Introductory Chapter: The Multiple Etiologies of Preeclampsia

*Nidhi Sharma*

*Preeclampsia is an "old" disease. "After more than a century of intensive research, preeclampsia and eclampsia remain an enigmatic set of conditions." Roberts JM, Cooper DW. Pathogenesis and genetics of preeclampsia. Lancet. 2001;357:53e6.*

### **1. Introduction**

Preeclampsssia or "gestosis" or "toxemia of pregnancy" is any condition predisposing to eclampsia or convulsions during pregnancy. The word eclampsia is derived from a Greek word *eklampsis* meaning "lightening" or convulsions. Preeclampsia is speculated to be a heterogeneous group of disorders caused by multiple etiologies. Understanding the pathophysiology of this syndrome is important as different etiologies have different pathological mechanisms and different predictive markers. Though the defect could have arisen in the renin-angiotensin system, cardiovascular system, liver enzyme deficiency, coagulation cascade, oxidative stress, or placental bed, the clinical picture is usually oversimplified as the maternal syndrome of hypertension, edema, and proteinuria.

The third world countries will benefit from the provision of adequate antenatal care after these high-risk women are identified. In the developed world, however, the emphasis is on early detection and prevention of preeclampsia.

During pregnancy, the physiology of cardiovascular system, renin-angiotensin system, pancreas changes, different organ reserves are put to test. Understanding preeclampsia requires the understanding of physiology of pregnancy. The blood flow in multiple organs is increased (**Figure 1**). Numerous studies at the embryoendometrial interphase have also suggested the association of impaired spiral artery remodeling in preeclampsia, but how exactly is the impaired remodeling mediated and what is the pathogenesis of maternal syndrome are still to be elucidated. Some clinical cases of maternal syndrome of preeclampsia also have normal placental histology, so all cases cannot be attributed to a primary placental defect.

Clinical, biochemical, and biophysical markers are used for prediction depending on the etiology of the maternal syndrome of preeclampsia in the pregnancy (**Figure 2a** and **b**). These biomarkers can specifically be used to diagnose the etiology of maternal syndrome as renal dysfunction (kallikrein-creatinine ratio, angiotensin sensitivity test), vascular resistance (uterine artery Doppler), coagulation disorders (platelet volume, fibronectin, prostacyclin, thromboxane), oxidative stress (lipid peroxidase, 8-isoprostane, antioxidants, anticardiolipin antibodies, homocysteine), vascular adaptation (placental growth factor, vascular endothelial growth factor, s-flut, sEng), and placental dysfunction and ischemia (placental CRH, CRH bp, activin, inhibin, hCG).

#### **Figure 1.**

Atypical postpartum preeclampsia has an entirely different pathophysiology; it can be associated with the puerperal defects that prevent the excretion of sodium, puerperal diuresis. It can also be caused by an impaired shift of intravascular fluid into the extravascular compartment (atrial natriuretic peptide in the first week after delivery, natriuresis and inhibition of aldosterone, angiotensin II, vasopressin).

In this chapter the emphasis is on the preclinical pathophysiology of stage 1 of preeclampsia before the development of clinically evident stage 2 of hypertension, edema, and proteinuria.

There are two sides of fetal maternal interface, the maternal and the fetal. At the maternal side, the most important change is the remodeling of the spiral arterioles in the uterine endometrium and myometrium. The spiral arteries supply the intervillous space with blood in which there are floating fetal villi. Decidual veins drain the intervillous space.

At the fetal side, there is the development of fetal villi containing fetal capillaries. The fetal capillaries are covered by mesenchyme and cytotrophoblast. As the cytotrophoblast proliferates, it differentiates into the syncytiotrophoblast that covers the fetal villi. The cytotrophoblast also penetrates into the decidual stroma as interstitial trophoblast and also into maternal spiral arteries as endovascular trophoblast. The changes on both sides of fetomaternal interphase are described vide infra.

**5**

*Introductory Chapter: The Multiple Etiologies of Preeclampsia*

**2. The maternal side of fetoplacental interface**

maternal blood [4].

