Pathophysiology of placental-derived fetal growth restriction

Placental-related fetal growth restriction arises primarily due to deficient remodeling of the uterine spiral arteries supplying the placenta during early pregnancy. The resultant malperfusion induces cell stress within the placental tissues, leading to selective suppression of protein synthesis and reduced cell proliferation. These effects are compounded in more severe cases by increased infarction and fibrin deposition. Consequently, there is a reduction in villous volume and surface area for maternal-fetal exchange. Extensive dysregulation of imprinted and nonimprinted gene expression occurs, affecting placental transport, endocrine, metabolic, and immune functions. Secondary changes involving dedifferentiation of smooth muscle cells surrounding the fetal arteries within placental stem villi correlate with absent or reversed end-diastolic umbilical artery blood flow, and with a reduction in birthweight. Many of the morphological changes, principally the intraplacental vascular lesions, can be imaged using ultrasound or magnetic resonance imaging scanning, enabling their development and progression to be followed in vivo. The changes are more severe in cases of growth restriction associated with preeclampsia compared to those with growth restriction alone, consistent with the greater degree of maternal vasculopathy reported in the former and more extensive macroscopic placental damage including infarcts, extensive fibrin deposition and microscopic villous developmental defects, atherosis of the spiral arteries, and noninfectious villitis. The higher level of stress may activate proinflammatory and apoptotic pathways within the syncytiotrophoblast, releasing factors that cause the maternal endothelial cell activation that distinguishes between the 2 conditions. Congenital anomalies of the umbilical cord and placental shape are the only placental-related conditions that are not associated with maldevelopment of the uteroplacental circulation, and their impact on fetal growth is limited. Placental-related fetal growth restriction arises primarily due to deficient remodeling of the uterine spiral arteries supplying the placenta during early pregnancy. The resultant malperfusion induces cell stress within the placental tissues, leading to selective suppression of protein synthesis and reduced cell proliferation. These effects are compounded in more severe cases by increased infarction and fibrin deposition. Consequently, there is a reduction in villous volume and surface area for maternal-fetal exchange. Extensive dysregulation of imprinted and nonimprinted gene expression occurs, affecting placental transport, endocrine, metabolic, and immune functions. Secondary changes involving dedifferentiation of smooth muscle cells surrounding the fetal arteries within placental stem villi correlate with absent or reversed end-diastolic umbilical artery blood flow, and with a reduction in birthweight. Many of the morphological changes, principally the intraplacental vascular lesions, can be imaged using ultrasound or magnetic resonance imaging scanning, enabling their development and progression to be followed in vivo. The changes are more severe in cases of growth restriction associated with preeclampsia compared to those with growth restriction alone, consistent with the greater degree of maternal vasculopathy reported in the former and more extensive macroscopic placental damage including infarcts, extensive fibrin deposition and microscopic villous developmental defects, atherosis of the spiral arteries, and noninfectious villitis. The higher level of stress may activate proinflammatory and apoptotic pathways within the syncytiotrophoblast, releasing factors that cause the maternal endothelial cell activation that distinguishes between the 2 conditions. Congenital anomalies of the umbilical cord and placental shape are the only placental-related conditions that are not associated with maldevelopment of the uteroplacental circulation, and their impact on fetal growth is limited. Click Video under article title in Contents at ajog.org Click Video under article title in Contents at ajog.org The kinetics of placental and fetal growth are closely interrelated, and are important features predicting postnatal health and in