis is performed, evidence for the association with preeclampsia either weakens or disappears. We have doubts that asymptomatic bacteriuria, which is not associated with a systemic inflammatory response,
      • Tambyah P.A.
      • Maki D.G.
      Catheter-associated urinary tract infection is rarely symptomatic: a prospective study of 1,497 catheterized patients.
      could cause preeclampsia.

      Other infections

      Isolated reports have documented instances in which preeclampsia was associated with malaria,
      • Sartelet H.
      • Rogier C.
      • Milko-Sartelet I.
      • Angel G.
      • Michel G.
      Malaria associated pre-eclampsia in Senegal.
      • Ndao C.T.
      • Dumont A.
      • Fievet N.
      • Doucoure S.
      • Gaye A.
      • Lehesran J.Y.
      Placental malarial infection as a risk factor for hypertensive disorders during pregnancy in Africa: a case-control study in an urban area of Senegal, West Africa.
      • Mruma H.A.
      • McQuillan R.
      • Norrie J.
      The association of malaria infection and gestational hypertension in Africa: systematic review and meta-analysis.
      cytomegalovirus,
      • Carreiras M.
      • Montagnani S.
      • Layrisse Z.
      Preeclampsia: a multifactorial disease resulting from the interaction of the feto-maternal HLA genotype and HCMV infection.
      ,
      • von Dadelszen P.
      • Magee L.A.
      • Krajden M.
      • et al.
      Levels of antibodies against cytomegalovirus and chlamydophila pneumoniae are increased in early onset pre-eclampsia.
      and human immunodeficiency virus,
      • Mattar R.
      • Amed A.M.
      • Lindsey P.C.
      • Sass N.
      • Daher S.
      Preeclampsia and HIV infection.
      ,
      • Nourollahpour Shiadeh M.
      • Riahi S.M.
      • Khani S.
      • et al.
      Human immunodeficiency virus and risk of pre-eclampsia and eclampsia in pregnant women: a meta-analysis on cohort studies.
      but the evidence is insufficient to support causality.

      Animal experiments

      Experimental observations supporting a causal relationship between infection and systemic inflammation and preeclampsia include that the administration of low-dose endotoxin in pregnant rats on the 14th day of gestation results in the development of high blood pressure, proteinuria, a low platelet count, and glomerular fibrinogen deposits.
      • Faas M.M.
      • Schuiling G.A.
      • Baller J.F.
      • Visscher C.A.
      • Bakker W.W.
      A new animal model for human preeclampsia: ultra-low-dose endotoxin infusion in pregnant rats.
      Bacterial endotoxin induces a systemic inflammatory response and activates thrombin through the release of tissue factor. These mechanisms have been implicated in the pathogenesis of preeclampsia.

      SARS-CoV-2 infection

      Early during the COVID-19 pandemic, it was recognized that a subset of nonpregnant patients developed hypertension,
      • Somani S.S.
      • Richter F.
      • Fuster V.
      • et al.
      Characterization of patients who return to hospital following discharge from hospitalization for COVID-19.
      • 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.
      proteinuria,
      • 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.
      • Martinez-Rojas M.A.
      • Vega-Vega O.
      • Bobadilla N.A.
      Is the kidney a target of SARS-CoV-2?.
      • Cheng Y.
      • Luo R.
      • Wang K.
      • et al.
      Kidney disease is associated with in-hospital death of patients with COVID-19.
      thrombocytopenia,
      • Rahi M.S.
      • Jindal V.
      • Reyes S.P.
      • Gunasekaran K.
      • Gupta R.
      • Jaiyesimi I.
      Hematologic disorders associated with COVID-19: a review.
      ,
      • Castro R.A.
      • Frishman W.H.
      Thrombotic complications of COVID-19 infection: a review.
      and elevated liver enzymes.
      • Li J.
      • Fan J.G.
      Characteristics and mechanism of liver injury in 2019 coronavirus disease.
      ,
      • Saviano A.
      • Wrensch F.
      • Ghany M.G.
      • Baumert T.F.
      Liver disease and coronavirus disease 2019: from pathogenesis to clinical care.
      This resembled preeclampsia and the hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. A recent meta-analysis demonstrated that SARS-CoV-2 infection during pregnancy is associated with a significant increase in the odds of developing preeclampsia (OR, 1.58; 95% CI, 1.39–1.8), preeclampsia with severe features (OR, 1.76; 95% CI, 1.18–2.63), eclampsia (OR, 1.97; 95% CI, 1.01–3.84), and HELLP syndrome (OR, 2.01; 95% CI, 1.48–2.97).
      • Conde-Agudelo A.
      • Romero R.
      SARS-COV-2 infection during pregnancy and risk of preeclampsia: a systematic review and meta-analysis.
      In addition, there is a dose-response relationship between SARS-CoV-2 infection and the subsequent development of preeclampsia (Figure 7).
      • Lai J.
      • Romero R.
      • Tarca A.L.
      • et al.
      SARS-COV-2 and the subsequent development of preeclampsia and preterm birth: evidence of a dose-response relationship supporting causality.
      Patients with severe COVID-19 had a 5-fold greater risk of preeclampsia than those with asymptomatic COVID-19.
      • Lai J.
      • Romero R.
      • Tarca A.L.
      • et al.
      SARS-COV-2 and the subsequent development of preeclampsia and preterm birth: evidence of a dose-response relationship supporting causality.
      The median interval between maternal SARS-CoV-2 infection and the subsequent development of preeclampsia is 3.8 weeks (interquartile range, 0.29–11.5).
      • Rosenbloom J.I.
      • Raghuraman N.
      • Carter E.B.
      • Kelly J.C.
      Coronavirus disease 2019 infection and hypertensive disorders of pregnancy.
      Therefore, SARS-CoV-2 infection meets several of the epidemiological postulates for causality.
      Figure thumbnail gr7
      Figure 7A dose-response relationship between the severity of SARS-CoV-2 infection and the subsequent development of preeclampsia
      The severity of COVID-19 and the risk of preeclampsia. 1) Asymptomatic: positive test for SARS-CoV-2 but no symptoms; 2) mild: signs and symptoms of COVID-19 but no shortness of breath, dyspnea, or abnormal chest imaging; 3) moderate: lower respiratory disease during clinical assessment or imaging and oxygen saturation ≥ 94% on room air; 4) severe: requiring high dependency or intensive care secondary to respiratory failure or multi-organ dysfunction. Severe vs. asymptomatic (p<0.01). SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; COVID-19, coronavirus disease 2019.
      Modified from Lai et al.
      • Lai J.
      • Romero R.
      • Tarca A.L.
      • et al.
      SARS-COV-2 and the subsequent development of preeclampsia and preterm birth: evidence of a dose-response relationship supporting causality.
      Jung. The etiology of preeclampsia. Am J Obstet Gynecol 2022.
      One mechanism whereby SARS-CoV-2 infection can be causally linked to preeclampsia is endothelial dysfunction. Indeed, SARS-CoV-2 can infect endothelial cells that normally express angiotensin-converting enzyme 2, one of the cell entry receptors for the virus, leading to endotheliitis.
      • Varga Z.
      • Flammer A.J.
      • Steiger P.
      • et al.
      Endothelial cell infection and endotheliitis in COVID-19.
      ,
      • Ackermann M.
      • Verleden S.E.
      • Kuehnel M.
      • et al.
      Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19.
      Endothelial infection can induce the activation of thrombin, intravascular inflammation (ie, a cytokine storm), and damage of the microvasculature in target organs; this ultimately leads to the multisystemic nature of the syndrome, which includes not only renal involvement but also central nervous system dysfunction and seizures.
      • Su H.
      • Yang M.
      • Wan C.
      • et al.
      Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China.
      • Sharifian-Dorche M.
      • Huot P.
      • Osherov M.
      • et al.
      Neurological complications of coronavirus infection; a comparative review and lessons learned during the COVID-19 pandemic.
      • Thakur V.
      • Ratho R.K.
      • Kumar P.
      • et al.
      Multi-organ involvement in COVID-19: beyond pulmonary manifestations.
      Therefore, an infectious process, which targets the endothelium, could lead to a syndrome similar to preeclampsia and eclampsia (Figure 8).
      Figure thumbnail gr8
      Figure 8Placental ischemia and SARS-CoV-2 infection can elicit intravascular inflammation and endothelial cell dysfunction
      Placental syncytiotrophoblast stress induces excessive release of sFlt-1 into the maternal circulation. sFlt-1 binds to free PlGF or VEGF (angiogenic factors) with high affinity, thus preventing their interaction with their cell-surface receptors (ie, VEGFR-1) on the endothelial cells, leading to endothelial dysfunction. SARS-CoV-2 also targets the endothelium which normally expresses ACE-2, one of the cell entry receptors for the virus, leading to endothelitis, which can induce intravascular inflammation (ie, cytokine storm) and endothelial dysfunction.
      ACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; sFlt-1, soluble fms-like tyrosine kinase-1; VEGFR-1, vascular endothelial growth factor receptor-1.
      Jung. The etiology of preeclampsia. Am J Obstet Gynecol 2022.
      A fascinating observation is that the recovery from COVID-19 has been followed by the disappearance of hypertension and proteinuria without delivery of fetus and placenta.
      • Mendoza M.
      • Garcia-Ruiz I.
      • Maiz N.
      • et al.
      Pre-eclampsia-like syndrome induced by severe COVID-19: a prospective observational study.
      It remains to be determined whether preeclampsia after SARS-CoV-2 infection requires placental involvement or, merely, endothelial cell dysfunction and intravascular inflammation.
      Serum and plasma concentrations of sFlt-1, a marker of endothelial dysfunction, are elevated in nonpregnant patients with COVID-19.
      • Giardini V.
      • Carrer A.
      • Casati M.
      • Contro E.
      • Vergani P.
      • Gambacorti-Passerini C.
      Increased sFLT-1/PlGF ratio in COVID-19: a novel link to angiotensin II-mediated endothelial dysfunction.
      This finding is consistent with another study in which pregnant women with severe COVID-19 had an elevated maternal plasma concentration of sFlt-1 and a high sFlt-1/PlGF ratio.
      • Espino-Y-Sosa S.
      • Martinez-Portilla R.J.
      • Torres-Torres J.
      • et al.
      Novel ratio soluble fms-like tyrosine kinase-1/angiotensin-II (sFlt-1/ANG-II) in pregnant women is associated with critical illness in COVID-19.
      Genetic susceptibility may explain why some women with COVID-19 infection develop preeclampsia but others do not.
      • Lee J.W.
      • Lee I.H.
      • Sato T.
      • Kong S.W.
      • Iimura T.
      Genetic variation analyses indicate conserved SARS-CoV-2-host interaction and varied genetic adaptation in immune response factors in modern human evolution.
      ,
      • Choudhary S.
      • Sreenivasulu K.
      • Mitra P.
      • Misra S.
      • Sharma P.
      Role of genetic variants and gene expression in the susceptibility and severity of COVID-19.

