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The Placenta as a Window to Maternal Vascular Health

  • W. Tony Parks
    Affiliations
    Department of Laboratory Medicine and Pathobiology, University of Toronto, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
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  • Janet M. Catov
    Correspondence
    Corresponding author. Magee-Womens Research Institute, 204 Craft Avenue, Suite A208, Pittsburgh, PA 15213.
    Affiliations
    Department of Obstetrics, Gynecology, and RS, University of Pittsburgh School of Medicine, 204 Craft Avenue, Pittsburgh, PA 15213, USA

    Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Magee-Womens Research Institute, 204 Craft Avenue, Suite A208, Pittsburgh, PA 15213, USA
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Open AccessPublished:December 19, 2019DOI:https://doi.org/10.1016/j.ogc.2019.10.001

      Keywords

      Key points

      • The placenta is evaluated to understand fetal health, and emerging evidence indicates that maternal vascular malperfusion (MVM) features may provide clues to women’s later life cardiovascular risk.
      • Pathologic changes that directly involve the maternal vascular supply to the placenta, collectively termed decidual vasculopathy, develop early in gestation, and their effects on maternal blood flow to the placenta may be etiologic for the other MVM findings.
      • A second group of MVM lesions includes those entities that likely arise subsequently in the pregnancy as a result of hypoxic/ischemic injury and oxidative damage to the placenta (small placental size, villous infarction, retroplacental hemorrhage, accelerated villous maturation, and distal villous hypoplasia).
      • MVM lesions are detected in each of the great obstetric syndromes, and emerging evidence suggests that decidual vasculopathy may be linked to future pregnancy complications, maternal dyslipidemia, higher blood pressure, and increased vascular resistance years after delivery.
      • Identification of the mechanisms leading to decidual vasculopathy may improve pregnancy health and contribute new sex-specific insights regarding the etiology of cardiovascular disease in women.

      Introduction

      Cardiovascular disease (CVD) in women remains a major health concern. Although it is now known that CVD manifests differently in women than in men, exploration of these differences is ongoing and incomplete. Optimal treatment regimens for women also remain to be determined. Despite an overall decline in the CVD death rate in the United States, the rate of decline has been slower for women compared with men. In addition, racial disparities in CVD in women stubbornly persist. CVD mortality is 70% higher in African American women compared with white women.
      • Mosca L.
      • Manson J.E.
      • Sutherland S.E.
      • et al.
      Cardiovascular disease in women: a statement for healthcare professionals from the American Heart Association. Writing Group.
      A generation ago, many pregnancy complications were considered to be isolated occurrences with limited recurrence risks and essentially no impact on the later life health of the mother. This comforting fiction began to unravel with the discovery that women with a history of preeclampsia have an increased risk for the early development of cardiovascular disease. It is now known that women with pregnancy complications including preeclampsia, preterm birth, and fetal growth restriction are at twofold to eightfold higher risk of CVD compared to women with uncomplicated pregnancies,.
      • Rich-Edwards J.W.
      • Fraser A.
      • Lawlor D.A.
      • et al.
      Pregnancy characteristics and women's future cardiovascular health: an underused opportunity to improve women's health?.
      Although the mechanisms that may explain this excess risk are unknown, the connection to preeclampsia may provide a clue. It has long been known that a subset of the placentas from women with preeclampsia will show aberrancies in the maternal vessels supplying the placenta and damage to the placental parenchyma consistent with hypoxic/ischemic or oxidative injury. This constellation of findings is termed maternal vascular malperfusion (MVM), and these lesions may hold the key to understanding and identifying the elevated risk for early CVD in women who experience adverse pregnancy outcomes. This intriguing possibility has only begun to be examined, but accumulating evidence is compelling. The authors review this new body of work and propose that understanding the etiology of MVM in the placenta may provide new mechanistic insight into the development of CVD in women.