particular cardiovascular adaptations in childhood.1Jaddoe V.W. De Jonge L.L. Hofman A. Franco O.H. Steegers E.A. Gaillard R. First trimester fetal growth restriction and cardiovascular risk factors in school age children: population based cohort study.BMJ. 2014; 348: g14Crossref PubMed Scopus (109) Google Scholar, 2Burton G.J. Fowden A.L. Thornburg K.L. Placental origins of chronic disease.Physiol Rev. 2016; 96: 1509-1565Crossref PubMed Google Scholar Fetal growth is dependent on nutrient availability, which in turn is related to the maternal diet, uteroplacental blood supply, placental villous development, and the capacity of the villous trophoblast and fetoplacental circulation to transport these nutrients. At birth, the fetoplacental weight ratio gives a retrospective indication of the efficiency of the placenta to support growth of the fetus, and estimates the potential risks for chronic diseases in later life through developmental programming.2Burton G.J. Fowden A.L. Thornburg K.L. Placental origins of chronic disease.Physiol Rev. 2016; 96: 1509-1565Crossref PubMed Google Scholar, 3Burkhardt T. Schaffer L. Schneider C. Zimmermann R. Kurmanavicius J. Reference values for the weight of freshly delivered term placentas and for placental weight-birth weight ratios.Eur J Obstet Gynecol Reprod Biol. 2006; 128: 248-252Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Fetal growth restriction (FGR) is defined as the failure of the fetus to achieve its genetically determined growth potential.4Resnik R. Intrauterine growth restriction.Obstet Gynecol. 2002; 99: 490-496Crossref PubMed Scopus (366) Google Scholar FGR can have many causes, but the majority of cases that are not associated with fetal congenital malformations, fetal genetic anomalies, or infectious etiology are thought to arise from compromise of the uterine circulation to the placenta. Sufficient dilatation of the uteroplacental circulation together with rapid villous angiogenesis are the key factors necessary for adequate placental development and function, and subsequent fetal growth. The etiopathology of FGR due to abnormal development of the uteroplacental circulation and its impact on placental development and structure has been studied for >5 decades.5Gruenwald P. Abnormalities of placental vascularity in relation to intrauterine deprivation and retardation of fetal growth. Significance of avascular chorionic villi.N Y State J Med. 1961; 61: 1508-1513PubMed Google Scholar Ultrasound imaging, and in particular color Doppler imaging, has allowed the study of both the umbilicoplacental and uteroplacental circulations from the first trimester of gestation onward.6Jauniaux E. Jurkovic D. Campbell S. Kurjak A. Hustin J. Investigation of placental circulations by color Doppler ultrasound.Am J Obstet Gynecol. 1991; 164: 486-488Abstract Full Text PDF PubMed Google Scholar, 7Jauniaux E. Jurkovic D. Campbell S. Hustin J. 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Fetal and umbilical Doppler ultrasound in high-risk pregnancies.Cochrane Database Syst Rev. 2017; 6: CD007529PubMed Google Scholar More recently, 3-dimensional Doppler imaging11Luria O. Barnea O. Shalev J. et al.Two-dimensional and three-dimensional Doppler assessment of fetal growth restriction with different severity and onset.Prenat Diagn. 2012; 32: 1174-1180Crossref PubMed Scopus (0) Google Scholar, 12Moran M.C. Mulcahy C. Zombori G. Ryan J. Downey P. Mcauliffe F.M. Placental volume, vasculature and calcification in pregnancies complicated by pre-eclampsia and intra-uterine growth restriction.Eur J Obstet Gynecol Reprod Biol. 2015; 195: 12-17Abstract Full Text Full Text PDF PubMed Google Scholar and magnetic resonance imaging (MRI)13Zhu M.Y. Milligan N. Keating S. et al.The hemodynamics of late-onset intrauterine growth restriction by MRI.Am J Obstet Gynecol. 2016; 214: 367.e1-367.e17Abstract Full Text Full Text PDF PubMed Google Scholar have been used to study the development of the placental and fetal circulations, but their use in clinical practice remains limited. Placental-related complications of pregnancy that lead to FGR have their pathophysiological roots in the early stages of placentation and can manifest themselves from the end of the first trimester of pregnancy when the definitive placenta is forming.14Jauniaux E. Poston L. Burton G.J. Placental-related diseases of pregnancy: involvement of oxidative stress and implications in human evolution.Hum Reprod Update. 