      Maternal intestinal dysbiosis

      The human gut microbiota plays an important role in host nutrition, harvesting of energy, and immune response to potential pathogens.
      • Bäckhed F.
      • Ding H.
      • Wang T.
      • et al.
      The gut microbiota as an environmental factor that regulates fat storage.
      • Ley R.E.
      • Turnbaugh P.J.
      • Klein S.
      • Gordon J.I.
      Microbial ecology: human gut microbes associated with obesity.
      • Turnbaugh P.J.
      • Ley R.E.
      • Mahowald M.A.
      • Magrini V.
      • Mardis E.R.
      • Gordon J.I.
      An obesity-associated gut microbiome with increased capacity for energy harvest.
      • Jia W.
      • Li H.
      • Zhao L.
      • Nicholson J.K.
      Gut microbiota: a potential new territory for drug targeting.
      • Hooper L.V.
      • Littman D.R.
      • Macpherson A.J.
      Interactions between the microbiota and the immune system.
      Normal pregnancy represents a state in which a major reorganization of energy distribution (harvesting, storage, and expenditure) is related to the need to support the growth and development of the fetus and placenta. Studies of the gut microbiota in the third trimester of pregnancy showed that there is an overall increase of Proteobacteria and Actinobacteria coupled with a reduction in microbial richness.
      • Koren O.
      • Goodrich J.K.
      • Cullender T.C.
      • et al.
      Host remodeling of the gut microbiome and metabolic changes during pregnancy.
      When the intestinal content from women with a normal pregnancy in the third trimester was administered to germ-free mice, it increased adiposity and insulin resistance,
      • Kimura I.
      • Miyamoto J.
      • Ohue-Kitano R.
      • et al.
      Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice.
      which have been attributed to the proinflammatory effects of the gut microbiota.
      • Koren O.
      • Goodrich J.K.
      • Cullender T.C.
      • et al.
      Host remodeling of the gut microbiome and metabolic changes during pregnancy.
      Gut dysbiosis, or an imbalance among the human gut’s microbial communities, is now implicated in the development of atherosclerosis,
      • Jonsson A.L.
      • Bäckhed F.
      Role of gut microbiota in atherosclerosis.
      ,
      • Sanchez-Rodriguez E.
      • Egea-Zorrilla A.
      • Plaza-Díaz J.
      • et al.
      The gut microbiota and its implication in the development of atherosclerosis and related cardiovascular diseases.
      hypertension,
      • Li J.
      • Zhao F.
      • Wang Y.
      • et al.
      Gut microbiota dysbiosis contributes to the development of hypertension.
      ,
      • Kim S.
      • Goel R.
      • Kumar A.
      • et al.
      Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure.
      proteinuria,
      • Kanbay M.
      • Onal E.M.
      • Afsar B.
      • et al.
      The crosstalk of gut microbiota and chronic kidney disease: role of inflammation, proteinuria, hypertension, and diabetes mellitus.
      cardiometabolic syndrome,
      • Leshem A.
      • Horesh N.
      • Elinav E.
      Fecal microbial transplantation and its potential application in cardiometabolic syndrome.
      ,
      • Kazemian N.
      • Mahmoudi M.
      • Halperin F.
      • Wu J.C.
      • Pakpour S.
      Gut microbiota and cardiovascular disease: opportunities and challenges.
      and recently, preeclampsia.
      • Dunlop A.L.
      • Mulle J.G.
      • Ferranti E.P.
      • Edwards S.
      • Dunn A.B.
      • Corwin E.J.
      Maternal microbiome and pregnancy outcomes that impact infant health: a review.
      • Hampton T.
      Do gut bacteria play a role in preeclampsia?.
      • Chen X.
      • Li P.
      • Liu M.
      • et al.
      Gut dysbiosis induces the development of pre-eclampsia through bacterial translocation.
      • Beckers K.F.
      • Sones J.L.
      Maternal microbiome and the hypertensive disorder of pregnancy, preeclampsia.
      • Altemani F.
      • Barrett H.L.
      • Gomez-Arango L.
      • et al.
      Pregnant women who develop preeclampsia have lower abundance of the butyrate-producer Coprococcus in their gut microbiota.
      A causal link between gut dysbiosis and cardiovascular disease has been proposed based on observations that the transplantation of fecal material from hypertensive and nonpregnant human subjects to germ-free mice led to hypertension.
      • Li J.
      • Zhao F.
      • Wang Y.
      • et al.
      Gut microbiota dysbiosis contributes to the development of hypertension.
      Similarly, fecal transplants from mice prone to atherosclerosis can transmit the condition to susceptible mice (eg, apolipoprotein E-null mice).
      • Gregory J.C.
      • Buffa J.A.
      • Org E.
      • et al.
      Transmission of atherosclerosis susceptibility with gut microbial transplantation.
      This effect has been attributed, at least in part, to trimethylamine N-oxide, a bacteria-derived metabolite from choline and carnitine that is present in gut dysbiosis and has been shown to accelerate the development of atherosclerosis.
      • Sanchez-Rodriguez E.
      • Egea-Zorrilla A.
      • Plaza-Díaz J.
      • et al.
      The gut microbiota and its implication in the development of atherosclerosis and related cardiovascular diseases.
      ,
      • Gregory J.C.
      • Buffa J.A.
      • Org E.
      • et al.
      Transmission of atherosclerosis susceptibility with gut microbial transplantation.
      Changes in the composition of human gut microbiota have been reported in preeclampsia
      • Hampton T.
      Do gut bacteria play a role in preeclampsia?.
      ,
      • Chen X.
      • Li P.
      • Liu M.
      • et al.
      Gut dysbiosis induces the development of pre-eclampsia through bacterial translocation.
      ,
      • Altemani F.
      • Barrett H.L.
      • Gomez-Arango L.
      • et al.
      Pregnant women who develop preeclampsia have lower abundance of the butyrate-producer Coprococcus in their gut microbiota.
      ,
      • Wang J.
      • Gu X.
      • Yang J.
      • Wei Y.
      • Zhao Y.
      Gut microbiota dysbiosis and increased plasma LPS and TMAO levels in patients with preeclampsia.
      and persist up to six weeks postpartum.
      • Lv L.J.
      • Li S.H.
      • Li S.C.
      • et al.
      Early-onset preeclampsia is associated with gut microbial alterations in antepartum and postpartum women.
      These changes included a reduction in the microbial burden of Firmicutes, Clostridia, Clostridiales, and Ruminococcus and an increase in Bacteroidetes, Proteobacteria, Actinobacteria, Bacteroidia, Gammaproteobacteria, and Enterobacteriaceae (Figure 9, A).
      • Wang J.
      • Gu X.
      • Yang J.
      • Wei Y.
      • Zhao Y.
      Gut microbiota dysbiosis and increased plasma LPS and TMAO levels in patients with preeclampsia.
      Importantly, fecal transplantation from pregnant women with preeclampsia to mice led to the development of the syndrome, and this provides evidence of causality.
      • Chen X.
      • Li P.
      • Liu M.
      • et al.
      Gut dysbiosis induces the development of pre-eclampsia through bacterial translocation.
      The experimental paradigm consisted of the administration of fecal material from pregnant women with and without preeclampsia to nonpregnant mice that had received antibiotics for five days (to change gut flora).
      • Chen X.
      • Li P.
      • Liu M.
      • et al.
      Gut dysbiosis induces the development of pre-eclampsia through bacterial translocation.
      Six weeks after the first fecal inoculation, mice were mated.
      • Chen X.
      • Li P.
      • Liu M.
      • et al.
      Gut dysbiosis induces the development of pre-eclampsia through bacterial translocation.
      Pregnant mice that had received the fecal microbiota transplant from mothers with preeclampsia developed high systolic blood pressure and proteinuria, and they delivered fewer live pups than mice that received fecal microbiota transplants from women with a normotensive pregnancy (Figure 9, B).
      • Chen X.
      • Li P.
      • Liu M.
      • et al.
      Gut dysbiosis induces the development of pre-eclampsia through bacterial translocation.
      Collectively, this evidence suggests a role for gut dysbiosis in preeclampsia. However, further investigation of the precise mechanisms that may explain this phenomenon and the different levels of susceptibility among pregnant women is necessary.
      Figure thumbnail gr9
      Figure 9Observational and experimental evidence linking maternal gut dysbiosis and preeclampsia
      A, Gut microbiota of patients with preeclampsia (red) and those with normal pregnancy (blue). Significant differences in relative abundance were reported for four genera (Firmicutes, Bacteroidetes, Proteobacterias, and Actinobacteria) between women with preeclampsia and those with normal pregnancy. The boxes represent the interquartile range between first and third quartiles and the line inside represents the median. Single asterisk represents P<.05. B, Maternal intestinal dysbiosis and preeclampsia. Mice that received fecal microbiota from patients with preeclampsia (red) had higher systolic blood pressure than mice that received fecal microbiota from normotensive pregnant women (blue) or those that received the phosphate-buffered saline (control, gray). Modified from Wang et al
      • Wang J.
      • Gu X.
      • Yang J.
      • Wei Y.
      • Zhao Y.
      Gut microbiota dysbiosis and increased plasma LPS and TMAO levels in patients with preeclampsia.
      and Chen et al.
      • Chen X.
      • Li P.
      • Liu M.
      • et al.
      Gut dysbiosis induces the development of pre-eclampsia through bacterial translocation.
      Jung. The etiology of preeclampsia. Am J Obstet Gynecol 2022.

      Gestational diabetes mellitus, maternal obesity, and metabolic syndrome

      Gestational diabetes mellitus

      Gestational diabetes mellitus is an independent risk factor for preeclampsia, after adjusting for confounders.
      • Schneider S.
      • Freerksen N.
      • Röhrig S.
      • Hoeft B.
      • Maul H.
      Gestational diabetes and preeclampsia--similar risk factor profiles?.
      ,
      • Weissgerber T.L.
      • Mudd L.M.
      Preeclampsia and diabetes.
      In a retrospective study of 647,392 pregnancies, women with gestational diabetes had an increased risk of preeclampsia (adjusted odds ratio [aOR], 1.29; 95% CI, 1.19–1.41).
      • Schneider S.
      • Freerksen N.
      • Röhrig S.
      • Hoeft B.
      • Maul H.
      Gestational diabetes and preeclampsia--similar risk factor profiles?.
      Preexisting diabetes mellitus has also been linked to the development of preeclampsia as reported in a systematic review (aRR, 3.56; 95% CI, 2.54–4.99).
      • Duckitt K.
      • Harrington D.
      Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies.
      Diabetes mellitus is considered to be strongly associated with late-onset rather than early-onset preeclampsia (early-onset: aOR, 1.87; 95% CI, 1.6–2.18; late-onset: aOR, 2.46; 95% CI, 2.32–2.61).
      • Lisonkova S.
      • Joseph K.S.
      Incidence of preeclampsia: risk factors and outcomes associated with early- versus late-onset disease.
      The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study Cooperative Research Group reported a significant positive association between the degree of maternal hyperglycemia and preeclampsia: the odds ratio for each standard deviation increase in glucose concentrations (fasting, 1 hour, and 2 hours after a 75 mg glucose tolerance test) ranged from 1.21 to 1.28.
      • Metzger B.E.
      • Lowe L.P.
      • et al.
      HAPO Study Cooperative Research Group
      Hyperglycemia and adverse pregnancy outcomes.
      The case for a causal role is strengthened by the observation that the treatment of gestational diabetes mellitus with diet,
      • Kinshella M.W.
      • Omar S.
      • Scherbinsky K.
      • et al.
      Maternal dietary patterns and pregnancy hypertension in low- and middle-income countries: a systematic review and meta-analysis.
      insulin,
      • Crowther C.A.
      • Hiller J.E.
      • Moss J.R.
      • et al.
      Effect of treatment of gestational diabetes mellitus on pregnancy outcomes.
      ,
      • Landon M.B.
      • Spong C.Y.
      • Thom E.
      • et al.
      A multicenter, randomized trial of treatment for mild gestational diabetes.
      and metformin
      • Romero R.
      • Erez O.
      • Hüttemann M.
      • et al.
      Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity.
      • Kalafat E.
      • Sukur Y.E.
      • Abdi A.
      • Thilaganathan B.
      • Khalil A.
      Metformin for prevention of hypertensive disorders of pregnancy in women with gestational diabetes or obesity: systematic review and meta-analysis of randomized trials.
      • Alqudah A.
      • McKinley M.C.
      • McNally R.
      • et al.
      Risk of pre-eclampsia in women taking metformin: a systematic review and meta-analysis.
      • Tarry-Adkins J.L.
      • Ozanne S.E.
      • Aiken C.E.
      Impact of metformin treatment during pregnancy on maternal outcomes: a systematic review/meta-analysis.
      reduces the risk of preeclampsia. Two randomized clinical trials have shown that the treatment of gestational diabetes mellitus with insulin reduces the risk of preeclampsia (adjusted treatment effect: 0.70; 95% CI, 0.51–0.95).
      • Crowther C.A.
      • Hiller J.E.
      • Moss J.R.
      • et al.
      Effect of treatment of gestational diabetes mellitus on pregnancy outcomes.
      ,
      • Landon M.B.
      • Spong C.Y.
      • Thom E.
      • et al.
      A multicenter, randomized trial of treatment for mild gestational diabetes.
      Metformin is associated with a reduced risk of preeclampsia (relative risk [RR], 0.68; 95% CI, 0.48–0.95)
      • Alqudah A.
      • McKinley M.C.
      • McNally R.
      • et al.
      Risk of pre-eclampsia in women taking metformin: a systematic review and meta-analysis.
      and prolongation of gestation in women with preterm preeclampsia (median, 18 days).
      • Cluver C.A.
      • Hiscock R.
      • Decloedt E.H.
      • et al.
      Use of metformin to prolong gestation in preterm pre-eclampsia: randomised, double blind, placebo controlled trial.
      Prenatal exercise has also been reported to decrease the rate of preeclampsia by 41% in a systematic review and meta-analysis.
      • Davenport M.H.
      • Ruchat S.M.
      • Poitras V.J.
      • et al.
      Prenatal exercise for the prevention of gestational diabetes mellitus and hypertensive disorders of pregnancy: a systematic review and meta-analysis.
      Collectively, the evidence suggests a causal relationship between gestational diabetes and preeclampsia given the consistency of association, the temporal relationship, and the efficacy of interventions, such as insulin and metformin, in reducing the rate of preeclampsia.