      Maternal vascular malperfusion

      Proper development and function of the hemochorial human placenta is critically dependent on pregnancy-induced adaptations of the maternal vascular system to the growing conceptus. Foremost among these is the remodeling of the decidual and inner myometrial segments of the maternal spiral arteries. From early in gestation through the first several weeks of the second trimester, specialized subsets of extravillous trophoblast (EVT) migrate from the fetomaternal interface into the maternal tissues.
      • Pijnenborg R.
      • Dixon G.
      • Robertson W.B.
      • et al.
      Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy.
      These cells are involved in a variety of functions, including modulation of the maternal immune response, promoting the attachment of the placenta to the uterus, and fostering the transfer of endometrial glandular secretions from the mother to the placenta.
      • Velicky P.
      • Knöfler M.
      • Pollheimer J.
      Function and control of human invasive trophoblast subtypes: Intrinsic vs. maternal control.
      • Moser G.
      • Gauster M.
      • Orendi K.
      • et al.
      Endoglandular trophoblast, an alternative route of trophoblast invasion? Analysis with novel confrontation co-culture models.
      • Moser G.
      • Weiss G.
      • Gauster M.
      • et al.
      Evidence from the very beginning: endoglandular trophoblasts penetrate and replace uterine glands in situ and in vitro.
      • Burton G.J.
      • Watson A.L.
      • Hempstock J.
      • et al.
      Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy.
      Arguably their most important task, however, is altering the structure and flow properties of the maternal spiral arteries. Embryonic and fetal oxygen requirements and tolerances vary throughout the gestation, and EVT-induced vascular alterations serve to modulate the oxygen and nutrient flow to the conceptus. Spiral arteries are the most distal uterine vasculature that enters the placenta, extending through the inner myometrium and the entirety of the decidua. Two or 3 spiral arteries generally run together, often coiling tightly around each other. In their native, un-remodeled state, these vessels have modest lumens maintained by a surrounding smooth muscle wall. This vascular smooth muscle wall retains the ability to constrict in response to neurogenic or hormonal signals, potentially endangering the blood flow to the placenta and fetus. To mitigate this risk, the invading EVTs initiate and promote the remodeling of the spiral arteries, a task likely dependent on interactions with uterine NK cells.
      • Velicky P.
      • Knöfler M.
      • Pollheimer J.
      Function and control of human invasive trophoblast subtypes: Intrinsic vs. maternal control.
      Remodeling leads to the complete dissolution of the smooth muscle wall, with replacement by fibrinoid
      • Pijnenborg R.
      • Vercruysse L.
      • Hanssens M.
      The uterine spiral arteries in human pregnancy: facts and controversies.
      (Fig. 1A). With the smooth muscle gone, spiral artery blood flow can no longer be directly controlled by the mother or the growing fetus. Remodeling also alters the arterial shapes. The narrow, tightly coiled spiral arteries widen along the remodeled segments, with the distal end developing a funnel shape. The opening of the remodeled spiral artery into the placenta is 5 to 10 times the diameter of an unaltered spiral artery.
      • Burton G.J.
      • Woods A.W.
      • Jauniaux E.
      • et al.
      Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy.
      These changes significantly increase the amount of blood that can flow into the placenta, while the funnel shape of the terminal arterial segment slows and smooths the flow of blood into the placenta.
      • Burton G.J.
      • Woods A.W.
      • Jauniaux E.
      • et al.
      Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy.
      Figure thumbnail gr1
      Fig. 1Decidual vasculopathy. (A) Remodeled spiral artery. This image shows adjacent spiral artery cross-sections from the basal plate, with loss of vascular smooth muscle, fibrinoid deposition in the walls, and EVT in the fibrinoid. (B) Mural hypertrophy. This image shows 4 vascular cross-sections, each identified by an asterisk. The smooth muscle walls show prominent muscular hypertrophy with a minimal luminal diameter. (C) Fibrinoid necrosis. This spiral artery shows replacement of the vascular wall by dense, deep red fibrinoid necrosis. (D) Atherosis with foamy macrophages. The lumen of this spiral artery also shows fibrinoid replacement of the vessel wall. Large numbers of foamy macrophages are also present in the vessel wall outside of the fibrinoid necrosis. Arrows point to some of the foamy macrophages.
      Early in gestation, the developing embryo is susceptible to oxidative damage.
      • Jauniaux E.
      • Watson A.L.
      • Hempstock J.
      • et al.
      Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure.
      ,
      • Jauniaux E.
      • Hempstock J.
      • Greenwold N.
      • et al.
      Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies.
      To help protect the embryo and early fetus, an additional subset of EVT invades the lumens of the spiral arteries, and these cells aggregate to form endovascular trophoblastic plugs that occlude or at least significantly obstruct the spiral arteries.