*in normal pregnancy and preeclampsia.*

**Figure 2.**

In humans' and primates' placental bed, at the embryo-endometrial interface, the extravillous trophoblastic cells of fetal origin penetrate not only the endometrium but also the subendometrial or junctional zone (JZ) myometrium [1–3]. These fetal origin cells also penetrate the interstitium, block the spiral vessel wall, and finally actually get incorporated into the vessel walls resulting in wide channels ensuring constant slow velocity uninterrupted blood flow to the placental sinuses. The fetal tertiary stem villi bathe in these placental sinuses and are gently sprinkled over by

*(a) Maternal syndrome of edema, hypertension, and proteinuria, and (b) podocyte and endothelial relation* 

It was emphasized by Brosen et al. [5] that this "physiological transformation" of spiral arterioles at the fetomaternal interphase was a result of the phagocytotic action of rapidly dividing and migrating fetal trophoblast that proliferate on vascular smooth muscles and elastic membranes [6]. Some years later a maternal role in spiral arteriolar remodeling was discovered since a few changes in the maternal vessel wall like dilatation of arterioles, immunosuppression, and rheological changes in the vessel wall and uterine decidua actually happen before the antidromic migration

The four steps of spiral arteriolar remodeling are explained below [8]. In the first step, there is maternal decidua-associated remodeling independent of the trophoblast. Encircling sheaths of edematous decidual cells around the vessels (Streeter's column) appear as early as postovulatory day 11 [3]. These swollen perivascular cells are usually originated from vascular smooth muscles of spiral arterioles. At 9 weeks of gestational age of the embryo, the maternal natural killer cells in the uterine decidua synthesize and secrete vascular endothelial growth factor (VEGF), placental growth factor (PLGF), and other angiopoietins [9, 10]. This results in vacuolation and disorganization of endothelial cells in the vascular lumen. In junctional zone or subendometrial myometrium, there are no immune-modified natural killer cells of pregnancy, and the penetrating interstitial trophoblast helps the release of VEGF and angiopoietins [9, 10]. This is concluded because the inter-

and proliferation of fetal trophoblast along the maternal vessel lumen [7].

stitial trophoblast enters the JZ a little later at 8 weeks.

*DOI: http://dx.doi.org/10.5772/intechopen.86177*

*The distribution of blood flow to maternal organs during pregnancy.*

*Introductory Chapter: The Multiple Etiologies of Preeclampsia DOI: http://dx.doi.org/10.5772/intechopen.86177*

**Figure 2.**

*Prediction of Maternal and Fetal Syndrome of Preeclampsia*

Atypical postpartum preeclampsia has an entirely different pathophysiology; it can be associated with the puerperal defects that prevent the excretion of sodium, puerperal diuresis. It can also be caused by an impaired shift of intravascular fluid into the extravascular compartment (atrial natriuretic peptide in the first week after delivery, natriuresis and inhibition of aldosterone, angiotensin II, vasopressin). In this chapter the emphasis is on the preclinical pathophysiology of stage 1 of preeclampsia before the development of clinically evident stage 2 of hypertension,

*The distribution of blood flow to maternal organs during pregnancy.*

There are two sides of fetal maternal interface, the maternal and the fetal. At the maternal side, the most important change is the remodeling of the spiral arterioles in the uterine endometrium and myometrium. The spiral arteries supply the intervillous space with blood in which there are floating fetal villi. Decidual veins drain

At the fetal side, there is the development of fetal villi containing fetal capillaries. The fetal capillaries are covered by mesenchyme and cytotrophoblast. As the cytotrophoblast proliferates, it differentiates into the syncytiotrophoblast that covers the fetal villi. The cytotrophoblast also penetrates into the decidual stroma as interstitial trophoblast and also into maternal spiral arteries as endovascular trophoblast. The changes on both sides of fetomaternal interphase are described vide infra.

**4**

edema, and proteinuria.

**Figure 1.**

the intervillous space.

*(a) Maternal syndrome of edema, hypertension, and proteinuria, and (b) podocyte and endothelial relation in normal pregnancy and preeclampsia.*

## **2. The maternal side of fetoplacental interface**

In humans' and primates' placental bed, at the embryo-endometrial interface, the extravillous trophoblastic cells of fetal origin penetrate not only the endometrium but also the subendometrial or junctional zone (JZ) myometrium [1–3]. These fetal origin cells also penetrate the interstitium, block the spiral vessel wall, and finally actually get incorporated into the vessel walls resulting in wide channels ensuring constant slow velocity uninterrupted blood flow to the placental sinuses. The fetal tertiary stem villi bathe in these placental sinuses and are gently sprinkled over by maternal blood [4].