      Maternal obesity

      Obesity, defined by a body mass index (BMI) of ≥30.0 kg/m2, is strongly associated with preeclampsia.
      • Sebire N.J.
      • Jolly M.
      • Harris J.P.
      • et al.
      Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London.
      • Roberts J.M.
      • Bodnar L.M.
      • Patrick T.E.
      • Powers R.W.
      The role of obesity in preeclampsia.
      • Chaemsaithong P.
      • Leung T.Y.
      • Sahota D.
      • et al.
      Body mass index at 11-13 weeks’ gestation and pregnancy complications in a Southern Chinese population: a retrospective cohort study.
      A meta-analysis of 29 prospective cohort studies (1,980,761 participants and 67,075 cases of preeclampsia) showed that maternal obesity was significantly associated with the development of preeclampsia (aOR, 2.93; 95% CI, 2.58–3.33), and the risk was higher in severe obesity (BMI≥35 kg/m2; aOR, 4.14; 95% CI, 3.61–4.75).
      • Wang Z.
      • Wang P.
      • Liu H.
      • et al.
      Maternal adiposity as an independent risk factor for pre-eclampsia: a meta-analysis of prospective cohort studies.
      A similar finding was reported in overweight women (BMI, 26.1–29.0 kg/m2) who had a higher risk of preeclampsia than women with a normal BMI (RR, 1.57; 95% CI, 1.49–1.64).
      • Conde-Agudelo A.
      • Belizán J.M.
      Risk factors for pre-eclampsia in a large cohort of Latin American and Caribbean women.
      A dose-dependent relationship has been reported between prepregnancy BMI and the risk of preeclampsia in both nulliparous and parous women in a large epidemiologic study (41,000 nulliparous and 29,000 multiparous women) (Figure 10).
      • Catov J.M.
      • Ness R.B.
      • Kip K.E.
      • Olsen J.
      Risk of early or severe pre-eclampsia related to pre-existing conditions.
      Data from the US Collaborative Perinatal Project indicated similar results for White and African American women (severe preeclampsia: African American, OR, 3.2; 95% CI, 2.5–5.0; White, OR, 3.4; 95% CI, 2.1–5.6).
      • Bodnar L.M.
      • Catov J.M.
      • Klebanoff M.A.
      • Ness R.B.
      • Roberts J.M.
      Prepregnancy body mass index and the occurrence of severe hypertensive disorders of pregnancy.
      Most studies report that obesity predisposes mainly to late-onset preeclampsia.
      • Duckitt K.
      • Harrington D.
      Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies.
      ,
      • Bodnar L.M.
      • Catov J.M.
      • Klebanoff M.A.
      • Ness R.B.
      • Roberts J.M.
      Prepregnancy body mass index and the occurrence of severe hypertensive disorders of pregnancy.
      However, a recent population-based study, which used US vital statistics data and included 15.8 million women (48,007 cases of early-onset disease and 777,715 cases of late-onset disease), demonstrated that maternal obesity is associated with an increased risk of both early-onset and late-onset disease (eg, BMI ≥40 kg/m2: early-onset disease, aRR, 2.18; 95% CI, 2.12–2.24; late-onset disease, aRR, 3.93; 95% CI, 3.91–3.96).
      • Bicocca M.J.
      • Mendez-Figueroa H.
      • Chauhan S.P.
      • Sibai B.M.
      Maternal obesity and the risk of early-onset and late-onset hypertensive disorders of pregnancy.
      In addition, preconceptional maternal weight loss, either by lifestyle modification or bariatric surgery, is effective in reducing the risk of preeclampsia (OR, 0.67; 95% CI, 0.51–0.88).
      • Schenkelaars N.
      • Rousian M.
      • Hoek J.
      • Schoenmakers S.
      • Willemsen S.
      • Steegers-Theunissen R.
      Preconceptional maternal weight loss and hypertensive disorders in pregnancy: a systematic review and meta-analysis.
      Figure thumbnail gr10
      Figure 10Probability of preeclampsia according to pre-pregnancy body mass index
      Probability of preeclampsia according to the prepregnancy BMI in both nulliparous (top line, red) and multiparous (bottom line, blue) women. Modified from Catov et al.
      • Catov J.M.
      • Ness R.B.
      • Kip K.E.
      • Olsen J.
      Risk of early or severe pre-eclampsia related to pre-existing conditions.
      BMI, body mass index.
      Jung. The etiology of preeclampsia. Am J Obstet Gynecol 2022.

      Metabolic syndrome

      The term “metabolic syndrome” refers to a cluster of metabolic abnormalities, including central obesity, insulin resistance, atherogenic dyslipidemia, and hypertension.
      • Hotamisligil G.S.
      Inflammation and metabolic disorders.
      ,
      • Kaur J.
      A comprehensive review on metabolic syndrome.
      This syndrome is strongly associated with systemic inflammation, oxidative stress, and endothelial dysfunction, all of which are features of preeclampsia.
      • Bakker W.
      • Eringa E.C.
      • Sipkema P.
      • van Hinsbergh V.W.
      Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity.
      • Funk S.D.
      • Yurdagul Jr., A.
      • Orr A.W.
      Hyperglycemia and endothelial dysfunction in atherosclerosis: lessons from type 1 diabetes.
      • Stekkinger E.
      • Scholten R.
      • van der Vlugt M.J.
      • van Dijk A.P.
      • Janssen M.C.
      • Spaanderman M.E.
      Metabolic syndrome and the risk for recurrent pre-eclampsia: a retrospective cohort study.
      • Spradley F.T.
      Metabolic abnormalities and obesity’s impact on the risk for developing preeclampsia.
      A retrospective cohort study of 212,463 women showed that the presence of prepregnancy metabolic syndrome is associated with an increased risk of preeclampsia (aOR, 1.48; 95% CI, 1.26–1.74).
      • Cho G.J.
      • Park J.H.
      • Shin S.A.
      • Oh M.J.
      • Seo H.S.
      Metabolic syndrome in the non-pregnant state is associated with the development of preeclampsia.
      Preeclampsia is also a risk factor for the subsequent development of metabolic syndrome after delivery.
      • Hubel C.A.
      Dyslipidemia, iron, and oxidative stress in preeclampsia: assessment of maternal and feto-placental interactions.
      • Pouta A.
      • Hartikainen A.L.
      • Sovio U.
      • et al.
      Manifestations of metabolic syndrome after hypertensive pregnancy.
      • Forest J.C.
      • Girouard J.
      • Massé J.
      • et al.
      Early occurrence of metabolic syndrome after hypertension in pregnancy.
      • Smith G.N.
      • Pudwell J.
      • Walker M.
      • Wen S.W.
      Risk estimation of metabolic syndrome at one and three years after a pregnancy complicated by preeclampsia.
      Moreover, bariatric surgery performed before pregnancy as a treatment for metabolic syndrome is associated with a lower rate of preeclampsia (aOR, 0.2; 95% CI, 0.09–0.44).
      • Bennett W.L.
      • Gilson M.M.
      • Jamshidi R.
      • et al.
      Impact of bariatric surgery on hypertensive disorders in pregnancy: retrospective analysis of insurance claims data.
      The mechanisms whereby insulin resistance predisposes to the development of preeclampsia are related to intravascular inflammation and endothelial cell dysfunction,
      • Jonk A.M.
      • Houben A.J.
      • de Jongh R.T.
      • Serné E.H.
      • Schaper N.C.
      • Stehouwer C.D.
      Microvascular dysfunction in obesity: a potential mechanism in the pathogenesis of obesity-associated insulin resistance and hypertension.
      ,
      • Muniyappa R.
      • Sowers J.R.
      Role of insulin resistance in endothelial dysfunction.
      which is the common pathway of the syndrome. Nonetheless, insulin resistance is neither required nor sufficient for the development of preeclampsia. The reason why some but not all patients with insulin resistance develop preeclampsia is unknown.

      Sleep disorders

      Sleep-disordered breathing, a term encompassing obstructive sleep apnea, snoring, periodic episodes of hypoxia, central apnea, and sleep hypopnea, is a risk factor for preeclampsia during pregnancy. A systematic review and meta-analysis of 120 studies, which included a total of 58,123,250 pregnant women, indicated that maternal sleep disturbances during pregnancy are associated with an increased risk of preeclampsia (OR, 2.80; 95% CI, 2.38–3.30)
      • Lu Q.
      • Zhang X.
      • Wang Y.
      • et al.
      Sleep disturbances during pregnancy and adverse maternal and fetal outcomes: a systematic review and meta-analysis.
      ; these disturbances included subjective sleep-disordered breathing (OR, 3.52; 95% CI, 2.58–4.79), obstructive sleep apnea (OR, 2.36; 95% CI, 2.00–2.79), and restless legs syndrome (OR, 1.83; 95% CI, 1.04–3.21).
      • Lu Q.
      • Zhang X.
      • Wang Y.
      • et al.
      Sleep disturbances during pregnancy and adverse maternal and fetal outcomes: a systematic review and meta-analysis.
      Snoring is defined as the vibration of respiratory structures resulting from turbulent flow when the upper airway narrows during sleep.
      • Dalmasso F.
      • Prota R.
      Snoring: analysis, measurement, clinical implications and applications.
      It is more common in pregnant women than in nonpregnant women (14%–23% vs 4%).
      • Loube D.I.
      • Poceta J.S.
      • Morales M.C.
      • Peacock M.D.
      • Mitler M.M.
      Self-reported snoring in pregnancy. Association with fetal outcome.
      ,
      • Franklin K.A.
      • Holmgren P.A.
      • Jönsson F.
      • Poromaa N.
      • Stenlund H.
      • Svanborg E.
      Snoring, pregnancy-induced hypertension, and growth retardation of the fetus.
      Snoring increases the risk of hypertension,
      • Hu F.B.
      • Willett W.C.
      • Colditz G.A.
      • et al.
      Prospective study of snoring and risk of hypertension in women.
      and new-onset snoring during pregnancy is associated with preeclampsia (OR, 1.59; 95% CI, 1.06–2.37).
      • O’Brien L.M.
      • Bullough A.S.
      • Owusu J.T.
      • et al.
      Pregnancy-onset habitual snoring, gestational hypertension, and preeclampsia: prospective cohort study.
      Evidence supporting a causal relationship between snoring and preeclampsia is that treatment with nasal continuous positive airway pressure (CPAP) improved blood pressure in women with preeclampsia.
      • Edwards N.
      • Blyton D.M.
      • Kirjavainen T.
      • Kesby G.J.
      • Sullivan C.E.
      Nasal continuous positive airway pressure reduces sleep-induced blood pressure increments in preeclampsia.
      ,
      • Whitehead C.
      • Tong S.
      • Wilson D.
      • Howard M.
      • Walker S.P.
      Treatment of early-onset preeclampsia with continuous positive airway pressure.
      Edwards et al
      • Edwards N.
      • Blyton D.M.
      • Kirjavainen T.
      • Kesby G.J.
      • Sullivan C.E.
      Nasal continuous positive airway pressure reduces sleep-induced blood pressure increments in preeclampsia.
      reported that autosetting nasal CPAP administered during sleep resulted in a marked reduction in blood pressure. Of interest, Bourjeily et al
      • Bourjeily G.
      • Curran P.
      • Butterfield K.
      • Maredia H.
      • Carpenter M.
      • Lambert-Messerlian G.
      Placenta-secreted circulating markers in pregnant women with obstructive sleep apnea.
      reported that pregnant women with obstructive sleep apnea presented a higher maternal plasma sFlt-1/PlGF ratio than those in a control group and that maternal sFlt-1 concentrations were decreased after CPAP treatment.
      • Daly A.
      • Robertson A.
      • Bobek G.
      • Middleton S.
      • Sullivan C.
      • Hennessy A.
      Sleep disordered breathing controlled by CPAP and sFlt-1 in a pregnant patient with chronic hypertension: case report and literature review.
      In normal pregnancy, blood pressure has a circadian rhythm with highest values at daytime. A reversed diurnal blood pressure rhythm (ie, nocturnal blood pressure is higher than diurnal pressure) has been reported in preeclampsia.
      • Redman C.W.
      • Beilin L.J.
      • Bonnar J.
      Reversed diurnal blood pressure rhythm in hypertensive pregnancies.
      ,
      • Beilin L.J.
      • Deacon J.
      • Michael C.A.
      • et al.
      Diurnal rhythms of blood pressure, plasma renin activity, angiotensin II and catecholamines in normotensive and hypertensive pregnancies.
      Polysomnography has shown that patients with preeclampsia have altered sleeping patterns,
      • Edwards N.
      • Blyton C.M.
      • Kesby G.J.
      • Wilcox I.
      • Sullivan C.E.
      Pre-eclampsia is associated with marked alterations in sleep architecture.
      specifically spending more time in slow-wave sleep than patients with a normal pregnancy (percentage of time spent in slow-wave sleep: 43±3 vs 21±2; P<.001).
      • Edwards N.
      • Blyton C.M.
      • Kesby G.J.
      • Wilcox I.
      • Sullivan C.E.
      Pre-eclampsia is associated with marked alterations in sleep architecture.
      One possible explanation for this finding is that cytokines, such as IL-1 and TNF-α, can increase the amount of slow-wave sleep
      • Edwards N.
      • Blyton C.M.
      • Kesby G.J.
      • Wilcox I.
      • Sullivan C.E.
      Pre-eclampsia is associated with marked alterations in sleep architecture.
      ; these cytokines are elevated in the maternal circulation of patients with preeclampsia.
      • Sacks G.P.
      • Studena K.
      • Sargent K.
      • Redman C.W.
      Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis.
      • Redman C.W.
      • Sacks G.P.
      • Sargent I.L.
      Preeclampsia: an excessive maternal inflammatory response to pregnancy.
      • Gervasi M.T.
      • Chaiworapongsa T.
      • Pacora P.
      • et al.
      Phenotypic and metabolic characteristics of monocytes and granulocytes in preeclampsia.
      The proposed mechanisms linking sleep disorders and preeclampsia involve intravascular inflammation and endothelial cell dysfunction.