      • Roberts V.H.J.
      • Morgan T.K.
      • Bednarek P.
      • et al.
      Early first trimester uteroplacental flow and the progressive disintegration of spiral artery plugs: new insights from contrast-enhanced ultrasound and tissue histopathology.
      ,
      • Hustin J.
      • Schaaps J.P.
      Echographic [corrected] and anatomic studies of the maternotrophoblastic border during the first trimester of pregnancy.
      Plasma, containing dissolved oxygen and nutrients, continues to reach the placental intervillous spaces, but maternal erythrocytes are excluded. This early feature of vascular remodeling maintains the oxygen concentration in the placenta at less than 20 mm Hg (3%–5%) through the first trimester,
      • Jauniaux E.
      • Watson A.L.
      • Hempstock J.
      • et al.
      Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure.
      ,
      • Rodesch F.
      • Simon P.
      • Donner C.
      • et al.
      Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy.
      while the surrounding maternal decidual oxygen concentration is 50 to 70 mm Hg (8%–10%).
      • Huppertz B.
      • Weiss G.
      • Moser G.
      Trophoblast invasion and oxygenation of the placenta: measurements versus presumptions.
      After the endovascular trophoblastic plugs dissolve at around 12 weeks of gestation, the oxygen concentration in the placenta rises to 40 to 50 mm Hg.
      • Jauniaux E.
      • Watson A.L.
      • Hempstock J.
      • et al.
      Onset of maternal arterial blood flow and placental oxidative stress. A possible factor in human early pregnancy failure.
      ,
      • Rodesch F.
      • Simon P.
      • Donner C.
      • et al.
      Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy.
      ,
      • Huppertz B.
      • Weiss G.
      • Moser G.
      Trophoblast invasion and oxygenation of the placenta: measurements versus presumptions.
      Remodeling of the spiral arteries can be considered as occurring in 2 waves. The first, described previously, takes place in the first trimester. This initial wave remodels the more superficial aspects of the spiral arteries. Vascular remodeling continues through the first half of the second trimester,
      • Pijnenborg R.
      • Dixon G.
      • Robertson W.B.
      • et al.
      Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy.
      ,
      • Pijnenborg R.
      • Bland J.M.
      • Robertson W.B.
      • et al.
      Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy.
      however, with deeper invasion of the EVT. This second trimester remodeling can eliminate the vascular smooth muscle through the full thickness of the decidua and the inner one-third of the myometrium. Remodeling does not occur uniformly, however, with the vessels beneath the placental periphery less efficiently remodeled than those beneath the central placenta. Spiral arteries in the decidua adherent to the extraplacental membranes are only invaded minimally if at all by EVT. The smooth muscle walls of these vessels become thin and may disappear, but the extensive remodeling noted beneath the placental parenchyma does not occur. Failure of the maternal spiral arteries to remodel leaves the placenta susceptible to hypoxic damage or hypoxia/reperfusion injury with oxidative damage.
      • Staff A.C.
      • Dechend R.
      • Redman C.W.
      Review: preeclampsia, acute atherosis of the spiral arteries and future cardiovascular disease: two new hypotheses.
      • Burton G.J.
      Oxygen, the Janus gas; its effects on human placental development and function.
      • Redman C.W.
      • Sargent I.L.
      Placental stress and pre-eclampsia: a revised view.
      The failure of spiral arteries to remodel and the resulting damage patterns collectively comprise MVM.
      Individual MVM lesions fall into 2 broad categories. The first group includes those pathologic changes that directly involve the maternal vascular supply to the placenta. Collectively termed decidual vasculopathy, these lesions likely develop early in gestation, and their effects on maternal blood flow to the placenta may be etiologic for the other MVM findings. Although decidual vasculopathy has long been described as a feature of placental pathology, the significance of these lesions came into focus through the histologic examination placental bed biopsies.
      • Brosens I.
      • Pijnenborg R.
      • Vercruysse L.
      • et al.
      The "great obstetrical syndromes" are associated with disorders of deep placentation.
      These studies evaluated the spiral arteries in myometrial and lower decidual segments of the uterus, areas not normally accessible on delivered placentas. In placental bed biopsies, most spiral artery segments from preeclamptic women show absent or incomplete remodeling, while nearly 90% of the spiral artery segments from normal pregnancies are completely remodeled.
      • Brosens K.
      Placenta bed disorders.
      Moreover, as reported by Brosens, these disorders of deep placentation are more common in each of the great obstetric syndromes.
      • Brosens I.
      • Pijnenborg R.
      • Vercruysse L.
      • et al.
      The "great obstetrical syndromes" are associated with disorders of deep placentation.
      Delivered placentas, containing no myometrium and only the most superficial portion of the decidua, show these changes far less frequently.