It was emphasized by Brosen et al. [5] that this "physiological transformation" of spiral arterioles at the fetomaternal interphase was a result of the phagocytotic action of rapidly dividing and migrating fetal trophoblast that proliferate on vascular smooth muscles and elastic membranes [6]. Some years later a maternal role in spiral arteriolar remodeling was discovered since a few changes in the maternal vessel wall like dilatation of arterioles, immunosuppression, and rheological changes in the vessel wall and uterine decidua actually happen before the antidromic migration and proliferation of fetal trophoblast along the maternal vessel lumen [7].

The four steps of spiral arteriolar remodeling are explained below [8]. In the first step, there is maternal decidua-associated remodeling independent of the trophoblast. Encircling sheaths of edematous decidual cells around the vessels (Streeter's column) appear as early as postovulatory day 11 [3]. These swollen perivascular cells are usually originated from vascular smooth muscles of spiral arterioles.

At 9 weeks of gestational age of the embryo, the maternal natural killer cells in the uterine decidua synthesize and secrete vascular endothelial growth factor (VEGF), placental growth factor (PLGF), and other angiopoietins [9, 10]. This results in vacuolation and disorganization of endothelial cells in the vascular lumen. In junctional zone or subendometrial myometrium, there are no immune-modified natural killer cells of pregnancy, and the penetrating interstitial trophoblast helps the release of VEGF and angiopoietins [9, 10]. This is concluded because the interstitial trophoblast enters the JZ a little later at 8 weeks.

After this there are actual trophoblastic proliferation and intra-arterial migration. Penetration can happen in the stroma (interstitial trophoblast) or inside the vessels (endovascular trophoblast). The endovascular course only takes place antidromically only in spiral arteries but not in veins (**Figure 3**).

The interstitial trophoblast subsequently fuses to form multinuclear giant cells, but endovascular trophoblast remains mononuclear and with phagocytosis tries to became a part of the vessel wall [11]. Though the multinuclear giant cells appear more evident on histology examination, it is the mononuclear cytotrophoblast that is more phagocytotic, and it proliferates widely the uterine endometrium and JZ myometrium within a short time (**Figure 4**). A large quantity of interstitial trophoblastic cells (basophilic mononuclear cells) proliferate in the extracellular space between the smooth muscles of the JZ myometrium. Trophoblast cells are distributed at the center at 8–14 weeks, and at 16–18 weeks, they are more migrated toward the periphery, thus following an enlarging ringlike pattern of centrifugal migration toward the periphery of the placental bed [12]. It is believed that as the trophoblastic cells fuse to form giant cells, they are gradually losing the ability for phagocytosis. During the transformation of the endometrium to decidua, there is a selective breakdown of extracellular matrix of stroma, and this occurs independent of fetal trophoblastic action.

The interstitial migration and proliferation of trophoblast into the decidua and JZ myometrium (extravascular trophoblast) precede the proliferation of trophoblast spiral arteries (endovascular trophoblast) by several weeks. The first thing the proliferating endovascular mononuclear trophoblast does is to plug the outlets of spiral arterioles at the fetomaternal interface and thus create a low-oxygen environment for the developing embryo. The embryo cannot tolerate a high oxygen tension. After 10 weeks the entire span of the spiral arteries in decidua contains trophoblast reaching even up to the superficial vascular JZ myometrium. Deep invasion of myometrial segments of the spiral arteries happens only after 15 weeks (the second wave of proliferation).

#### **Figure 3.**

*(A) Unmodified spiral artery showing endothelium and vascular smooth muscle, (B) Decidua associated remodeling with disorganization of vascular smooth muscles, (C) Interstitial Trophoblast migration enhances vascular smooth muscle disorganization, (D) Endovascular Trophoblast temporarily replaces to endothelium, (E) Intramural incorporation of endovascular trophoblast and deposition of fibrinoid, replacing the vascular smooth muscle, (F) Reendothelialisation and intimal thickening.*

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trophoblast.

**Figure 4.**

*12–16 weeks.*

endothelial progenitor cells.

