Introduction
Hypertension can present in pregnancy in three ways: chronic hypertension, a medical issue that precedes and continues during pregnancy, gestational hypertension (GH), or preeclampsia. New-onset non-obstetric hypertension is exceptionally rare and not considered here. Chronic hypertension (CHT) affects about 1–5% of pregnancies [1]. Preeclampsia complicates about 2–5% of pregnancies [2,3] and gestational hypertension 2–17%, depending on parity and patient population [4,5]. These different categories of hypertension do not occur in isolation. Chronic hypertension is a major risk factor for preeclampsia (named superimposed preeclampsia). GH may be an early sign of preeclampsia in some women. All three forms of hypertension increase the risk of fetal growth retardation (FGR).
Preeclamptic hypertension is a form of secondary hypertension. The cause is the placenta. When it is delivered, the problem for the mother is resolved, but may impose the difficulties of preterm delivery on the baby, preeclampsia being one of the most common reasons for iatrogenic prematurity [6].
The placenta is, of course, the supply line for the fetus. When FGR is caused by failure to achieve optimal fetal growth, this is often secondary to placentally mediated problems. In this review, the term FGR, unless otherwise stated, is used to mean FGR mediated by placental dysfunction, usually secondary to abnormal uteroplacental perfusion.
Preeclampsia is defined as a syndrome comprising new-onset hypertension and proteinuria in the second half of pregnancy, which was not present before pregnancy and does not persist afterward. Syndromes are common in all branches of medicine. They assist clinical practice, but do not help, and often hinder, understanding of pathogenesis by promoting a focus on secondary features evident to the clinician. Recent revised definitions from ACOG [7] do not include FGR as a possible component of the syndrome, but allow non-proteinuric variants, whereas the Australasian definition includes both [8].
GH typically precedes proteinuria. But not all GH evolves into preeclampsia. It is more likely the earlier the onset. Before 30 weeks, nearly half of those who present with GH develop preeclampsia compared to around 5% of those at term [9]. GH without proteinuria is more common than preeclampsia and has fewer adverse outcomes, which is consistent with it being a form of incipient preeclampsia. As for preeclampsia, it involves more primiparae [10], more FGR [11], and a greater susceptibility to long-term cardiovascular disease [12], especially if it recurs in more than one pregnancy [13]. A recent review concludes that GH is a mixture of women with incipient preeclampsia and of those with undiagnosed chronic hypertension [14]. CHT is a major risk factor for so-called superimposed preeclampsia, especially preterm preeclampsia. Even in the absence of proteinuria, it predisposes to FGR, for example [15].
Two questions can be asked. First, does maternal hypertension directly cause placental dysfunction and thereby FGR? Second, does placental dysfunction of other causes lead to FGR on the one hand and maternal hypertension on the other? The two possibilities are not mutually exclusive.
Uteroplacental Hemodynamics
The placenta is the key to understanding the relation between maternal hypertension and FGR; the issue centers on uteroplacental hemodynamic function and how, when it is disordered, the ensuing placental dysfunction causes preeclampsia and placentally mediated FGR.
The placenta is extraordinarily complex, with two circulations – uteroplacental and fetoplacental – that coexist with a genetically disparate mother. Unlike all other fetal organs, it reaches maximal capacity and function before birth. Its development has to be fast. Given its short life span, deviations from normality have major effects on intrauterine fetal health. The placenta is characterized by its unique cell type – trophoblast. Villous trophoblast is a major part of the placenta, with proliferative unicellular villous cytotrophoblast maintaining and replenishing the overlying non-proliferative multinucleate syncytiotrophoblast. The placenta is attached to the uterine wall by anchoring villi that are more than anchors. The anchoring villi represent bridges where proliferative extravillous trophoblast migrates to invade the placental bed and plays a major part in ensuring an adequate uteroplacental blood flow. These cytotrophoblast are, in effect, ambassadors for fetal trade that negotiate adequate supplies from the mother. Such “negotiations” require that the placenta must evade maternal immune rejection yet divert a large proportion (20%) of maternal cardiac output to supply its needs [16], receive an adequate but not excessive supply of oxygen for oxidative metabolism, and take control of maternal metabolism to ensure good nutrition for the fetus. Placentation is the term used to describe early placental development, when its maternal blood supply is established, and involves both an initial phase of endocrine priming followed by a second phase that is dependent on the presence of extravillous trophoblast cells [17].