      Dedicual vasculopathy

      Four distinct manifestations of decidual vasculopathy have been identified.
      • Redline R.W.
      • Boyd T.
      • Campbell V.
      • et al.
      Maternal vascular underperfusion: nosology and reproducibility of placental reaction patterns.
      ,
      • Khong T.Y.
      • Mooney E.E.
      • Ariel I.
      • et al.
      Sampling and definitions of placental lesions: amsterdam placental workshop group consensus statement.
      These include absent or incomplete remodeling of a basal plate spiral artery, mural hypertrophy, fibrinoid necrosis, and atherosis. Absent or incomplete remodeling of a basal plate spiral artery (alternatively termed persistence of a muscularized basal plate artery) is the most basic of these lesions.
      • Khong T.Y.
      • Mooney E.E.
      • Ariel I.
      • et al.
      Sampling and definitions of placental lesions: amsterdam placental workshop group consensus statement.
      The name is entirely descriptive of the pathologic findings. EVT invasion is focally inadequate to remodel a spiral artery beneath the placenta, resulting in the retention of at least part of the vascular smooth muscle wall. Although complete absence of remodeling is the most striking and definitive appearance for this entity, incomplete remodeling is more common; only a portion of the vessel remains un-remodeled, with retention of a segment of the smooth muscle wall. Because the spiral arteries of the extraplacental membranes may retain a small amount of smooth muscle in their walls, absent or incomplete remodeling cannot be identified in these vessels and can only be diagnosed in the basal plate arteries.
      Mural hypertrophy manifests as a thickening of the smooth muscle wall of a spiral artery (Fig. 1B). Although this entity can occur either in the placental basal plate or in the extraplacental membranes, it is found more commonly in the spiral arteries of the extraplacental membranes. The extensive remodeling that occurs in the placental basal plate generally removes all smooth muscle from the spiral arteries, precluding the development of mural hypertrophy. Uncommonly, a basal plate vessel with absence of vascular remodeling will additionally undergo mural hypertrophy. Although thickening of the smooth muscle wall of a small artery or arteriole may be found in response to chronic hypertension elsewhere in the body, mural hypertrophy can occur in relation to the placenta even in the absence of chronic hypertension.
      Like mural hypertrophy, fibrinoid necrosis may occur either in the arteries of the placental basal plate or the extraplacental membranes. Fibrinoid necrosis has a striking appearance, with replacement of the normal vessel wall by a prominent layer of waxy, deep red material (Fig. 1C). Normal fibrinoid replacement of a spiral artery wall may at times appear similar to fibrinoid necrosis, but normal fibrinoid has a lighter pink-red color, and EVT will often be found within the fibrinoid. Confusingly, fibrinoid in this context may refer to either of 2 entirely different entities. The fibrinoid that is deposited in spiral artery walls as a consequence of normal vascular remodeling is comprised of extracellular matrix type material. Fibrinoid necrosis represents the remnant degenerated debris of the vascular smooth muscle wall.
      Atherosis, the final subtype of decidual vasculopathy, has features strikingly similar to large vessel atherosclerosis (Fig. 1D). Atherosis is characterized by the presence of foamy macrophages within the walls of the spiral arteries. These foamy macrophages are frequently embedded within or adjacent to the fibrinoid material of fibrinoid necrosis, and atherosis and fibrinoid necrosis commonly co-occur. Fibrinoid necrosis may actually develop first, with atherosis appearing later in the course of the disease.
      • Khong T.Y.
      Acute atherosis in pregnancies complicated by hypertension, small-for-gestational-age infants, and diabetes mellitus.
      Atherosis is found in only 0.4% of placentas from uncomplicated pregnancies.
      • 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.
      The incidence is increased in pregnancies with adverse outcomes, occurring in 10.2% of placentas from preeclamptic pregnancies, 9% of placentas following a fetal death, 1.7% of pregnancies with a small for gestational age fetus, and 1.2% of pregnancies with spontaneous preterm labor.
      • 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.
      The presence of atherosis in a placenta results in a sixfold higher likelihood of that placenta showing other evidence of MVM.
      • Kim Y.M.
      • Chaemsaithong P.
      • Romero R.
      • et al.
      Placental lesions associated with acute atherosis.
      Perhaps first hypothesized by Staff and colleagues,
      • Staff A.C.
      • Dechend R.
      • Redman C.W.
      Review: preeclampsia, acute atherosis of the spiral arteries and future cardiovascular disease: two new hypotheses.
      this maternal vessel pathology in a transient organ, the placenta, requires only a few months of gestation to form and may provide an accelerated life course model of vessel susceptibility to metabolic and vascular impairments later in life in the face of challenges such as aging and weight gain.