      Molar pregnancy

      Hydatidiform mole, a gestational trophoblastic disease characterized by abnormal proliferation of trophoblastic and hydropic changes of the chorionic villi, is associated with preeclampsia
      • Vassilakos P.
      • Riotton G.
      • Kajii T.
      Hydatidiform mole: two entities. A morphologic and cytogenetic study with some clinical consideration.
      that sometimes presents before 20 weeks of gestation.
      • Kohorn E.I.
      Molar pregnancy: presentation and diagnosis.
      • Soto-Wright V.
      • Bernstein M.
      • Goldstein D.P.
      • Berkowitz R.S.
      The changing clinical presentation of complete molar pregnancy.
      • Jauniaux E.
      Partial moles: from postnatal to prenatal diagnosis.
      • Zilberman Sharon N.
      • Maymon R.
      • Melcer Y.
      • Jauniaux E.
      Obstetric outcomes of twin pregnancies presenting with a complete hydatidiform mole and coexistent normal fetus: a systematic review and meta-analysis.
      The frequency of preeclampsia in patients with hydatidiform mole ranges from 27% to 40% and is higher in patients untreated until the second trimester.
      • Kohorn E.I.
      Molar pregnancy: presentation and diagnosis.
      • Soto-Wright V.
      • Bernstein M.
      • Goldstein D.P.
      • Berkowitz R.S.
      The changing clinical presentation of complete molar pregnancy.
      • Jauniaux E.
      Partial moles: from postnatal to prenatal diagnosis.
      • Zilberman Sharon N.
      • Maymon R.
      • Melcer Y.
      • Jauniaux E.
      Obstetric outcomes of twin pregnancies presenting with a complete hydatidiform mole and coexistent normal fetus: a systematic review and meta-analysis.
      The mechanism whereby a complete hydatidiform mole causes preeclampsia is thought to involve an excess production of sFlt-1. Maternal serum sFlt-1 concentrations are 2- to 3-fold higher in patients with hydatidiform mole than in gestational age-matched controls
      • Koga K.
      • Osuga Y.
      • Tajima T.
      • et al.
      Elevated serum soluble fms-like tyrosine kinase 1 (sFlt1) level in women with hydatidiform mole.
      ; an increased expression of sFlt-1 in the molar tissue has also been reported.
      • Kanter D.
      • Lindheimer M.D.
      • Wang E.
      • et al.
      Angiogenic dysfunction in molar pregnancy.
      Placentas with hydatidiform mole have increased expression of LIGHT (TNFSF14, or tumor necrosis factor superfamily member 14), which is colocalized with sFlt-1 in the molar tissue.
      • Iriyama T.
      • Wang G.
      • Yoshikawa M.
      • et al.
      Increased LIGHT leading to sFlt-1 elevation underlies the pathogenic link between hydatidiform mole and preeclampsia.
      Chorionic villi in molar tissue are edematous or hydropic and are often avascular or display markedly reduced vessel density.
      • Kohorn E.I.
      Molar pregnancy: presentation and diagnosis.
      These villus capillary changes may lead to excessive production of sFlt-1 and preeclampsia.

      Fetal diseases

      Specific fetal diseases associated with the development of preeclampsia include: (1) Ballantyne or mirror syndrome
      • John A.H.
      • Duncan A.S.
      The maternal syndrome associated with hydrops foetalis.
      ,
      • Gedikbasi A.
      • Oztarhan K.
      • Gunenc Z.
      • et al.
      Preeclampsia due to fetal non-immune hydrops: mirror syndrome and review of literature.
      ; (2) trisomy 13 or triploidy
      • Broekhuizen F.F.
      • Elejalde R.
      • Hamilton P.R.
      Early-onset preeclampsia, triploidy and fetal hydrops.
      ,
      • Dotters-Katz S.K.
      • Hardisty E.
      • Campbell E.
      • Vora N.
      Trisomy 13-confined placental mosaicism: is there an increased risk of gestational hypertensive disorders?.
      ; and (3) unique complications of multiple gestations (eg, twin-to-twin transfusion syndrome or selective fetal growth restriction).
      • Giorgione V.
      • Bhide A.
      • Bhate R.
      • Reed K.
      • Khalil A.
      Are twin pregnancies complicated by weight discordance or fetal growth restriction at higher risk of preeclampsia?.
      Ballantyne or mirror syndrome reflects a simultaneous edematous state of the mother, fetus, and placenta (also called triple edema).
      • O’Driscoll D.T.
      A fluid retention syndrome associated with severe iso-immunization to the rhesus factor.
      ,
      • Kaiser I.H.
      Ballantyne and triple edema.
      This syndrome has been observed in rhesus isoimmunization,
      • O’Driscoll D.T.
      A fluid retention syndrome associated with severe iso-immunization to the rhesus factor.
      cytomegalovirus,
      • Rana S.
      • Venkatesha S.
      • DePaepe M.
      • Chien E.K.
      • Paglia M.
      • Karumanchi S.A.
      Cytomegalovirus-induced mirror syndrome associated with elevated levels of circulating antiangiogenic factors.
      parvovirus B19 infection,
      • Brochot C.
      • Collinet P.
      • Provost N.
      • Subtil D.
      Mirror syndrome due to parvovirus B19 hydrops complicated by severe maternal pulmonary effusion.
      Ebstein’s anomaly,
      • Braun T.
      • Brauer M.
      • Fuchs I.
      • et al.
      Mirror syndrome: a systematic review of fetal associated conditions, maternal presentation and perinatal outcome.
      aneurysms of the vein of Galen,
      • Ordorica S.A.
      • Marks F.
      • Frieden F.J.
      • Hoskins I.A.
      • Young B.K.
      Aneurysm of the vein of Galen: a new cause for Ballantyne syndrome.
      fetal supraventricular tachycardia,
      • Sherer D.M.
      • Sadovksy E.
      • Menashe M.
      • Mordel N.
      • Rein A.J.
      Fetal ventricular tachycardia associated with nonimmunologic hydrops fetalis. A case report.
      ,
      • Midgley D.Y.
      • Harding K.
      The mirror syndrome.
      and placental chorioangiomas.
      • Dorman S.L.
      • Cardwell M.S.
      Ballantyne syndrome caused by a large placental chorioangioma.
      In mirror syndrome, the mother may develop proteinuria, hypertension, and even severe preeclampsia.
      • John A.H.
      • Duncan A.S.
      The maternal syndrome associated with hydrops foetalis.
      ,
      • Gedikbasi A.
      • Oztarhan K.
      • Gunenc Z.
      • et al.
      Preeclampsia due to fetal non-immune hydrops: mirror syndrome and review of literature.
      ,
      • Braun T.
      • Brauer M.
      • Fuchs I.
      • et al.
      Mirror syndrome: a systematic review of fetal associated conditions, maternal presentation and perinatal outcome.
      ,
      • Allarakia S.
      • Khayat H.A.
      • Karami M.M.
      • et al.
      Characteristics and management of mirror syndrome: a systematic review (1956-2016).
      Approximately 60% of patients with mirror syndrome have hypertension.
      • John A.H.
      • Duncan A.S.
      The maternal syndrome associated with hydrops foetalis.
      ,
      • Gedikbasi A.
      • Oztarhan K.
      • Gunenc Z.
      • et al.
      Preeclampsia due to fetal non-immune hydrops: mirror syndrome and review of literature.
      ,
      • Braun T.
      • Brauer M.
      • Fuchs I.
      • et al.
      Mirror syndrome: a systematic review of fetal associated conditions, maternal presentation and perinatal outcome.
      ,
      • Allarakia S.
      • Khayat H.A.
      • Karami M.M.
      • et al.
      Characteristics and management of mirror syndrome: a systematic review (1956-2016).
      The reversal of preeclampsia and Ballantyne syndrome can occur after intrauterine transfusion in parvovirus-induced hydrops without delivery.
      • Duthie S.J.
      • Walkinshaw S.A.
      Parvovirus associated fetal hydrops: reversal of pregnancy induced proteinuric hypertension by in utero fetal transfusion.
      Patients with mirror syndrome can have an increased maternal plasma concentration of sFlt-1
      • Espinoza J.
      • Romero R.
      • Nien J.K.
      • et al.
      A role of the anti-angiogenic factor sVEGFR-1 in the ‘mirror syndrome’ (Ballantyne’s syndrome).
      that can return to normal after intrauterine transfusion.
      • Stepan H.
      • Faber R.
      Elevated sFlt1 level and preeclampsia with parvovirus-induced hydrops.
      ,
      • Goa S.
      • Mimura K.
      • Kakigano A.
      • et al.
      Normalisation of angiogenic imbalance after intra-uterine transfusion for mirror syndrome caused by parvovirus B19.
      Another example of preeclampsia associated with fetal disease is trisomy 13, or triploidy.
      • Broekhuizen F.F.
      • Elejalde R.
      • Hamilton P.R.
      Early-onset preeclampsia, triploidy and fetal hydrops.
      ,
      • Dotters-Katz S.K.
      • Hardisty E.
      • Campbell E.
      • Vora N.
      Trisomy 13-confined placental mosaicism: is there an increased risk of gestational hypertensive disorders?.
      ,
      • Kakigano A.
      • Mimura K.
      • Kanagawa T.
      • et al.
      Imbalance of angiogenic factors and avascular edematous cystic villi in a trisomy 13 pregnancy: a case report.
      In a case control study, the frequency of preeclampsia was higher in cases with trisomy 13 than in the control group with normal karyotype (44% vs 8%, P=.001).
      • Tuohy J.F.
      • James D.K.
      Pre-eclampsia and trisomy 13.
      Women with a trisomy 13 pregnancy have a higher serum sFlt-1/PlGF ratio,
      • Bdolah Y.
      • Palomaki G.E.
      • Yaron Y.
      • et al.
      Circulating angiogenic proteins in trisomy 13.
      and their placentas show greater staining for sFlt-1 than those of euploid and trisomy 21 pregnancies.
      • Silasi M.
      • Rana S.
      • Powe C.
      • et al.
      Placental expression of angiogenic factors in trisomy 13.
      Interestingly, sFlt-1 is located on chromosome 13, suggesting that an extra copy of chromosome 13 may lead to increased production of sFlt-1.
      • Kakigano A.
      • Mimura K.
      • Kanagawa T.
      • et al.
      Imbalance of angiogenic factors and avascular edematous cystic villi in a trisomy 13 pregnancy: a case report.
      ,
      • Silasi M.
      • Rana S.
      • Powe C.
      • et al.
      Placental expression of angiogenic factors in trisomy 13.
      Multiple gestations complicated by twin-to-twin transfusion syndrome or selective fetal growth restriction are at a greater risk for preeclampsia.
      • Giorgione V.
      • Bhide A.
      • Bhate R.
      • Reed K.
      • Khalil A.
      Are twin pregnancies complicated by weight discordance or fetal growth restriction at higher risk of preeclampsia?.
      Selective termination of 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.
      or the death of one twin,
      • Sarhanis P.
      • Pugh D.H.
      Resolution of pre-eclampsia following intrauterine death of one twin.
      can lead to the resolution of hypertension and proteinuria as well as to the improvement in the angiogenic and antiangiogenic profiles.
      • Hladunewich M.A.
      • Steinberg G.
      • Karumanchi S.A.
      • et al.
      Angiogenic factor abnormalities and fetal demise in a twin pregnancy.
      ,
      • Fox C.E.
      • Lash G.E.
      • Pretlove S.J.
      • Chan B.C.
      • Holder R.
      • Kilby M.D.
      Maternal plasma and amniotic fluid angiogenic factors and their receptors in monochorionic twin pregnancies complicated by twin-to-twin transfusion syndrome.
      These observations suggest that preeclampsia can resolve without delivery and that fetal compromise may induce the syndrome in some cases.