*Introductory Chapter: The Multiple Etiologies of Preeclampsia*

The third step is called as trophoblast-induced remodeling when the trophoblast cells actually become a part of the arterial wall. This vascular incorporation happens when the fetal trophoblast actually penetrates the maternal endothelium. Electron micrography studies of maternal decidua have revealed that the trophoblast penetrates between the healthy endothelial cells and crosses the underlying basement membrane. The smooth muscle penetration results in replacement of maternal endothelial cells with trophoblast embedded within a fibroid matrix, probably secreted by the trophoblast itself. The intraluminal trophoblastic cells now incorporated into the vessel wall now assume a spiderlike shape because of increasing accumulation of fibrinoid materials around the cell processes. The intraluminal trophoblast always remains mononuclear or at the most becomes binuclear. This is opposite to the interstitial

*(a) Placental oxygen tension curve, (b) trophoblastic penetration and placental oxygenation at 7–11 and* 

The fourth step of re-endothelialization occurs when the maternal vascular lining is repaired by endothelial remnants, which were still present after the intramural invasion. A new endothelial covering may also be derived from circulating

*DOI: http://dx.doi.org/10.5772/intechopen.86177*

*Introductory Chapter: The Multiple Etiologies of Preeclampsia DOI: http://dx.doi.org/10.5772/intechopen.86177*

**Figure 4.**

*Prediction of Maternal and Fetal Syndrome of Preeclampsia*

antidromically only in spiral arteries but not in veins (**Figure 3**).

of stroma, and this occurs independent of fetal trophoblastic action.

After this there are actual trophoblastic proliferation and intra-arterial migration. Penetration can happen in the stroma (interstitial trophoblast) or inside the vessels (endovascular trophoblast). The endovascular course only takes place

The interstitial trophoblast subsequently fuses to form multinuclear giant cells, but endovascular trophoblast remains mononuclear and with phagocytosis tries to became a part of the vessel wall [11]. Though the multinuclear giant cells appear more evident on histology examination, it is the mononuclear cytotrophoblast that is more phagocytotic, and it proliferates widely the uterine endometrium and JZ myometrium within a short time (**Figure 4**). A large quantity of interstitial trophoblastic cells (basophilic mononuclear cells) proliferate in the extracellular space between the smooth muscles of the JZ myometrium. Trophoblast cells are distributed at the center at 8–14 weeks, and at 16–18 weeks, they are more migrated toward the periphery, thus following an enlarging ringlike pattern of centrifugal migration toward the periphery of the placental bed [12]. It is believed that as the trophoblastic cells fuse to form giant cells, they are gradually losing the ability for phagocytosis. During the transformation of the endometrium to decidua, there is a selective breakdown of extracellular matrix

The interstitial migration and proliferation of trophoblast into the decidua and JZ myometrium (extravascular trophoblast) precede the proliferation of trophoblast spiral arteries (endovascular trophoblast) by several weeks. The first thing the proliferating endovascular mononuclear trophoblast does is to plug the outlets of spiral arterioles at the fetomaternal interface and thus create a low-oxygen environment for the developing embryo. The embryo cannot tolerate a high oxygen tension. After 10 weeks the entire span of the spiral arteries in decidua contains trophoblast reaching even up to the superficial vascular JZ myometrium. Deep invasion of myometrial segments of the spiral arteries happens only after 15 weeks (the second

*(A) Unmodified spiral artery showing endothelium and vascular smooth muscle, (B) Decidua associated remodeling with disorganization of vascular smooth muscles, (C) Interstitial Trophoblast migration enhances vascular smooth muscle disorganization, (D) Endovascular Trophoblast temporarily replaces to endothelium, (E) Intramural incorporation of endovascular trophoblast and deposition of fibrinoid, replacing the vascular* 

*smooth muscle, (F) Reendothelialisation and intimal thickening.*

**6**

**Figure 3.**

wave of proliferation).

*(a) Placental oxygen tension curve, (b) trophoblastic penetration and placental oxygenation at 7–11 and 12–16 weeks.*

The third step is called as trophoblast-induced remodeling when the trophoblast cells actually become a part of the arterial wall. This vascular incorporation happens when the fetal trophoblast actually penetrates the maternal endothelium. Electron micrography studies of maternal decidua have revealed that the trophoblast penetrates between the healthy endothelial cells and crosses the underlying basement membrane. The smooth muscle penetration results in replacement of maternal endothelial cells with trophoblast embedded within a fibroid matrix, probably secreted by the trophoblast itself. The intraluminal trophoblastic cells now incorporated into the vessel wall now assume a spiderlike shape because of increasing accumulation of fibrinoid materials around the cell processes. The intraluminal trophoblast always remains mononuclear or at the most becomes binuclear. This is opposite to the interstitial trophoblast.