The Uterine, Arcuate and Radial Arteries during Pregnancy
Volume blood flow to the placenta is determined by the larger radial, arcuate, and uterine arteries, which dilate enormously in very early pregnancy, amplifying changes that have already started in the luteal phase of the menstrual cycle [16]. The underlying mechanisms are not well defined, but do not involve direct contact with extravillous cytotrophoblast. Possible explanations invoke shear stress, more nitric oxide synthesis and increased hCG (human chorionic gonadotropin), estrogen, progesterone, relaxin, and placental growth factor (PlGF) production [16]. For example, endothelial nitric oxide synthase activity increases eightfold in uterine arteries from pregnant compared to non-pregnant women [18].
While intervillous maternal blood flow is controlled upstream by the larger radial arteries [19], profound dilatation and remodeling at the tips of the much smaller spiral arteries (see later in this chapter) slows blood flow velocities [19]. Other aspects of the circulation may be important such as maternal venous hemodynamics, which may have substantial effects on intervillous blood pressure. Maternal venous hypertension is transmitted retrogradely into the intervillous space, where if it is high it can compress the chorionic villous capillaries [20], perfused at very low pressures, so reducing their function. The clinical implications are not well documented or yet understood.
Large hemodynamic changes occur during pregnancy: systemically in the mother and locally in the uterus. Maternal arterial pressure is only one aspect of a larger and more complex process that ensures perfusion of the placenta in terms of blood flow volume, velocity, and perfusing pressure. Clinicians pay so much attention to blood pressure not because it is necessarily important in the pathogenesis of disorders like preeclampsia, but simply because it is what can be measured and monitored in pregnant women.
Placentation
The early development of the placenta has been summarized ([21] and Figure 4.1). Trophoblast differentiates early into villous and extravillous subsets: the former is associated with formation of the chorionic villous tree (branching morphogenesis) and the latter with invasion of the placental bed by extravillous cytotrophoblast, which stimulates spiral artery remodeling and development of adequate uteroplacental perfusion. Before 8 weeks, invasive endovascular plugs of trophoblast block the spiral arteries [22]. As a result, there is minimal hemochorial perfusion. The fetus is sustained by “histotrophic” nutrition [23], mediated by uterine glandular secretions, in a hypoxic environment. The uteroplacental circulation opens in a staged way, beginning at the placental pole furthest from the insertion of the umbilical cord and progressing centripetally from there [24]. As each artery unplugs, oxygenation of the relevant sectors of peripheral placental lobule increases relatively quickly. The ensuing oxidative stress atrophies the immature chorionic villi, leaving the chorionic layer of the decidua parietalis as a remnant of this process. Antioxidant defenses begin to strengthen after 8 weeks such that when the more central spiral arteries open, villous integrity is preserved as the definitive placenta begins to form, including a functional fetoplacental circulation. The intervillous circulation is fully established later, at the end of the first trimester [24].
Figure 4.1 Trophoblast differentiation and early origins of preeclampsia and FGR.
This is a theoretical model to relate early placental development to preeclampsia (PE) and fetal growth restriction (FGR).
If the early differentiation of trophoblast into its villous and extravillous derivatives is suboptimal, this may result in a combination of PE and FGR. If only the villous pathway is affected, reduced placental growth and distal villous hypoplasia is likely to be more important (lower left, see text). If only the extravillous pathway is affected, preeclampsia is more likely (lower right).