      Autoimmune mechanisms: a role for antibodies against angiotensin II type I receptor

      Preeclampsia is not traditionally considered an autoimmune disorder. However, the possibility of an autoimmune mechanism of disease has been investigated for several decades, given that patients with systemic autoimmune diseases such as systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS) are at increased risk for preeclampsia (SLE: RR, 1.91; 95% CI, 1.44–2.53; APS: RR, 1.81; 95% CI, 1.33–2.45).
      • Bundhun P.K.
      • Soogund M.Z.
      • Huang F.
      Impact of systemic lupus erythematosus on maternal and fetal outcomes following pregnancy: a meta-analysis of studies published between years 2001-2016.
      • Saccone G.
      • Berghella V.
      • Maruotti G.M.
      • et al.
      Antiphospholipid antibody profile based obstetric outcomes of primary antiphospholipid syndrome: the pregnants study.
      • Liu L.
      • Sun D.
      Pregnancy outcomes in patients with primary antiphospholipid syndrome: a systematic review and meta-analysis.
      • Dong Y.
      • Yuan F.
      • Dai Z.
      • Wang Z.
      • Zhu Y.
      • Wang B.
      Preeclampsia in systemic lupus erythematosus pregnancy: a systematic review and meta-analysis.
      Similarly, several studies have shown that specific autoantibodies, such as anti-β2 glycoprotein-I (ab2GPI), anticardiolipin antibodies (aCL), or lupus anticoagulant (LA), are associated with preeclampsia.
      • Saccone G.
      • Berghella V.
      • Maruotti G.M.
      • et al.
      Antiphospholipid antibody profile based obstetric outcomes of primary antiphospholipid syndrome: the pregnants study.
      ,
      • Lee R.M.
      • Brown M.A.
      • Branch D.W.
      • Ward K.
      • Silver R.M.
      Anticardiolipin and anti-beta2-glycoprotein-I antibodies in preeclampsia.
      However, the most compelling case for the role of an autoimmune mechanism in the pathogenesis of preeclampsia can be made with antibodies against the angiotensin II receptor.
      Nearly two decades ago, Wallukat et al
      • Wallukat G.
      • Homuth V.
      • Fischer T.
      • et al.
      Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor.
      reported that women with preeclampsia had antibodies that bind to the angiotensin II type I receptor (AT1-AA). Subsequently, substantial evidence has accumulated supporting the role of AT1-AA in the pathogenesis of preeclampsia. Such evidence includes: (1) 80% of women with preeclampsia have increased concentrations of AT1-AA in maternal serum at the time of diagnosis
      • Yang X.
      • Wang F.
      • Chang H.
      • et al.
      Autoantibody against AT1 receptor from preeclamptic patients induces vasoconstriction through angiotensin receptor activation.
      ; (2) the concentration of AT1-AA in maternal serum correlates with the severity of hypertension and proteinuria
      • Siddiqui A.H.
      • Irani R.A.
      • Blackwell S.C.
      • Ramin S.M.
      • Kellems R.E.
      • Xia Y.
      Angiotensin receptor agonistic autoantibody is highly prevalent in preeclampsia: correlation with disease severity.
      ; and (3) the administration of AT1-AA to pregnant rats leads to hypertension, proteinuria, glomerular capillary endotheliosis,
      • Zhou C.C.
      • Zhang Y.
      • Irani R.A.
      • et al.
      Angiotensin receptor agonistic autoantibodies induce pre-eclampsia in pregnant mice.
      an increased production of sFlt-1 and soluble endoglin.
      • Parrish M.R.
      • Murphy S.R.
      • Rutland S.
      • et al.
      The effect of immune factors, tumor necrosis factor-alpha, and agonistic autoantibodies to the angiotensin II type I receptor on soluble fms-like tyrosine-1 and soluble endoglin production in response to hypertension during pregnancy.
      The increase in mean arterial pressure can be attenuated by the administration of an AT1-receptor blocker (losartan). It is noteworthy that a longitudinal study did not find that the maternal plasma concentration of ATI-AA increased prior to the diagnosis of preeclampsia.
      • Aggarwal S.
      • Sunderland N.
      • Thornton C.
      • Xu B.
      • Hennessy A.
      • Makris A.
      A longitudinal analysis of angiotensin II type 1 receptor antibody and angiogenic markers in pregnancy.
      What causes the excessive production of AT1-AA? Placental ischemia, caused by a reduction in uterine perfusion pressure, has been shown to increase the concentration of serum AT1-AA in pregnant rats.
      • LaMarca B.
      • Wallukat G.
      • Llinas M.
      • Herse F.
      • Dechend R.
      • Granger J.P.
      Autoantibodies to the angiotensin type I receptor in response to placental ischemia and tumor necrosis factor alpha in pregnant rats.
      The importance of this in preeclampsia has been inferred by the observation that inhibition of AT1-AA by the administration of an epitope-binding peptide can reduce maternal blood pressure and plasma concentrations of endothelin-1, sFlt-1, and isoprostanes, which are markers of oxidative stress.
      • Cunningham Jr., M.W.
      • Castillo J.
      • Ibrahim T.
      • et al.
      AT1-AA (angiotensin II Type 1 receptor agonistic autoantibody) blockade prevents preeclamptic symptoms in placental ischemic rats.
      Other factors that can modify the activity of AT1-AA are cytokines. Indeed, the administration of TNF-α,
      • LaMarca B.
      • Wallukat G.
      • Llinas M.
      • Herse F.
      • Dechend R.
      • Granger J.P.
      Autoantibodies to the angiotensin type I receptor in response to placental ischemia and tumor necrosis factor alpha in pregnant rats.
      ,
      • Li J.
      • LaMarca B.
      • Reckelhoff J.F.
      A model of preeclampsia in rats: the reduced uterine perfusion pressure (RUPP) model.
      IL-6,
      • Li J.
      • LaMarca B.
      • Reckelhoff J.F.
      A model of preeclampsia in rats: the reduced uterine perfusion pressure (RUPP) model.
      ,
      • Lamarca B.
      • Speed J.
      • Ray L.F.
      • et al.
      Hypertension in response to IL-6 during pregnancy: role of AT1-receptor activation.
      and IL-17
      • Dhillion P.
      • Wallace K.
      • Herse F.
      • et al.
      IL-17-mediated oxidative stress is an important stimulator of AT1-AA and hypertension during pregnancy.
      to pregnant rats enhances AT1-AA activity and can induce preeclampsia, which is prevented by AT1-AA blockage.
      • Cunningham Jr., M.W.
      • Castillo J.
      • Ibrahim T.
      • et al.
      AT1-AA (angiotensin II Type 1 receptor agonistic autoantibody) blockade prevents preeclamptic symptoms in placental ischemic rats.