The fourth step of re-endothelialization occurs when the maternal vascular lining is repaired by endothelial remnants, which were still present after the intramural invasion. A new endothelial covering may also be derived from circulating endothelial progenitor cells.

**Figure 5.**

*(a) Syncytial apoptotic shedding in normal pregnancy, (b) trophoblastic penetration and proliferation in preeclampsia.*

Investigations of Jauniaux have outlined the different times in gestation at which the decidual spiral arteries and junctional zone spiral arteries get remodeled in decidual association (step 1) and endovascular trophoblast association (step 2). Placental oxygenation increases as gestation advances (**Figure 4a** and **b**). There is no connection between the spiral arteries and the intervillous space at 7 weeks. And they appear at 8 weeks. Even before this communication, the decidual spiral arteries have remodeled (**Figure 5**). At 7–10 weeks, there is first wave of remodeling of decidual spiral arteries and early rise of intervillous flow. The second wave of remodeling, from 15 weeks onward, in which the endovascular trophoblast is observed in the junctional myometrium, is well after the steep rise in placental oxygenation. The decidua-associated spiral remodeling of the myometrium happens at 8–14 weeks, while trophoblastic-associated remodeling of the myometrium happens only after 15 weeks. The early decidua-associated remodeling of the junctional myometrium essentially prepares for the rise in uteroplacental flow, while the subsequent trophoblast-associated remodeling only stabilizes the vessel, and the increased flow is maintained.

#### **2.1 Topology of vascular remodeling**

A lateral gradient of diminished invasion has been seen at the periphery of the placental bed as compared to the center of the placental bed. Even in normal pregnancies, the junctional myometrium spiral arteries are remodeled only at the center, and there is an absence of junctional zone myometrial vascular remodeling at the periphery of the placental bed. In preeclampsia the trophoblast-associated remodeling is restricted to the decidual spiral arteries even in the center of the placental bed. One

**9**

*Introductory Chapter: The Multiple Etiologies of Preeclampsia*

**High risk Possible explanation Prediction by Clinical features**

Maternal history Maternal

Early first trimester scan

Maternal history, insulin resistance, glucose intolerance

APLA, ANA, protein essay and genetic screening

ABO incompatibility,

Rh

incompatibility screening

Uteroplacental artery flow waveforms, angiotensin II type 1 receptor agonistic antibodies

Serum levels, plasma and tissue expression of the long pentraxin 3

levels

Serum levels

Ratio of angiogenic (placental growth factors, VEGF) and antiangiogenic factors (s-flut and s-endoglin)

syndrome, proteinuria, hypertension, edema

Defective infiltration of decidua by natural killer cells, ligand receptor interaction of leukocyte

migration and intersignal. Ineffective blocking of spiral vessels and oxidative stress and embryo-endometrial interphase

Impaired apoptosis of hyperplastic arterial smooth muscles of spiral

Impaired fibrin deposition

Exaggerated maternal healing tissue response

cardiovascular system

8-isoprostane, antioxidants, hypertriglyceridemia, hemoglobin, iron, transferrin, albumin

isoforms

Renal disease Kallikrein-creatinine Serum/urine

Platelet volume, fibronectin, prostacyclin,

Placental peptides, CRH, CRH bp, activin, inhibin,

thromboxane

HCG

arteries

by trophoblasts

populations

*DOI: http://dx.doi.org/10.5772/intechopen.86177*

Molar pregnancy Failed trophoblastic

Vascular resistance Noncompliant maternal

Oxidant stress Lipid peroxidase,

Teenage pregnancy, short interval of pregnancy since menarche, no prior intercourse, and primipaternity

Chronic hypertension, high altitude pregnancy, increased maternal age, and diabetes

Connective tissue disorders, SLE, APLA. Factor 2 and factor 5 Leiden mutations, serpin gene mutations, and protein C and protein S

deficiencies

Rh incompatibility, hyperhomocysteinemia

Coagulation, fibrinolysis system, platelet activation, markers of vascular function