Unplugging of the spiral arteries, which starts placental perfusion, is a key turning point in placental development. The remnants of the trophoblast plugs that remain adherent to the arterial wall form a transient pseudoendothelium. They also penetrate the underlying artery wall and either directly or, in concert with maternal cells, dramatically remodel the ends of the spiral arteries from small elastic arteries, encircled by smooth muscle cell layers, into structure-less funnels, widest at their distal tips, with non-contractile fibrinoid walls, devoid of internal and external elastic laminae, smooth muscle, or adventitia [25]. This remodeling has long been considered to be how uteroplacental blood flow is expanded.
However, the remodeled tips of spiral arteries do not increase blood flow into the intervillous space, but reduce its velocity, pressure, and pulsatility, which minimize hydrostatic and oxidative damage to the chorionic villi [18]. During pregnancy, uterine hemodynamics are adapted in two phases: first involving the large arteries that determine volume flow and later affecting the terminal spiral arteries that determine the flow velocity [16].
This restructuring is deficient in preeclampsia and placentally mediated FGR. The remodeling normally extends as far as the myometrial segments of the arteries but is shallower where there is FGR with or without preeclampsia (Figure 4.2). In this case the flow from the artery into the intervillous space is not so much reduced, but pulsatile and at an increased pressure. As explained later, this imposes stresses on the syncytiotrophoblast lining of the chorionic villi, leading to dysfunctional placental-maternal signaling.
Figure 4.2 Poor placentation in FGR (fetal growth retardation) with or without preeclampsia.
A. Spiral artery remodeling (from weeks 8–18) normally extends into the myometrial segments, associated with endovascular invasion of trophoblast, which before 8–10 weeks plugs the arteries prior to the hemochorial circulation opening. This promotes low-velocity, steady blood flow into the intervillous space.
B. In FGR, with or without preeclampsia, the remodeling is abnormally shallow and fails to reach the myometrium. A collar of vascular smooth muscle (at point B) is retained that can contract and impede flow, which is at high velocity and pulsatile.
Maternal Hypertension and Fetal Growth Restriction: Mechanisms
The impact of antecedent maternal hypertension on placentation is not understood. Its association with FGR can be rationalized only by understanding the biological mechanisms. The fetus does not “sense” maternal hypertension. Nor does the placenta, in direct contact with the maternal circulation, appear to have baroceptors. However, it is crucial that the blood pressure in the intervillous space is kept low (below 20 mm Hg [25], so that it does not compress the capillaries of the chorionic villi, which are fragile structures filled at very low blood pressure, which can be easily collapsed and thereby lose effective function.
Placental Dysfunction as a Cause of Secondary Maternal Hypertension
By the year 2000, it was understood that preeclampsia was associated with dysfunctional uteroplacental perfusion that caused hypoxia with or without oxidative stress (not the same thing – see later in this chapter) and release of one or more, as yet unknown, placental factors into the maternal circulation that stimulate hypertension and other features of the syndrome. This was summarized in our two-stage model of preeclampsia [27]. In line with this model, we consider first what is happening in the placenta and second the downstream consequences in maternal systems. The unifying process in the placenta is biological stress [28].
Biological Stress, Pregnancy and Placentally Mediated Disease
Biological stress arises when a cell, tissue, or body system deviates from its set point of homeostasis. Such deviations are intrinsic to every moment of life and are managed by stress responses, which quickly restore equilibrium. It is self-evident that they encompass a huge range of responses that ensure survival. At the cellular level, there are four outcomes to stress: normality is restored; the cell gives up, is disassembled and cleared away (apoptosis); the cell disintegrates and spills its contents into its surrounds (necrosis); or the cell survives, but homeostasis is not restored and is replaced by chronic stress. The last is the basis of many if not all chronic illnesses. One aspect of the stress response is autophagy. While intracellular components are normally degraded and reused for cell maintenance, in stressed cells, this process is increased. Another aspect of cell stress is release of membrane microvesicles (summarized in [28]).