      Other maternal vascular malperfusion lesions

      The second group of individual MVM lesions includes those entities that likely arise subsequently in the pregnancy as a result of hypoxic/ischemic injury and oxidative damage to the placenta. Those entities included in the Amsterdam criteria for MVM include small placental size, villous infarction, retroplacental hemorrhage, accelerated villous maturation, and distal villous hypoplasia.
      • Khong T.Y.
      • Mooney E.E.
      • Ariel I.
      • et al.
      Sampling and definitions of placental lesions: amsterdam placental workshop group consensus statement.
      Villous infarction (Fig. 2D) is one of the most easily recognized MVM lesions.
      • Redline R.W.
      • Boyd T.
      • Campbell V.
      • et al.
      Maternal vascular underperfusion: nosology and reproducibility of placental reaction patterns.
      ,
      • Khong T.Y.
      • Mooney E.E.
      • Ariel I.
      • et al.
      Sampling and definitions of placental lesions: amsterdam placental workshop group consensus statement.
      Thirty to 60 spiral arteries typically supply a placenta with maternal blood.
      • Burton G.J.
      • Woods A.W.
      • Jauniaux E.
      • et al.
      Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy.
      Occlusion of one or more of these arteries results in the death of the villi overlying the spiral artery opening. The zone of infarction extends laterally and vertically from the occluded vessel, ending where the mixing of blood from adjacent spiral arteries is sufficient to maintain the viability of the villi. Infarcts thus usually occur along the basal plate and are broad-based with wedge or pyramidal shapes. A gradient of hypoxic damage will often extend from the infarcted tissue into the nearby surviving villi.
      Figure thumbnail gr2
      Fig. 2MVM Lesions. (A) Normal villous maturation for 37 weeks. This image shows a low power view of normal villi in a 37-week placenta. (B) Accelerated villous maturation for 37 weeks. This image shows a low power view of accelerated villous maturation in a 37-week placenta. The villi are notably smaller than the normal villi, and a high percentage of the villi contain at least 1 syncytial knot. (C) Distal villous hypoplasia. The villi in this image are narrow and elongated with minimal branching. This architecture leaves the villi widely spaced and easily recognized. (D) Old (remote) villous infarction. This image shows a remote infarct filling nearly the entirety of the panel. The affected villous structures show degeneration with loss color intensity. Arrows highlight the border with the viable villi present along the upper border of the image. (E) Increased syncytial knots. This image contains numerous small terminal villi, most harboring at least one densely basophilic syncytial knot. (F) Increased intervillous fibrin. This image shows an elongated aggregate of intervillous fibrin that adheres to several viable villi. Asterisks indicate the intervillous fibrin.
      One of the most frequent MVM lesions is accelerated villous maturation (Fig. 2A, B). The placenta is a short-lived organ that undergoes near-continuous change throughout its limited lifespan. The placental villi correspondingly vary in a predictable pattern throughout a normal gestation, a process termed villous maturation. Several different types of villi have been described, and their proportions change as the gestation progresses. Estimating the appropriateness of the villous proportions to the gestational age provides 1 means of assessing villous maturation. More generally, placental villi undergo several unidirectional changes during a pregnancy. First trimester villi are large, with abundant loose stroma, centrally placed vessels and 2 complete circumferential layers of surrounding trophoblast (an inner cytotrophoblast layer and an outer syncytiotrophoblast layer). As the pregnancy progresses, each of these characteristics is altered. With increasing gestational age, the villi become smaller. Their stroma becomes denser, particularly for the larger villi. The villous vessels come to predominate at the villous periphery, where they dilate into sinusoidal vessels. And the trophoblast layers thin, with aggregation of the syncytiotrophoblast nuclei. These changes serve to optimize gas and nutrient exchange as the pregnancy progresses. Under hypoxic stress, this orderly maturational process can be accelerated, so that the villi take on the appearance (and functional properties) of villi older than their gestational age. The assessment of villous maturation is considerably easier in a preterm placenta, where the accelerated villi match the villous appearance of a later gestational age, than in a term placenta, where the features of hypermaturation are more subtle.
      Distal villous hypoplasia (Fig. 2C) is an entity that typically arises only after prolonged fetal hypoxia, often in a placenta showing other evidence of accelerated villous maturation. Distal villous hypoplasia is characterized by nonbranching angiogenesis of the villi. The villi appear long and thin with little branching. The intervillous space is open, with widely scattered villi. Syncytial knots are generally increased. Distal villous hypoplasia has been associated with absent or reversed end-diastolic flow in the umbilical artery, an increased pulsatility index in the uterine artery, and fetal growth restriction.
      • Krebs C.
      • Macara L.M.
      • Leiser R.
      • et al.
      Intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery is associated with maldevelopment of the placental terminal villous tree.
      • Veerbeek J.H.
      • Nikkels P.G.
      • Torrance H.L.
      • et al.
      Placental pathology in early intrauterine growth restriction associated with maternal hypertension.
      • Orabona R.
      • Donzelli C.M.
      • Falchetti M.
      • et al.
      Placental histological patterns and uterine artery Doppler velocimetry in pregnancies complicated by early or late pre-eclampsia.
      Several additional MVM lesions often co-occur with accelerated villous maturation, and some of these features in the past have been tabulated as independent markers for MVM. Increased syncytial knots (Fig. 2E) have long been recognized as a feature of accelerated villous maturation and MVM. The syncytiotrophoblast comprises the outer layer covering the placental villi. This layer, which is a true syncytium, functions as the endothelium for the placenta, and is the primary zone of contact between maternal blood and the placenta. Syncytiotrophoblast nuclei often group together, and this clustering becomes more pronounced with increasing gestational age. When 5 or more syncytiotrophoblast nuclei cluster and form a rounded bulge above the villous surface, this entity is termed a syncytial knot.
      • Loukeris K.
      • Sela R.
      • Baergen R.N.
      Syncytial knots as a reflection of placental maturity: reference values for 20 to 40 weeks' gestational age.
      Norms have been developed for the percentage of terminal villi containing a syncytial knot at each week of gestation, and these values can be employed to detect increased syncytial knotting.
      • Loukeris K.
      • Sela R.
      • Baergen R.N.
      Syncytial knots as a reflection of placental maturity: reference values for 20 to 40 weeks' gestational age.
      Increased amounts of fibrinoid (Fig. 2F) may also be deposited in placentas with accelerated villous maturation. Fibrinoid in this context consists of a mixture of extracellular matrix type material and products of the coagulation cascade. These small foci are usually found within and extending from a villus, often contacting and cementing adjacent villi. Fibrinoid is also often deposited along the surfaces of larger stem villi.