Placental ischemia secondary to any of the above

**High risk Possible explanation Prediction by Clinical features** Teenage pregnancy, short interval of pregnancy since menarche, no prior intercourse, and primipaternity Defective infiltration of decidua by natural killer cells, ligand receptor interaction of leukocyte populations Maternal history Maternal syndrome, proteinuria, hypertension, edema Molar pregnancy Failed trophoblastic migration and intersignal. Ineffective blocking of spiral vessels and oxidative stress and embryo-endometrial interphase Early first trimester scan Chronic hypertension, high altitude pregnancy, increased maternal age, and diabetes Impaired apoptosis of hyperplastic arterial smooth muscles of spiral arteries Maternal history, insulin resistance, glucose intolerance Connective tissue disorders, SLE, APLA. Factor 2 and factor 5 Leiden mutations, serpin gene mutations, and protein C and protein S deficiencies Impaired fibrin deposition by trophoblasts APLA, ANA, protein essay and genetic screening Rh incompatibility, hyperhomocysteinemia Exaggerated maternal healing tissue response ABO incompatibility, Rh incompatibility screening Vascular resistance Noncompliant maternal cardiovascular system Uteroplacental artery flow waveforms, angiotensin II type 1 receptor agonistic antibodies Oxidant stress Lipid peroxidase, 8-isoprostane, antioxidants, hypertriglyceridemia, hemoglobin, iron, transferrin, albumin isoforms Serum levels, plasma and tissue expression of the long pentraxin 3 Renal disease Kallikrein-creatinine Serum/urine levels Coagulation, fibrinolysis system, platelet activation, markers of vascular function Platelet volume, fibronectin, prostacyclin, thromboxane Serum levels Placental ischemia secondary to any of the above Placental peptides, CRH, CRH bp, activin, inhibin, HCG Ratio of angiogenic (placental growth factors, VEGF) and antiangiogenic factors (s-flut and s-endoglin)

*Introductory Chapter: The Multiple Etiologies of Preeclampsia DOI: http://dx.doi.org/10.5772/intechopen.86177*

*Prediction of Maternal and Fetal Syndrome of Preeclampsia*

Investigations of Jauniaux have outlined the different times in gestation at which

the decidual spiral arteries and junctional zone spiral arteries get remodeled in decidual association (step 1) and endovascular trophoblast association (step 2). Placental oxygenation increases as gestation advances (**Figure 4a** and **b**). There is no connection between the spiral arteries and the intervillous space at 7 weeks. And they appear at 8 weeks. Even before this communication, the decidual spiral arteries have remodeled (**Figure 5**). At 7–10 weeks, there is first wave of remodeling of decidual spiral arteries and early rise of intervillous flow. The second wave of remodeling, from 15 weeks onward, in which the endovascular trophoblast is observed in the junctional myometrium, is well after the steep rise in placental oxygenation. The decidua-associated spiral remodeling of the myometrium happens at 8–14 weeks, while trophoblastic-associated remodeling of the myometrium happens only after 15 weeks. The early decidua-associated remodeling of the junctional myometrium essentially prepares for the rise in uteroplacental flow, while the subsequent trophoblast-associated remodeling only stabilizes the vessel, and the

*(a) Syncytial apoptotic shedding in normal pregnancy, (b) trophoblastic penetration and proliferation in* 

A lateral gradient of diminished invasion has been seen at the periphery of the placental bed as compared to the center of the placental bed. Even in normal pregnancies, the junctional myometrium spiral arteries are remodeled only at the center, and there is an absence of junctional zone myometrial vascular remodeling at the periphery of the placental bed. In preeclampsia the trophoblast-associated remodeling is restricted to the decidual spiral arteries even in the center of the placental bed. One

**8**

**Figure 5.**

*preeclampsia.*

increased flow is maintained.

**2.1 Topology of vascular remodeling**


**Table 1.**

*Possible prediction of various subtypes of preeclampsia.*

study demonstrated that even decidual segments might show incomplete remodeling. It is imperative that the placental bed biopsy should be taken from an adequately central space and not lateral. There are less interstitial giant cells in the myometrium and more stacked endometrial glands pushed by the placenta at the periphery of the placental bed.