It is important to recognize that normal pregnancy itself is a major biological stress for the mother, imposed by the placenta. Most mothers adapt and cope, using stress responses that we artlessly call normal pregnancy physiology, for example, the early increases in the maternal pulse rate and leucocyte count already evident in the first trimester. If the placenta becomes stressed, it imposes an extra burden for the mother to be added to the already considerable load of her normal pregnancy. A common and important placental stress arises from dysfunctional maternal-placental perfusion. Because the placenta is the fetal lifeline, this can lead to FGR and chronic fetal hypoxemia. But placental signaling to the mother also becomes deranged, for example, causing maternal cardiovascular dysfunction – which is what we call preeclampsia.
Stress Responses and Syncytiotrophoblast (STB)
A wide range of stresses are resolved by a relatively small number of integrated responses that restore equilibrium. A classical stress response is inflammation, which is activated by external or internal triggers, not just infection (external danger), but also by accumulation of dangerous waste products, or biochemical damage to basic cellular molecules (internal danger). Stress may be generated by deficient or excess supplies to meet metabolic needs: oxygen, glucose, protein, water, and so on. Hypoxia and hyperoxia are both dangerous, as are both hypoglycemia and hyperglycemia, for example.
The placental syncytiotrophoblast is a microvillus epithelium and the functional interface between mother and baby, sustaining fetal respiration, nutrition, and waste disposal. Because it lines the intervillous space, perfused by maternal blood, it serves as a virtual maternal endothelium. Dysfunctional maternal perfusion usually causes intervillous hypoxia. During hypoxia, cellular protein synthesis slows [28]. If severe, what is called the unfolded protein response is activated in the protein factory of the cell, the endoplasmic reticulum, which then prioritizes synthesis of proteins that promote recovery at the expense of other proteins. There are negative aspects (shut down of some functions) and positive aspects (increased production of rescue factors, such as antioxidants). This is called endoplasmic reticulum stress (ER stress). Under these conditions, the recovering cell may be vulnerable to sudden restoration of normoxia, which causes oxidative damage, otherwise known as oxidative stress (Figure 4.3). Normally the cell can quench leakages of reactive oxygen species (ROS). Unquenched ROS indiscriminately oxidize all cellular constituents and impair or change their functions. Intermittent fluctuations in oxygenation may result from uterine contractions (such as during labor) or changes in maternal posture or perfusion; the ensuing oxidative damage is termed ischemia-reperfusion injury [30].
Figure 4.3 Syncytiotrophoblast, hypoxia, and oxidative stress.
Hypoxia evokes a stress response that prioritizes protein synthesis to factors that protect cell viability and support recovery from a transient insult. Before this is achieved, the cell becomes vulnerable to additional insults, of which one is sudden restoration of normoxia. The cell then suffers oxidative stress, which increases its chances of dying (dotted arrow).
Autophagy (also known as autophagocytosis): a catabolic process that recycles cellular constituents. It is a major mechanism whereby a stressed cell reallocates nutrients to more essential processes.
Growth arrest: cell division ceases.
Apoptosis: controlled cell death.
Necrosis: uncontrolled cell death.
The target tissue in preeclampsia is the maternal endothelium [31]. Its dysfunction can explain many if not all features of the maternal syndrome [32]. Generalized endothelial activation affects arterial function, but also underlies the much more widespread pathology of vascular inflammation [33], which includes altered metabolism, the complex liver dependent acute phase response, and increased insulin resistance [32]. Diverse inflammatory stimuli reduce nitric oxide bioavailability in the endothelium, thereby impairing flow-mediated vasodilation and increasing arterial pressure [34]. Chronic vascular inflammation underlies chronic hypertension and arterial disease, specifically the artery disease associated with obesity and the metabolic syndrome [35]. The same mechanisms underlie the hypertension of preeclampsia [33].
STB Stress, Hypertension, and FGR
In more severe preeclampsia, there is clear histopathological evidence of STB stress: increased necrosis, apoptosis, and autophagy. The placental release of STB microvesicles, another stress response, is also increased [28]. The maternal vascular inflammatory response is what would be predicted because maternal stress systems respond to the damaged syncytial surface of the placenta as if it were maternal tissue. Vascular inflammation explains more features of preeclampsia than any other biological mechanism [33], but cannot account directly for maternal hypertension, the key feature of the disorder.