      Placental aging

      Cells and organisms have a finite lifespan. Human cells in culture can multiply (mitosis) a limited number of times (the Hayflick limit) before they stop dividing and, subsequently, undergo programmed cell death, or apoptosis.
      • Hayflick L.
      • Moorhead P.S.
      The serial cultivation of human diploid cell strains.
      The placenta is also thought to have a prespecified lifetime, and as age advances, the functional capacity of placental cells declines. Placental aging has been described for several decades,
      • Martin B.J.
      • Spicer S.S.
      Ultrastructural features of cellular maturation and aging in human trophoblast.
      ,
      • Burstein R.
      • Frankel S.
      • Soule S.D.
      • Blumenthal H.T.
      Aging of the placenta: autoimmune theory of senescence.
      and premature aging has been implicated as a mechanism of disease for obstetrical outcomes, eg, preeclampsia,
      • Biron-Shental T.
      • Sukenik-Halevy R.
      • Sharon Y.
      • et al.
      Short telomeres may play a role in placental dysfunction in preeclampsia and intrauterine growth restriction.
      ,
      • Mayne B.T.
      • Leemaqz S.Y.
      • Smith A.K.
      • Breen J.
      • Roberts C.T.
      • Bianco-Miotto T.
      Accelerated placental aging in early onset preeclampsia pregnancies identified by DNA methylation.
      fetal growth restriction,
      • Biron-Shental T.
      • Sukenik-Halevy R.
      • Sharon Y.
      • et al.
      Short telomeres may play a role in placental dysfunction in preeclampsia and intrauterine growth restriction.
      ,
      • Sultana Z.
      • Maiti K.
      • Dedman L.
      • Smith R.
      Is there a role for placental senescence in the genesis of obstetric complications and fetal growth restriction?.
      fetal death,
      • Maiti K.
      • Sultana Z.
      • Aitken R.J.
      • et al.
      Evidence that fetal death is associated with placental aging.
      and preterm labor.
      • Gomez-Lopez N.
      • Romero R.
      • Plazyo O.
      • et al.
      Preterm labor in the absence of acute histologic chorioamnionitis is characterized by cellular senescence of the chorioamniotic membranes.
      Cytotrophoblasts are replicating cells, but the syncytiotrophoblast is generated by fusion and, therefore, is in a state of senescence (defined as the inability to multiply). Evidence supporting the concept that senescence is present in the normal syncytiotrophoblast includes the following findings: (1) high lysosomal activity indicated by staining with beta-galactosidase; (2) increased expression of cyclin-dependent kinase, p53, p21, and p16; and (3) the presence of syncytial knots, proposed to be equivalent to senescence-associated heterochromatic foci, which are clusters of chromatin in the nucleus of senescent cells.
      • Redman C.W.G.
      • Staff A.C.
      • Roberts J.M.
      Syncytiotrophoblast stress in preeclampsia: the convergence point for multiple pathways.
      • Cindrova-Davies T.
      • Fogarty N.M.E.
      • Jones C.J.P.
      • Kingdom J.
      • Burton G.J.
      Evidence of oxidative stress-induced senescence in mature, post-mature and pathological human placentas.
      • Higuchi S.
      • Miyamoto T.
      • Kobara H.
      • et al.
      Trophoblast type-specific expression of senescence markers in the human placenta.
      Cindrova-Davies et al
      • Cindrova-Davies T.
      • Fogarty N.M.E.
      • Jones C.J.P.
      • Kingdom J.
      • Burton G.J.
      Evidence of oxidative stress-induced senescence in mature, post-mature and pathological human placentas.
      demonstrated that markers of senescence increase in normal placentas as a function of advancing gestational age.
      Placentas of patients with preeclampsia exhibit greater expression of p53, p21, and p16, shorter telomeres,
      • Biron-Shental T.
      • Sukenik-Halevy R.
      • Sharon Y.
      • et al.
      Short telomeres may play a role in placental dysfunction in preeclampsia and intrauterine growth restriction.
      and reduced telomerase activity.
      • Londero A.P.
      • Orsaria M.
      • Marzinotto S.
      • et al.
      Placental aging and oxidation damage in a tissue micro-array model: an immunohistochemistry study.
      ,
      • Cox L.S.
      • Redman C.
      The role of cellular senescence in ageing of the placenta.
      Redman et al
      • Redman C.W.G.
      • Staff A.C.
      • Roberts J.M.
      Syncytiotrophoblast stress in preeclampsia: the convergence point for multiple pathways.
      have proposed that with advancing gestational age some patients develop a “twilight placenta,” a condition in which the organ is affected by senescence. When placental growth reaches its limits at term, terminal villi become overcrowded with diminished intervillous space, leading to respiratory failure of the placenta (Figure 11) and contributing to intervillous hypoxia and syncytiotrophoblast stress.
      • Mayhew T.M.
      • Barker B.L.
      Villous trophoblast: morphometric perspectives on growth, differentiation, turnover and deposition of fibrin-type fibrinoid during gestation.
      • Redman C.W.
      • Sargent I.L.
      • Staff A.C.
      IFPA Senior Award Lecture: making sense of pre-eclampsia - two placental causes of preeclampsia?.
      • Serov A.S.
      • Salafia C.M.
      • Brownbill P.
      • Grebenkov D.S.
      • Filoche M.
      Optimal villi density for maximal oxygen uptake in the human placenta.
      A twilight placenta has been invoked as a potential cause for late pregnancy complications such as late-onset preeclampsia,
      • 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.
      ,
      • Muralimanoharan S.
      • Maloyan A.
      • Mele J.
      • Guo C.
      • Myatt L.G.
      • Myatt L.
      MIR-210 modulates mitochondrial respiration in placenta with preeclampsia.
      unexplained term stillbirth, or fetal death in prolonged pregnancy.
      • Maiti K.
      • Sultana Z.
      • Aitken R.J.
      • et al.
      Evidence that fetal death is associated with placental aging.
      ,
      • Cox L.S.
      • Redman C.
      The role of cellular senescence in ageing of the placenta.
      ,
      • Smith R.
      • Maiti K.
      • Aitken R.J.
      Unexplained antepartum stillbirth: a consequence of placental aging?.
      At present, there is not an easy or practical way to determine placental age; however, recent studies have identified an epigenetic clock for placental dating,
      • Tekola-Ayele F.
      • Zeng X.
      • Ouidir M.
      • et al.
      DNA methylation loci in placenta associated with birthweight and expression of genes relevant for early development and adult diseases.
      which may be used to examine the role of placental aging in pregnancy complications in the future.
      Figure thumbnail gr11
      Figure 11Relationship between villi density in the placenta and maximum oxygen uptake based on mathematical modeling
      A, Placentas with low villi density (rarefied villi) have low oxygen uptake, as fetal villi are rare. By contrast, in placentas with high villous density (villous overcrowding), there is no intervillous space for oxygen exchange. The optimal villi density for the oxygen uptake was 0.47±0.06, calculated from histomorphometrical data for villi and intervillous volumes of placentas. B, Cross-section of the placenta: (1) rarefied villi in preeclampsia; (2) normal placenta; and (3) villous overcrowding in diabetes mellitus. Hematoxylin and eosin stains and scale represents 50 μm. Modified from Serov et al.
      • Serov A.S.
      • Salafia C.M.
      • Brownbill P.
      • Grebenkov D.S.
      • Filoche M.
      Optimal villi density for maximal oxygen uptake in the human placenta.
      Jung. The etiology of preeclampsia. Am J Obstet Gynecol 2022.

      Breakdown of maternal-fetal immune tolerance

      Viviparity involves the coexistence of two individuals (mother and fetus) with different genetic makeups. The placenta and fetus are viewed as the most successful transplant in biology (often referred to as a semiallograft because of maternal and paternal contributions), and the mechanisms responsible for immune tolerance have been the subject of investigation for decades.
      • Moffett A.
      • Loke C.
      Immunology of placentation in eutherian mammals.
      • Leslie M.
      Immunology. Fetal immune system hushes attacks on maternal cells.
      • Burlingham W.J.
      A lesson in tolerance--maternal instruction to fetal cells.
      • Rowe J.H.
      • Ertelt J.M.
      • Xin L.
      • Way S.S.
      Pregnancy imprints regulatory memory that sustains anergy to fetal antigen.
      • Betz A.G.
      Immunology: tolerating pregnancy.
      • Williams Z.
      Inducing tolerance to pregnancy.
      Two typical features of the adaptive immune system are memory and specificity.
      • Colvin R.B.
      • Smith R.N.
      Antibody-mediated organ-allograft rejection.
      • Alegre M.L.
      • Florquin S.
      • Goldman M.
      Cellular mechanisms underlying acute graft rejection: time for reassessment.
      • Kim I.K.
      • Bedi D.S.
      • Denecke C.
      • Ge X.
      • Tullius S.G.
      Impact of innate and adaptive immunity on rejection and tolerance.
      A role for the immune system in the pathogenesis of preeclampsia has been proposed as the syndrome is more common in primigravidas and in multigravidas with different fathers (primipaternity).
      • Robillard P.Y.
      • Dekker G.
      • Chaouat G.
      • Hulsey T.C.
      • Saftlas A.
      Epidemiological studies on primipaternity and immunology in preeclampsia--a statement after twelve years of workshops.
      ,
      • Robillard P.Y.
      • Dekker G.
      • Chaouat G.
      • Elliot M.G.
      • Scioscia M.
      High incidence of early onset preeclampsia is probably the rule and not the exception worldwide. 20th anniversary of the reunion workshop. A summary.
      A memory-like phenomenon that protects mothers against paternal antigens in subsequent pregnancies has been invoked to explain the predilection for primigravidas.
      • Gamliel M.
      • Goldman-Wohl D.
      • Isaacson B.
      • et al.
      Trained memory of human uterine NK cells enhances their function in subsequent pregnancies.
      The higher frequency of preeclampsia in multigravidas with pregnancies from different fathers has been attributed to an immune process specific to paternally derived antigens.
      • Trupin L.S.
      • Simon L.P.
      • Eskenazi B.
      Change in paternity: a risk factor for preeclampsia in multiparas.
      ,
      • Li D.K.
      • Wi S.
      Changing paternity and the risk of preeclampsia/eclampsia in the subsequent pregnancy.
      Additional evidence for this is that preeclampsia is more common in pregnancies resulting from egg donation in which placenta and fetus are complete grafts rather than semiallografts.
      • Perni S.C.
      • Predanic M.
      • Cho J.E.
      • Baergen R.N.
      Placental pathology and pregnancy outcomes in donor and non-donor oocyte in vitro fertilization pregnancies.
      The placenta and fetus, express both paternal and maternal antigens.
      • Koch C.A.
      • Platt J.L.
      Natural mechanisms for evading graft rejection: the fetus as an allograft.
      • Chaouat G.
      • Petitbarat M.
      • Dubanchet S.
      • Rahmati M.
      • Ledée N.
      Tolerance to the foetal allograft?.
      • Erlebacher A.
      Mechanisms of T cell tolerance towards the allogeneic fetus.
      The syncytiotrophoblast is in direct contact with maternal blood, thus the maternal immune system is exposed to paternal antigens expressed by the placenta.
      • Moffett A.
      • Loke C.
      Immunology of placentation in eutherian mammals.
      Immune tolerance is considered important for successful pregnancy,
      • Rowe J.H.
      • Ertelt J.M.
      • Xin L.
      • Way S.S.
      Pregnancy imprints regulatory memory that sustains anergy to fetal antigen.
      ,
      • Erlebacher A.
      Why isn’t the fetus rejected?.
      ,
      • Trowsdale J.
      • Betz A.G.
      Mother’s little helpers: mechanisms of maternal-fetal tolerance.
      and a breakdown of tolerance can lead to maternal antifetal rejection, placental damage, and pregnancy complications that may include preeclampsia. Placental lesions, which represent manifestations of maternal antifetal rejection, are villitis of unknown etiology (VUE),
      • Knox W.F.
      • Fox H.
      Villitis of unknown aetiology: its incidence and significance in placentae from a British population.
      • Labarrere C.
      • Althabe O.
      Chronic villitis of unknown etiology and maternal arterial lesions in preeclamptic pregnancies.
      • Kim M.J.
      • Romero R.
      • Kim C.J.
      • et al.
      Villitis of unknown etiology is associated with a distinct pattern of chemokine up-regulation in the feto-maternal and placental compartments: implications for conjoint maternal allograft rejection and maternal anti-fetal graft-versus-host disease.
      • Benzon S.
      • Zekić Tomaš S.
      • Benzon Z.
      • Vulić M.
      • Kuzmić Prusac I.
      Involvement of T lymphocytes in the placentae with villitis of unknown etiology from pregnancies complicated with preeclampsia.
      massive perivillous fibrin deposition,
      • Whitten A.E.
      • Romero R.
      • Korzeniewski S.J.
      • et al.
      Evidence of an imbalance of angiogenic/antiangiogenic factors in massive perivillous fibrin deposition (maternal floor infarction): a placental lesion associated with recurrent miscarriage and fetal death.
      ,
      • Romero R.
      • Whitten A.
      • Korzeniewski S.J.
      • et al.
      Maternal floor infarction/massive perivillous fibrin deposition: a manifestation of maternal antifetal rejection?.
      chronic chorioamnionitis,
      • Lee J.
      • Romero R.
      • Dong Z.
      • et al.
      Unexplained fetal death has a biological signature of maternal anti-fetal rejection: chronic chorioamnionitis and alloimmune anti-human leucocyte antigen antibodies.
      • Kim C.J.
      • Romero R.
      • Chaemsaithong P.
      • Kim J.S.
      Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance.
      • Maymon E.
      • Romero R.
      • Bhatti G.
      • et al.
      Chronic inflammatory lesions of the placenta are associated with an up-regulation of amniotic fluid CXCR3: a marker of allograft rejection.
      chronic intervillositis, and chronic deciduitis of the placental basal plate.
      • Kim C.J.
      • Romero R.
      • Chaemsaithong P.
      • Kim J.S.
      Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance.
      In VUE, the battleground for immune damage is the chorionic villi, and maternal T-cells infiltrate the villous tree (Figure 12, A and B).
      • Kim C.J.
      • Romero R.
      • Chaemsaithong P.
      • Kim J.S.
      Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance.
      The frequency of chronic villitis is higher in late-onset preeclampsia than in normal pregnancy but not in early-onset preeclampsia (Figure 12, C).
      • Labarrere C.
      • Althabe O.
      Chronic villitis of unknown etiology and maternal arterial lesions in preeclamptic pregnancies.
      ,
      • Stanek J.
      Histological features of shallow placental implantation unify early-onset and late-onset preeclampsia.
      Massive perivillous fibrin deposition is characterized by extensive deposition of fibrinoid material in the intervillous space, hypoplasia, and sclerosis of the engulfed villi.
      • Kim C.J.
      • Romero R.
      • Chaemsaithong P.
      • Kim J.S.
      Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance.
      This lesion is associated with preeclampsia in one in five cases.
      • Devisme L.
      • Chauvière C.
      • Franquet-Ansart H.
      • et al.
      Perinatal outcome of placental massive perivillous fibrin deposition: a case-control study.
      Figure thumbnail gr12
      Figure 12Villitis of unknown etiology as a pathologic manifestation of maternal anti-fetal rejection
      A, Circulating maternal T cells entering the intervillous space can infiltrate the villous tree. After maternal T-cell infiltration, Hofbauer cells (fetal placental macrophages) are activated. This can be interpreted as evidence of semiallograft rejection because maternal T cells (recipient of the semiallograft) infiltrate the placenta (semiallograft). B, Normal chorionic villi showing the villous core with fetal vessels and stroma. The intervillous space contains maternal red blood cells. The rest of the image shows cross-sections of the villous tree of the placenta; chorionic villi are lined with syncytiotrophoblast. Inside the villi, fetal capillaries are observed. C, Destructive inflammation of the chorionic villus (asterisk). The inflammatory process is diagnosed by the presence of an infiltration of mononuclear cells. Obliteration of the villous capillaries is also seen in comparison to unaffected villi adjacent to the distorted villus (asterisk). Unaffected villi (black arrow). D, Destructive inflammation of the chorionic villi (asterisk). Immunoperoxidase staining for CD8+ T cells. Cells stained in brown express CD8 on their surface and are therefore cytotoxic lymphocytes. These cells are of maternal origin, and are derived from the intervillous space. Original magnification (B-D), 200 x. E, The frequency of villitis of unknown etiology is higher in late-onset preeclampsia than normal pregnancy (p<0.001). Modified from Kim et al.
      • Kim C.J.
      • Romero R.
      • Chaemsaithong P.
      • Kim J.S.
      Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance.
      and Stanek et al.
      • Stanek J.
      Histological features of shallow placental implantation unify early-onset and late-onset preeclampsia.
      Jung. The etiology of preeclampsia. Am J Obstet Gynecol 2022.
      Maternal-fetal genetic incompatibility has been implicated in the genesis of preeclampsia. Placentation is regulated by interactions between members of the killer cell immunoglobulin-like receptors (KIRs) expressed by decidual natural killer (dNK) cells and trophoblast human leukocyte antigen (HLA)-C molecules.
      • 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.
      • Colucci F.
      The role of KIR and HLA interactions in pregnancy complications.
      Extravillous trophoblasts are specialized fetal cells that invade the decidua basalis, where they come into direct contact with maternal immune cells, such as dNK cells, macrophages, T cells, B cells, and dendritic cells.
      • Faas M.M.
      • de Vos P.
      Uterine NK cells and macrophages in pregnancy.
      Extravillous trophoblasts do not express major classical MHC I molecules such as HLA-A and HLA-B. Instead, these cells express HLA-C and non-classical MHC I molecules (HLA-E and HLA-G).
      • Papúchová H.
      • Meissner T.B.
      • Li Q.
      • Strominger J.L.
      • Tilburgs T.
      The dual role of HLA-C in tolerance and immunity at the maternal-fetal interface.
      The latter two are largely monomorphic, whereas HLA-C is polymorphic and will vary according to the genetic makeup of the father.
      • Parham P.
      • Moffett A.
      Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution.
      HLA-C molecules on the surface of extravillous trophoblasts are recognized by receptors of dNK cells called KIRs.
      • Apps R.
      • Murphy S.P.
      • Fernando R.
      • Gardner L.
      • Ahad T.
      • Moffett A.
      Human leucocyte antigen (HLA) expression of primary trophoblast cells and placental cell lines, determined using single antigen beads to characterize allotype specificities of anti-HLA antibodies.
      Both maternal KIR and fetal HLA-C genes are highly polymorphic, and the interaction between HLA-C and KIRs has a unique role in placentation by facilitating trophoblast invasion of the decidua and the physiologic transformation of the spiral arteries.
      Some maternal fetal genotypes for HLA-C and KIR favor a well-developed placentation and others do not. Moffett et al
      • 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.
      have shown that normal pregnancy is more common when a mother has the KIR BB genotype and the fetus has HLA-C1 genes, whereas preeclampsia is more frequent when a mother carries the KIR AA genotype with fetal HLA-C2 genes (HLA-C2 vs HLA-C1 in KIR AA mothers: 45% vs 20%; OR, 2.38; 95% CI, 1.45–3.90). By contrast, Johnsen et al
      • Johnsen G.M.
      • Størvold G.L.
      • Drabbels J.J.M.
      • et al.
      The combination of maternal KIR-B and fetal HLA-C2 is associated with decidua basalis acute atherosis in pregnancies with preeclampsia.
      reported that fetal HLA-C2 combined with maternal KIR BB was associated with placental lesions of acute atherosis. Patients with preeclampsia and acute atherosis presented this specific genetic combination in 60% of cases.
      • Johnsen G.M.
      • Størvold G.L.
      • Drabbels J.J.M.
      • et al.
      The combination of maternal KIR-B and fetal HLA-C2 is associated with decidua basalis acute atherosis in pregnancies with preeclampsia.
      The mechanism whereby a breakdown of maternal-fetal immune tolerance leads to preeclampsia seems to involve defective placentation, an example of the convergence of an immune disorder with uteroplacental ischemia. Such can be the case for other etiologic factors in preeclampsia. For further details of immunologic mechanisms of preeclampsia, the reader is referred to the review article by Robillard et al
      • Robillard P.-Y.
      • Dekker G.
      • Scioscia M.
      • Saito S.
      Progress in the understanding of the pathophysiology of immunological maladaptation related to early onset preeclampsia and metabolic syndrome related to late onset preeclampsia.
      in this Supplement and to an upcoming publication by our group (Romero R, personal communication).