2006; 12: 747-755Crossref PubMed Scopus (401) Google Scholar, 15Burton G.J. Jauniaux E. The cytotrophoblastic shell and complications of pregnancy.Placenta. 2017; 60: 134-139Crossref PubMed Scopus (35) Google Scholar Considerable remodeling of the placenta takes place toward the end of the first trimester/start of the second trimester, associated with onset of the maternal arterial circulation when the placenta becomes fully hemochorial. Events at this time potentially impact the final size of the placenta, and hence it functional capacity. This concept is supported by findings in utero showing that pregnancies complicated with FGR, with or without accompanying preeclampsia later in pregnancy, have a smaller placenta volume and higher uterine resistance to blood flow compared to healthy controls from the beginning of the second trimester.9Velauthar L. Plana M.N. Kalidindi M. et al.First-trimester uterine artery Doppler and adverse pregnancy outcome: a meta-analysis involving 55,974 women.Ultrasound Obstet Gynecol. 2014; 43: 500-507Crossref PubMed Scopus (113) Google Scholar The relationships between abnormal placental development and FGR are complex. Isolating the placental causes of FGR can be difficult as many clinical studies are small, retrospective, and often multivariate with confounding factors such as maternal smoking and ethnicity. Also, many potential stressors converge on the same intracellular pathways, and separating the influence of, for example, glucose as compared to oxygen deprivation during periods of ischemia is impossible. To provide a coherent account of how the FGR phenotype may arise we first consider the development of the normal placenta before discussing the molecular and clinical pathologies. Initial development of the placenta takes place within the superficial layer of the endometrium, and by the end of the third week postconception villi have formed over the entire chorionic sac. This precocious growth is supported and stimulated by secretions from the underlying endometrial glands (Figure 1),16Burton G.J. Watson A.L. Hempstock J. Skepper J.N. Jauniaux E. Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy.J Clin Endocrinol Metab. 2002; 87: 2954-2959Crossref PubMed Scopus (247) Google Scholar, 17Burton G.J. Jauniaux E. Charnock-Jones D.S. Human early placental development: potential roles of the endometrial glands.Placenta. 2007; 28: S64-S69Crossref PubMed Scopus (90) Google Scholar so-called histotrophic nutrition. The carbohydrate- and lipid-rich secretions are delivered through openings in the developing basal plate into the intervillous space, from where they are taken up by the syncytiotrophoblast. As well as providing nutrients, the secretions contain numerous growth factors that stimulate placental cell proliferation in vitro, and most likely play an important role in regulating development and differentiation in vivo.18Maruo T. Matsuo H. Murata K. Mochizuki M. Gestational age-dependent dual action of epidermal growth factor on human placenta early in gestation.J Clin Endocrinol Metab. 1992; 75: 1362-1367Crossref PubMed Scopus (0) Google Scholar, 19Burton G.J. Scioscia M. Rademacher T.W. Endometrial secretions: creating a stimulatory microenvironment within the human early placenta. Implications for the etiopathogenesis of pre-eclampsia.J Reprod Immunol. 2011; 89: 118-125Crossref PubMed Scopus (0) Google Scholar, 20Filant J. Spencer T.E. Uterine glands: biological roles in conceptus implantation, uterine receptivity and decidualization.Int J Dev Biol. 2014; 58: 107-116Crossref PubMed Scopus (67) Google Scholar The absence of significant maternal blood flow at this stage means that initial development takes place in a low oxygen concentration, which is physiological and should not be considered hypoxic.21Cindrova-Davies T. Van Patot M.T. Gardner L. Jauniaux E. Burton G.J. Charnock-Jones D.S. Energy status and HIF signaling in chorionic villi show no evidence of hypoxic stress during human early placental development.Mol Hum Reprod. 