      Maternal vascular malperfusion lesions and maternal vascular health

      In the context of maternal later life CVD, the various forms of decidual vasculopathy likely provide the most direct and compelling evidence that a mother’s vasculature may be abnormal and therefore more susceptible to early CVD. Their rarity in delivered placentas, however, limits their utility in individual cases. The secondary MVM lesions, although providing only indirect evidence for maternal vascular proclivity for early CVD, are more readily and frequently detected, and they may therefore function better as a screening test for an increased risk of early maternal CVD.
      The maternal prepregnancy cardiometabolic profile is likely related to both placental health and long-term CVD. The few studies that evaluate the trajectory of prepregnancy factors, pregnancy complications, and progression to long-term cardiometabolic disease reveal that the risk identified by pregnancy complications is not well explained by prepregnancy features. The authors have reported that preterm birth is linked to maternal metabolic syndrome after delivery even after accounting for metabolic features measured before conception (blood pressure, waist circumference, triglycerides, fasting glucose, and high-density lipoprotein cholesterol).
      • Catov J.
      • Althouse A.
      • Lewis C.
      • et al.
      Preterm delivery and metabolic syndrome in women followed from prepregnancy through 25 years later.
      Remarkably similar results have been reported in a Scandinavian cohort, where blood pressure was higher after delivery in women with hypertension in pregnancy, accounting for prepregnancy blood pressure.
      • Romundstad P.R.
      • Magnussen E.B.
      • Smith G.D.
      • et al.
      Hypertension in pregnancy and later cardiovascular risk: common antecedents?.
      There are several limitations with these studies that the placenta may help resolve. Pregnancy complications are heterogeneous, and the placenta may distinguish subtypes. Second, although traditional CVD risk factors may be antecedents to MVM and these complications, they are themselves imprecise. Like occult CVD risk that is not apparent until patients are challenged on a treadmill, pregnancy is a biologic stressor that may more successfully separate high- and low-risk women than risk factors measured before conception. Further, the placenta, with its own 9-month life course, may catalog maternal vascular impairments and mark cardiometabolic risk after pregnancy. If true, MVM lesions in the placenta may represent perhaps the earliest evidence of CVD risk in women. In addition, while prepregnancy blood pressure, lipids, and insulin resistance are often unavailable to clinicians, the placenta is accessible at every delivery. Thus, even if risk identified by the placenta was pre-existing, the placenta offers an efficient, cost-effective, and potentially robust tissue-specific indicator of this risk revealed at delivery.
      Although MVM lesions have a well-established association with preeclampsia and growth restriction,
      • Parks W.T.
      Placental hypoxia: the lesions of maternal malperfusion.
      and perhaps up to one-third of spontaneous preterm births,
      • Romero R.
      • Dey S.K.
      • Fisher S.J.
      Preterm labor: one syndrome, many causes.
      there are few epidemiologic studies regarding prevalence of these lesions in the setting of normal and complicated pregnancies. Decidual bed biopsies, which suggested that almost all cases of severe pre-eclampsia involved profound maternal spiral artery impairments
      • Brosens I.A.
      • Robertson W.B.
      • Dixon H.G.
      The role of the spiral arteries in the pathogenesis of preeclampsia.
      are not feasible on a population level. Instead, newer cohort studies have shed new light upon the prevalence and consequences of MVM lesions. In a cohort of 944 healthy women with uncomplicated pregnancies, Romero and colleagues reported that 35.7% had evidence of MVM lesions, with 7.6% having multiple vascular pathologies.
      Hauspurg has recently reported that MVM lesions in otherwise uncomplicated pregnancies were related to a 1.6-fold excess risk of adverse pregnancy complications in a subsequent pregnancy.
      • Hauspurg A.
      • Redman E.K.
      • Assibey-Mensah V.
      • et al.
      Placental findings in non-hypertensive term pregnancies and association with future adverse pregnancy outcomes: a cohort study.
      Indeed, decidual vasculopathy accounted for much of this association, and was related to a 2.5-fold excess risk for subsequent pregnancy complications. Another report using this same clinical cohort of more than 20,000 births with placental histology data indicated that black women were 14% more likely to have MVM lesions and 58% more likely to have decidual vasculopathy compared with white women.