      Endocrine disorders

      Several endocrine disorders have been associated with preeclampsia
      • Okoror C.E.M.
      • Enabudoso E.J.
      • Okoror O.T.
      • Okonkwo C.A.
      Serum calcium-magnesium ratio in women with pre-eclampsia at a tertiary hospital in Nigeria.
      • Hultin H.
      • Hellman P.
      • Lundgren E.
      • et al.
      Association of parathyroid adenoma and pregnancy with preeclampsia.
      • Caimari F.
      • Valassi E.
      • Garbayo P.
      • et al.
      Cushing’s syndrome and pregnancy outcomes: a systematic review of published cases.
      • Baghlaf H.A.
      • Badeghiesh A.M.
      • Suarthana E.
      • Dahan M.H.
      The effect of Cushing’s syndrome on pregnancy complication rates: analysis of more than 9 million deliveries.
      • Landau E.
      • Amar L.
      Primary aldosteronism and pregnancy.
      • Quartermaine G.
      • Lambert K.
      • Rees K.
      • et al.
      Hormone-secreting adrenal tumours cause severe hypertension and high rates of poor pregnancy outcome; a UK Obstetric Surveillance System study with case control comparisons.
      • Oliva R.
      • Angelos P.
      • Kaplan E.
      • Bakris G.
      Pheochromocytoma in pregnancy: a case series and review.
      • Dusitkasem S.
      • Herndon B.H.
      • Paluzzi D.
      • Kuhn J.
      • Small R.H.
      • Coffman J.C.
      From bad to worse: paraganglioma diagnosis during induction of labor for coexisting preeclampsia.
      ; however the evidence to support causality is not strong. This section will review the evidence in support of the association and the proposed mechanisms for activation of the common pathway of preeclampsia.

      Hyperparathyroidism

      Normal pregnancy is characterized by changes in maternal calcium hemostasis, which are thought to occur to meet fetal demands. By term, the fetus has 30 g of calcium, 20 g of phosphorus, and 0.8 g of magnesium, and 80% of calcium is deposited during the third trimester.
      • Kovacs C.S.
      Maternal mineral and bone metabolism during pregnancy, lactation, and post-weaning recovery.
      The evidence that links altered calcium hemostasis to preeclampsia is as follows: (1) hypocalcemia is a risk factor for preeclampsia (OR, 7.63; 95% CI, 1.64–35.37)
      • Okoror C.E.M.
      • Enabudoso E.J.
      • Okoror O.T.
      • Okonkwo C.A.
      Serum calcium-magnesium ratio in women with pre-eclampsia at a tertiary hospital in Nigeria.
      ; (2) low vitamin D concentration in early pregnancy is associated with a 5-fold increased risk for preeclampsia
      • Bodnar L.M.
      • Catov J.M.
      • Simhan H.N.
      • Holick M.F.
      • Powers R.W.
      • Roberts J.M.
      Maternal vitamin D deficiency increases the risk of preeclampsia.
      ; (3) hyperparathyroidism is commonly found in pregnant women with low calcium and vitamin D
      • Scholl T.O.
      • Chen X.
      • Stein T.P.
      Vitamin D, secondary hyperparathyroidism, and preeclampsia.
      ,
      • Wheeler B.J.
      • Taylor B.J.
      • de Lange M.
      • et al.
      A longitudinal study of 25-hydroxy vitamin D and parathyroid hormone status throughout pregnancy and exclusive lactation in New Zealand mothers and their infants at 45° S.
      ; (4) patients diagnosed with parathyroid adenoma are at increased risk for preeclampsia (OR, 6.89; 95% CI, 2.30–20.58)
      • Hultin H.
      • Hellman P.
      • Lundgren E.
      • et al.
      Association of parathyroid adenoma and pregnancy with preeclampsia.
      ; (5) absence of vitamin D prophylaxis in the mother’s childhood is associated with a higher risk of preeclampsia
      • Hyppönen E.
      • Hartikainen A.L.
      • Sovio U.
      • Järvelin M.R.
      • Pouta A.
      Does vitamin D supplementation in infancy reduce the risk of pre-eclampsia?.
      ; and (6) administration of vitamin D combined with calcium or multivitamin supplement has been shown to reduce blood pressure and the frequency of preeclampsia in a randomized trial.
      • Marya R.K.
      • Rathee S.
      • Manrow M.
      Effect of calcium and vitamin D supplementation on toxaemia of pregnancy.
      ,
      • Palacios C.
      • Kostiuk L.K.
      • Peña-Rosas J.P.
      Vitamin D supplementation for women during pregnancy.
      The proposed mechanisms whereby primary hyperparathyroidism leads to preeclampsia are endothelial cell damage, increased insulin resistance, left ventricular hypertrophy, and dyslipidemia.
      • Nilsson I.L.
      • Aberg J.
      • Rastad J.
      • Lind L.
      Left ventricular systolic and diastolic function and exercise testing in primary hyperparathyroidism-effects of parathyroidectomy.
      ,
      • Hagström E.
      • Lundgren E.
      • Rastad J.
      • Hellman P.
      Metabolic abnormalities in patients with normocalcemic hyperparathyroidism detected at a population-based screening.