2015; 21: 296-308Crossref PubMed Scopus (0) Google Scholar This environment is thought to protect the embryo from damaging reactive oxygen species (ROS) during the period of organogenesis, but may also serve to maintain stem cell potential.22Burton G.J. Jauniaux E. Charnock-Jones D.S. The influence of the intrauterine environment on human placental development.Int J Dev Biol. 2010; 54: 303-312Crossref PubMed Scopus (174) Google Scholar Once the main organs have differentiated there is a need for a greater supply of oxygen to support faster fetal growth,23Van Uitert E.M. Exalto N. Burton G.J. et al.Human embryonic growth trajectories and associations with fetal growth and birthweight.Hum Reprod. 2013; 28: 1753-1761Crossref PubMed Google Scholar and hence there must be a switch from histotrophic nutrition to hemotrophic supply from the maternal circulation. The human hemochorial form of placentation poses major hemodynamic challenges. In particular, a high volume of maternal arterial blood flow has to be delivered to the placenta at a sufficiently low pressure and velocity to prevent mechanical damage to the delicate villous trees.24Burton G.J. Woods A.W. Jauniaux E. Kingdom J.C. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy.Placenta. 2009; 30: 473-482Crossref PubMed Scopus (568) Google Scholar In normal pregnancies, the arcuate and radial arterial components of the uterine vasculature dilate under the combined effects of estrogen, progesterone, human chorionic gonadotropin, and other hormones and factors secreted by the placenta. The dilation accommodates the increased uterine flow of pregnancy, and is so marked that by around 20 weeks of gestation the diameter of the arcuate arteries is equal to that of the uterine artery.25Burchell C. Arterial blood flow in the human intervillous space.Am J Obstet Gynecol. 1969; 98: 303-311Abstract Full Text PDF Scopus (38) Google Scholar The more distal elements of the uteroplacental vasculature undergo additional extensive remodeling under the influence of extravillous trophoblast cells that migrate out from the placenta during early pregnancy. This remodeling involves the loss of smooth muscle cells and elastin from the arterial walls, and their replacement by fibrinoid material.26Pijnenborg R. Vercruysse L. Hanssens M. The uterine spiral arteries in human pregnancy: facts and controversies.Placenta. 2006; 27: 939-958Crossref PubMed Scopus (656) Google Scholar As a result, these segments of the uteroplacental vasculature become inert flaccid conduits, incapable of vasoconstriction. The extravillous trophoblast cells arise from the anchoring villi that are attached to the developing basal plate, and pass down the lumens of the spiral arteries as endovascular trophoblast, and through the decidual stroma as interstitial trophoblast. The migration of endovascular trophoblast is so extensive during the first trimester that the cells effectively plug the mouths of the spiral arteries, restricting flow to a slow seepage of plasma through a network of intercellular spaces (Figure 2).27Hustin J. Schaaps J.P. Echographic and anatomic studies of the maternotrophoblastic border during the first trimester of pregnancy.Am J Obstet Gynecol. 1987; 157: 162-168Abstract Full Text PDF PubMed Google Scholar, 28Burton G.J. Jauniaux E. Watson A.L. Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy; the Boyd Collection revisited.Am J Obstet Gynecol. 1999; 181: 718-724Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar The plugs begin to break down toward the end of the first trimester, and it is only after approximately 10 weeks of gestation that the maternal arterial circulation to the intervillous space is fully established, as confirmed by measurements of the rise in intraplacental oxygen concentration.29Rodesch F. Simon P. Donner C. Jauniaux E. Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy.Obstet Gynecol. 1992; 80: 283-285PubMed Google Scholar, 30Jauniaux E. Watson A.L. Ozturk O. Quick D. Burton G. In-vivo measurement of intrauterine gases and acid-base values in early human pregnancy.Hum Reprod. 1999; 14: 2901-2904Crossref PubMed Scopus (0) Google Scholar The interstitial trophoblast cells interact with the maternal immune system, in particular the uterine natural killer cells. Together, the extravillous trophoblast and natural killer cells are thought to release proteases and cytokines that stimulate dedifferentiation and loss of the smooth muscle cells within the arterial walls.31Harris L.K. Review: Trophoblast-vascular cell interactions in early pregnancy: how to remodel a vessel.Placenta. 