      • Assibey-Mensah V.
      • Parks W.T.
      • Gernand A.D.
      • et al.
      Race and risk of maternal vascular malperfusion lesions in the placenta.
      These race differences were detected in term and preterm births, and in complicated as well as uncomplicated pregnancies. Evidence of race/ethnicity associations with MVM is, however, equivocal, perhaps due to study differences. For example, the Romero cohort was 81% black and thus likely lacking the population diversity needed to detect race differences. A re-examination of Collaborative Perinatal Project data from more than 50,000 placentas delivered in the early 1960s also did not detect race differences in MVM. Pathology approaches from more than 50 years ago, however, included only fibrinoid necrosis of the vessel walls the definition of decidual vasculopathy, while contemporary criteria include absence of vascular remodeling and mural hypertrophy of decidual arterioles as additional key diagnostic features.
      • Khong T.Y.
      • Mooney E.E.
      • Ariel I.
      • et al.
      Sampling and definitions of placental lesions: amsterdam placental workshop group consensus statement.
      The Pregnancy Outcomes and Community Health (POUCH) Study, a pregnancy cohort recruited from 5 Michigan communities (1998–2004, n = 1039), reported that black compared with white/other women (20% vs 7%).and obese compared with normal weight women (17% vs 6%) were more likely to have evidence of poor spiral artery remodeling.
      • Kelly R.
      • Holzman C.
      • Senagore P.
      • et al.
      Placental vascular pathology findings and pathways to preterm delivery.
      Taken together, these race- and obesity-related findings are consistent with the notion that MVM, and decidual vasculopathy in particular, may be related to a prepregnancy maternal susceptibility that persists or exacerbates after pregnancy. If true, MVM may identify a high-risk group of women in the years after delivery.
      There are only a handful of studies to pursue the cardiovascular determinants and sequelae of MVM. Stevens and colleagues
      • Stevens D.U.
      • Al-Nasiry S.
      • Fajta M.M.
      • et al.
      Cardiovascular and thrombogenic risk of decidual vasculopathy in preeclampsia.
      studied women with preeclampsia with and without decidual vasculopathy 7 months, on average, after delivery. Preeclampsia with DV was associated with higher diastolic blood pressure, lower left ventricular stroke volume (71 vs 76 mL, P=.032), higher total peripheral vascular resistance (1546 vs 1385, P=.009), and a higher percentage of low plasma volume (34% vs 19%, P=.030) compared with preeclampsia without DV. Two other studies have attempted to improve the decidual characterization of spiral artery impairments by including research biopsy specimen collection approaches. One demonstrated that at delivery, women older than 35 with acute atherosis had higher low-density lipoprotein cholesterol (LDL-C) and higher concentrations of apolipoprotein-B, the most atherogenic lipid component, compared to women without atherosis.
      • Moe K.
      • Alnaes-Katjavivi P.
      • Storvold G.L.
      • et al.
      Classical cardiovascular risk markers in pregnancy and associations to uteroplacental acute atherosis.
      Another study of women the day after delivery indicated women with atherosis (n = 3) had higher triglycerides and LDL-C compared to those without atherosis.
      • Veerbeek J.H.
      • Brouwers L.
      • Koster M.P.
      • et al.
      Spiral artery remodeling and maternal cardiovascular risk: the spiral artery remodeling (SPAR) study.
      Because a minority of preeclampsia cases have evidence of DV, it is possible that the placental vascular lesion rather than the clinical presentation of preeclampsia may be an important CVD risk marker. If true, then non-PE births with MVM may also mark women at higher CVD risk. The authors’ group tested this possibility in a study of women with prior non-preeclamptic preterm births with and without MVM and inflammatory lesions. Not only was the presence of both lesions associated with the worst neonatal outcomes,
      • Catov J.M.
      • Scifres C.M.
      • Caritis S.N.
      • et al.
      Neonatal outcomes following preterm birth classified according to placental features.
      co-occurrence of MVM and inflammatory lesions was also associated with a higher maternal cardiovascular risk burden in the decade after delivery compared to both women with term births and women with preterm births without these placental pathology findings.
      • Catov J.M.
      • Muldoon M.F.
      • Reis S.E.
      • et al.
      Preterm birth with placental evidence of malperfusion is associated with cardiovascular risk factors after pregnancy: a prospective cohort study.