      Cushing syndrome, aldosteronism, pheochromocytoma, and paraganglioma

      Cushing syndrome is associated with an increased risk of preeclampsia (aOR, 2.20; 95% CI, 1.18–4.41).
      • Caimari F.
      • Valassi E.
      • Garbayo P.
      • et al.
      Cushing’s syndrome and pregnancy outcomes: a systematic review of published cases.
      ,
      • Baghlaf H.A.
      • Badeghiesh A.M.
      • Suarthana E.
      • Dahan M.H.
      The effect of Cushing’s syndrome on pregnancy complication rates: analysis of more than 9 million deliveries.
      In nonpregnant subjects, chronic glucocorticoid excess of Cushing syndrome is commonly associated with an increased cardiometabolic risk through an increase in proinflammatory adipokine production, alteration of coagulation, platelet function, and endothelial activation.
      • Trementino L.
      • Arnaldi G.
      • Appolloni G.
      • et al.
      Coagulopathy in Cushing’s syndrome.
      • Isidori A.M.
      • Minnetti M.
      • Sbardella E.
      • Graziadio C.
      • Grossman A.B.
      Mechanisms in endocrinology: the spectrum of haemostatic abnormalities in glucocorticoid excess and defect.
      • Pivonello R.
      • De Martino M.C.
      • Iacuaniello D.
      • et al.
      Metabolic alterations and cardiovascular outcomes of cortisol excess.
      Primary aldosteronism is the most common form of endocrine hypertension, and it can be caused by an aldosterone-producing adenoma or a bilateral adrenal hyperplasia.
      • Monticone S.
      • Burrello J.
      • Tizzani D.
      • et al.
      Prevalence and clinical manifestations of primary aldosteronism encountered in primary care practice.
      ,
      • Käyser S.C.
      • Deinum J.
      • de Grauw W.J.
      • et al.
      Prevalence of primary aldosteronism in primary care: a cross-sectional study.
      Increased aldosterone secretion suppresses renin activity, leading to hypertension, hypokalemia, and hypernatremia.
      • Hollenberg N.K.
      Aldosterone in the development and progression of renal injury.
      ,
      • Liang W.
      • Chen C.
      • Shi J.
      • et al.
      Disparate effects of eplerenone, amlodipine and telmisartan on podocyte injury in aldosterone-infused rats.
      Twenty-five percent of women with this disorder develop preeclampsia.
      • Landau E.
      • Amar L.
      Primary aldosteronism and pregnancy.
      ,
      • Quartermaine G.
      • Lambert K.
      • Rees K.
      • et al.
      Hormone-secreting adrenal tumours cause severe hypertension and high rates of poor pregnancy outcome; a UK Obstetric Surveillance System study with case control comparisons.
      Pheochromocytoma and paraganglioma are rare catecholamine-producing tumors, with a reported frequency of 1 in 54,000 pregnancies.
      • Lenders J.W.M.
      • Langton K.
      • Langenhuijsen J.F.
      • Eisenhofer G.
      Pheochromocytoma and pregnancy.
      An excess of catecholamines released by these tumors can elicit signs or symptoms similar to preeclampsia (eg, hypertension, headache, and proteinuria), making the diagnosis of pheochromocytoma during pregnancy difficult.
      • Lenders J.W.M.
      • Langton K.
      • Langenhuijsen J.F.
      • Eisenhofer G.
      Pheochromocytoma and pregnancy.
      ,
      • Mohamed Ismail N.A.
      • Abd Rahman R.
      • Abd Wahab N.
      • Muhammad R.
      • Nor Azmi K.
      Pheochromocytoma and pregnancy: a difficult and dangerous ordeal.
      A recent meta-analysis that included 204 pregnant patients with pheochromocytoma and paraganglioma showed that 20% of patients were initially misdiagnosed with preeclampsia.
      • Langton K.
      • Tufton N.
      • Akker S.
      • et al.
      Pregnancy and phaeochromocytoma/paraganglioma: clinical clues affecting diagnosis and outcome - a systematic review.
      Maternal and fetal mortality were as high as 28% and 27%, respectively, when there was a delay in diagnosis and treatment.
      • Langton K.
      • Tufton N.
      • Akker S.
      • et al.
      Pregnancy and phaeochromocytoma/paraganglioma: clinical clues affecting diagnosis and outcome - a systematic review.
      ,
      • Kamari Y.
      • Sharabi Y.
      • Leiba A.
      • Peleg E.
      • Apter S.
      • Grossman E.
      Peripartum hypertension from pheochromocytoma: a rare and challenging entity.
      Only a few studies have reported that patients with pheochromocytoma develop superimposed preeclampsia;
      • Oliva R.
      • Angelos P.
      • Kaplan E.
      • Bakris G.
      Pheochromocytoma in pregnancy: a case series and review.
      ,
      • Dusitkasem S.
      • Herndon B.H.
      • Paluzzi D.
      • Kuhn J.
      • Small R.H.
      • Coffman J.C.
      From bad to worse: paraganglioma diagnosis during induction of labor for coexisting preeclampsia.
      therefore, the existence of an association is not yet clear.
      • Langton K.
      • Tufton N.
      • Akker S.
      • et al.
      Pregnancy and phaeochromocytoma/paraganglioma: clinical clues affecting diagnosis and outcome - a systematic review.

      Conclusion

      Multiple and sometimes overlapping insults can induce an adaptive vascular response in pregnancy, which can be recognized clinically by the presence of hypertension and proteinuria (or other signs of multisystemic involvement). When this response becomes maladaptive, it can cause target organ damage and become potentially life-threatening to the mother and fetus.
      At present, the classification of the syndrome is largely based on the gestational age at the time of diagnosis (early-onset vs late-onset preeclampsia). Early-onset preeclampsia is associated with defective placentation, whereas late-onset preeclampsia seems to be related to the mismatch between maternal perfusion and fetoplacental demands, along with a maternal predisposition to cardiovascular disease. Hence, the need to identify the fundamental causes of the vascular dysfunction responsible for preeclampsia to develop comprehensive predictive models and preventive interventions. This review highlights the multiple etiologies of the syndrome of preeclampsia. We propose that multiple etiologic factors converge to cause endothelial cell dysfunction, intravascular inflammation, and syncytiotrophoblast stress. The recognition that a viral infection such as COVID-19 can induce preeclampsia raises challenging questions of whether preeclampsia is a pregnancy-specific disorder caused by the placenta and cured only by delivery. Further research is required to assess the relative contribution of each cause of this elusive disease.

      References

        • Young J.
        The etiology of eclampsia and albuminuria and their relation to accidental hæmorrhage.
        Trans Edinb Obstet Soc. 1914; 39: 153-202
        • Dixon W.E.
        • Taylor F.E.
        An epidiascopic demonstration on “the physiological action of the placenta.”.
        Proc R Soc Med. 1908; 1: 11-13
        • Ogden E.
        • Hildebrand G.J.
        • Page E.W.
        Rise of blood pressure during ischemia of the gravid uterus.
        Experimental Biology and Medicine. 1940; 43: 49-51
        • Chaiworapongsa T.
        • Chaemsaithong P.
        • Yeo L.
        • Romero R.
        Pre-eclampsia part 1: current understanding of its pathophysiology.
        Nat Rev Nephrol. 2014; 10: 466-480
        • Kumar D.
        Chronic placental ischemia in relation to toxemias of pregnancy: a preliminary report.
        Am J Obstet Gynecol. 1962; 84: 1323-1329
        • Piering W.F.
        • Garancis J.G.
        • Becker C.G.
        • Beres J.A.
        • Lemann Jr., J.
        Preeclampsia related to a functioning extrauterine placenta: report of a case and 25-year follow-up.
        Am J Kidney Dis. 1993; 21: 310-313
        • Berger M.
        • Cavanagh D.
        Toxemia of pregnancy. The hypertensive effect of acute experimental placental ischemia.
        Am J Obstet Gynecol. 1963; 87: 293-305
        • Browne J.C.
        • Veall N.
        The maternal placental blood flow in normotensive and hypertensive women.
        J Obstet Gynaecol Br Emp. 1953; 60: 141-147
        • Janisch H.
        • Leodolter S.
        Results of placental circulation measurements in hazard pregnancies.
        Z Geburtshilfe Perinatol. 1973; 177: 74-80
        • Olkkonen H.S.
        • Suonio S.
        • Haring P.
        Determination of placental blood flow by external monitoring of 113In.
        Nuklearmedizin. 1976; 15: 168-172
      1. Lippert TH, Cloeren SE, Fridrich R. Assessment of uteroplacental hemodynamics in complicated pregnancy. Int J Gynaecol Obstet 1978–1979;16:274–280.

        • Käär K.
        • Jouppila P.
        • Kuikka J.
        • Luotola H.
        • Toivanen J.
        • Rekonen A.
        Intervillous blood flow in normal and complicated late pregnancy measured by means of an intravenous 133Xe method.
        Acta Obstet Gynecol Scand. 1980; 59: 7-10
        • 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
        • Alexander B.T.
        • Kassab S.E.
        • Miller M.T.
        • et al.
        Reduced uterine perfusion pressure during pregnancy in the rat is associated with increases in arterial pressure and changes in renal nitric oxide.
        Hypertension. 2001; 37: 1191-1195
        • Makris A.
        • Thornton C.
        • Thompson J.
        • et al.
        Uteroplacental ischemia results in proteinuric hypertension and elevated sFLT-1.
        Kidney Int. 2007; 71: 977-984
        • Turanov A.A.
        • Lo A.
        • Hassler M.R.
        • et al.
        RNAi modulation of placental sFLT1 for the treatment of preeclampsia.
        Nat Biotechnol. 2018; ([Epub ahead of print])
        • Bakrania B.A.
        • George E.M.
        • Granger J.P.
        Animal models of preeclampsia: investigating pathophysiology and therapeutic targets.
        Am J Obstet Gynecol. 2020; ([Epub ahead of print])
        • Brosens I.
        [Spiraled arterioles of the decidua basalis in the hypertensive complications of pregnancy. Anatomoclinical study].
        Bull Soc R Belge Gynecol Obstet. 1963; 33: 61-72
        • Brosens I.
        A study of the spiral arteries of the decidua basalis in normotensive and hypertensive pregnancies.
        J Obstet Gynaecol Br Commonw. 1964; 71: 222-230
        • Melchiorre K.
        • Giorgione V.
        • Thilaganathan B.
        The placenta and preeclampsia: villain or victim?.
        Am J Obstet Gynecol. 2021; ([Epub ahead of print])
        • McMaster-Fay R.A.
        Uteroplacental vascular syndromes: theories, hypotheses and controversies.
        Clin Obstet Gynecol Reprod Med. 2018; 4
        • Espinoza J.
        • Romero R.
        • Mee Kim Y.
        • et al.
        Normal and abnormal transformation of the spiral arteries during pregnancy.
        J Perinat Med. 2006; 34: 447-458
        • Labarrere C.A.
        • DiCarlo H.L.
        • Bammerlin E.
        • et al.
        Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta.
        Am J Obstet Gynecol. 2017; 216: 287.e1-287.e16
        • Hertig A.
        Vascular pathology in hypertensive albuminuric toxemias of pregnancy.
        Clinics. 1945; 4: 602
        • De Wolf F.
        • Robertson W.B.
        • Brosens I.
        The ultrastructure of acute atherosis in hypertensive pregnancy.
        Am J Obstet Gynecol. 1975; 123: 164-174
        • Staff A.C.
        • Johnsen G.M.
        • Dechend R.
        • Redman C.W.G.
        Preeclampsia and uteroplacental acute atherosis: immune and inflammatory factors.
        J Reprod Immunol. 2014; 101–102: 120-126
        • Kim Y.M.
        • Chaemsaithong P.
        • Romero R.
        • et al.
        Placental lesions associated with acute atherosis.
        J Matern Fetal Neonatal Med. 2015; 28: 1554-1562
        • Falco M.L.
        • Sivanathan J.
        • Laoreti A.
        • Thilaganathan B.
        • Khalil A.
        Placental histopathology associated with pre-eclampsia: systematic review and meta-analysis.
        Ultrasound Obstet Gynecol. 2017; 50: 295-301
        • Staff A.C.
        • Fjeldstad H.E.
        • Fosheim I.K.
        • et al.
        Failure of physiological transformation and spiral artery atherosis: their roles in preeclampsia.
        Am J Obstet Gynecol. 2020; ([Epub ahead of print])
        • 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
        • Kim Y.M.
        • Bujold E.
        • Chaiworapongsa T.
        • et al.
        Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes.
        Am J Obstet Gynecol. 2003; 189: 1063-1069
        • Kim Y.M.
        • Chaiworapongsa T.
        • Gomez R.
        • et al.
        Failure of physiologic transformation of the spiral arteries in the placental bed in preterm premature rupture of membranes.
        Am J Obstet Gynecol. 2002; 187: 1137-1142
        • Labarrere C.
        • Alonso J.
        • Manni J.
        • Domenichini E.
        • Althabe O.
        Immunohistochemical findings in acute atherosis associated with intrauterine growth retardation.
        Am J Reprod Immunol Microbiol. 1985; 7: 149-155
        • Khong T.Y.
        Acute atherosis in pregnancies complicated by hypertension, small-for-gestational-age infants, and diabetes mellitus.
        Arch Pathol Lab Med. 1991; 115: 722-725
        • Romero R.
        • Kusanovic J.P.
        • Chaiworapongsa T.
        • Hassan S.S.
        Placental bed disorders in preterm labor, preterm PROM, spontaneous abortion and abruptio placentae.
        Best Pract Res Clin Obstet Gynaecol. 2011; 25: 313-327
        • 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
        • 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
        • 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