2010; 31: S93-S98Crossref PubMed Scopus (125) Google Scholar, 32Whitley G.S. Cartwright J.E. Cellular and molecular regulation of spiral artery remodeling: lessons from the cardiovascular field.Placenta. 2010; 31: 465-474Crossref PubMed Scopus (0) Google Scholar Thus, a degree of activation of the natural killer cells is necessary, and genetic studies have revealed that these immune interactions may regulate birthweight across the microsomic-macrosomic range.33Moffett A. Hiby S.E. Sharkey A.M. The role of the maternal immune system in the regulation of human birthweight.Philos Trans R Soc Lond B Biol Sci. 2015; 370: 20140071Crossref PubMed Scopus (41) Google Scholar The arterial remodeling extends as far as the inner third of the myometrium, and so encompasses the hypercontractile segment of a spiral artery in the junctional zone. Consequently, there are 2 principal effects of the remodeling: firstly, dilation of the mouth of the artery reduces the velocity and pulsatility of the maternal inflow into the placental intervillous space, and secondly the loss of smooth muscle reduces the risk of spontaneous vasoconstriction.24Burton G.J. Woods A.W. Jauniaux E. Kingdom J.C. Rheological and physiological consequences of conversion of the maternal spiral arteries for uteroplacental blood flow during human pregnancy.Placenta. 2009; 30: 473-482Crossref PubMed Scopus (568) Google Scholar Remodeling of the spiral arteries extends into the second trimester, and possibly even longer. Ultrasound assessment of a cohort of 58 normotensive women revealed that blood flow from the mouths of the spiral arteries is pulsatile in all cases up to 20 weeks, and that pulsatility decreases thereafter with advancing gestational age.34Collins S.L. Birks J.S. Stevenson G.N. Papageorghiou A.T. Noble J.A. Impey L. Measurement of spiral artery jets: general principles and differences observed in small-for-gestational-age pregnancies.Ultrasound Obstet Gynecol. 2012; 40: 171-178Crossref PubMed Scopus (0) Google Scholar By 34 weeks, 37% of women showed no pulsatile inflow into the placenta. The early or primitive placenta undergoes extensive remodeling toward the end of the first trimester. Regression of villi starts over the superficial pole of the gestational sac (Figure 3, A) and gradually extends until only those villi covering the deep pole in contact with the placental bed remain as the definitive discoid placenta. This profound remodeling raises questions regarding how and when the size and shape of the placental disc are determined, and whether further expansion and recruitment of spiral arteries can occur in later pregnancy under adverse conditions. The remodeling is associated with onset of the maternal circulation to the placenta, which starts most commonly in the peripheral regions and extends to the central zone over the next few weeks.35Jauniaux E. Hempstock J. Greenwold N. Burton G.J. Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies.Am J Pathol. 2003; 162: 115-125Abstract Full Text Full Text PDF PubMed Google Scholar This pattern inversely reflects the degree of extravillous trophoblast invasion across the placental bed, which is greatest in the central region where it has been established the longest.36Pijnenborg R. Bland J.M. Robertson W.B. Dixon G. Brosens I. The pattern of interstitial trophoblastic invasion of the myometrium in early human pregnancy.Placenta. 1981; 2: 303-316Crossref PubMed Scopus (201) Google Scholar Hence, plugging of the arteries by endovascular trophoblast is more extensive in the center than in the periphery. The early onset of blood flow in the periphery causes a locally high level of oxidative stress (Figure 3, B), which induces activation of the apoptotic cascade. Consequently, the villi regress, leaving only avascular, hypocellular ghosts that are incorporated into the smooth membranes (Figure 3, C and D).35Jauniaux E. Hempstock J. Greenwold N. Burton G.J. Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies.Am J Pathol. 2003; 162: 115-125Abstract Full Text Full Text PDF PubMed Google Scholar At the same time, expression and activity of the principal antioxidant enzymes within the placenta increase,37Jauniaux E. 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