This difficulty was largely resolved by the discovery of how angiogenic and antiangiogenic factors of placental origin contribute to the preeclampsia syndrome [36]. Vascular endothelial growth factor (VEGF) is the best known of several angiogenic factors. It is not produced by syncytiotrophoblast, whereas its close cousin, placental growth factor (PlGF), is. Note that PlGF is not placental specific. PlGF is normally produced in non-pregnant individuals from the heart and other tissues at low levels [37]. Antiangiogenic factors dysregulated in preeclampsia include soluble VEGF receptor-1 (sVEGFR-1, also known as sFLT1) and soluble endoglin (sENG). The typical but by no means consistent pattern of preeclampsia is an excess of circulating anti-angiogenic sVEGFR-1 and sENG, and a deficit of pro-angiogenic PlGF, also preceding the clinical onset of the syndrome.
The availability of circulating free VEGF and PlGF is reduced in preeclampsia. Both VEGF and PlGF help maintain the integrity of maternal endothelium. The consequences of VEGF deficiency have been well documented by the use of synthetic inhibitors of VEGF to treat cancer in non-pregnant patients. Proteinuria as well as hypertension, sometimes severe, are side effects. The evidence is that maternal hypertension is not mediated directly by a deficiency of vascular nitric oxide, which is the expected consequence of VEGF deprivation [38]. Instead it seems to arise from vascular oxidative stress, which is a by-product of disordered nitric oxide synthesis (Figure 4.4). Endothelin is a powerful endothelium derived vasoconstrictor that promotes vascular inflammation and oxidative stress, as observed in preeclampsia [39].
Figure 4.4 The association of FGR and hypertension with poor placentation.
Poor spiral artery remodeling leads to syncytiotrophoblast oxidative stress, which has two downstream consequences. The mother’s circulation is destabilized by excess STB-derived sFlt-1 (and other factors), which deprive her vascular endothelium of VEGF and stimulate overproduction of endothelin and maternal hypertension (see Figure 4.7a). The placenta suffers impairment of protein synthesis (endoplasmic reticulum stress), which is strongly associated with FGR.
FGR and ER Stress
The relation between STB stress and FGR is intuitively easy to envisage. Apart from loss of maternal-placental transport functions, the presence of ER stress distinguishes a preeclampsia placenta with FGR from a preeclampsia placenta without FGR. This is clearly seen by electron microscopy in the syncytium. Measurements specific to the syncytium are not yet available, but analysis of whole placental villous tissue confirms that ER stress is strongly linked to FGR [40]. This makes sense because the endoplasmic reticulum is the major producer of proteins within cells.
Biomarkers of STB Stress
In preeclampsia and FGR mediated by placental vascular dysfunction, both sFlt-1 and soluble endoglin production by syncytiotrophoblast increase despite ER stress, which would be expected to lead to less protein production. There are several other markers that increase similarly, for example, leptin, activin-A, inhibin-A, and corticotrophin-releasing hormone, all of which are potential biomarkers for preeclampsia. There are likely to be many more since the stress response is wide ranging. They will all reflect the problem in the placental syncytium. How they might modify the maternal syndrome is not fully clarified, but it is to be expected that they will, in concert, by their peripheral actions add to the complexity and heterogeneity of the maternal syndrome, while signaling the placental problem that affect fetal growth. Increased production from a tissue suffering ER stress is typical of what might be termed a positive stress response. These circulating proteins are therefore STB stress response markers and not preeclampsia biomarkers, as is often considered. The reduction in circulating PlGF in these contexts is typical of a negative stress response. The cause of this placental stress is dysfunctional uteroplacental perfusion, which may lead to hypoxia, ischemia or ischemia reperfusion, and oxidative stress. This is a plausible model of maternal hypertension as a secondary consequence of STB stress caused by uteroplacental mal-perfusion secondary to poor placentation (Figure 4.5).