      Summary

      More studies are needed to identify the mechanisms leading to impaired spiral artery remodeling. For example, studies that characterize decidual features more susceptible to MVM are needed. This tissue is remote and not easily accessed at delivery. Liquid biopsy approaches may help, as might novel imaging developments. This knowledge can then be leveraged to understand mechanisms that may link this pathology in the placenta to future pregnancy health and long-term maternal health. A recent review suggested that a sequence of endothelial injury, fragmentation, and repair in the vessel wall was implicated in DV, with the possibility that a parallel process in the systemic vasculature may also occur.
      • Hecht J.L.
      • Zsengeller Z.K.
      • Spiel M.
      • et al.
      Revisiting decidual vasculopathy.
      This may be due to activation of a local or systemic renin-angiotensin system,
      • Morgan T.
      • Craven C.
      • Ward K.
      Human spiral artery renin-angiotensin system.
      immune-mediated injury,
      • Sones J.L.
      • Lob H.E.
      • Isroff C.E.
      • et al.
      Role of decidual natural killer cells, interleukin-15, and interferon-γ in placental development and preeclampsia.
      or other unknown mechanisms. For example, higher concentrations of circulating angiogenic factors are detected in women with placental evidence of malperfusion, raising the possibility that impaired angiogenesis may be either a precursor or consequence of these pathologies.
      • Baltajian K.
      • Hecht J.L.
      • Wenger J.B.
      • et al.
      Placental lesions of vascular insufficiency are associated with anti-angiogenic state in women with preeclampsia.
      ,
      • Schmella M.J.
      • Assibey-Mensah V.
      • Parks W.T.
      • et al.
      Plasma concentrations of soluble endoglin in the maternal circulation are associated with maternal vascular malperfusion lesions in the placenta of women with preeclampsia.
      Although the placenta has been studied for decades as critical for fetal and newborn health, what it may reveal regarding maternal health is an emerging question. The standardization of placental histology evaluations, increased effort to characterize the developing placenta using noninvasive molecular methods, and development of novel imaging techniques to understand impairments in placental perfusion de novo now also make feasible the possibility that clues to maternal vascular health may also be detected in the placenta.

      Disclosure

      The authors have nothing to disclose.

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