Perspectives on the Pathogenesis and Complications of PE

Abstract

Preeclampsia is a multisystem disorder characterized by hypertension and proteinuria after 20 weeks of gestation. Globally, it is the leading cause of fetal and maternal morbidity and mortality. Nearly 8–10% of women develop hypertension during pregnancy worldwide. Although the actual pathogenesis of PE has not been fully understood, the only cure for the disease is delivery. So, the growing evidence suggests that improper spiral artery remodeling creates placental hypoxia and leads to altered immune response followed by endothelial dysfunction, the release of angiogenic and antiangiogenic factors, and various other vasoactive factors into the maternal circulation. Reliable biochemical markers are needed for the diagnosis of PE at the earliest. MMPs are differentially expressed as a result of the trophoblast invasion’s distinct temporal features. Early in the gestational period, MMPs create the conditions for the ensuing incursion to the placental bed. Endothelial dysfunction is the cause of the clinical sign of the mother such as impairment of the hepatic endothelium causing the HELLP syndrome to develop, impairment of the cerebral endothelium causing refractory neurological problems, or even eclampsia. Also, this chapter reveals the various maternal consequences like HELLP syndrome, Seizure, future cardiovascular events, and end-organ dysfunction; fetal complications include premature delivery, respiratory distress, IUGR, etc.

1. Introduction

Preeclampsia (PE), a multisystem illness, includes hypertension, proteinuria, abnormal maternal biochemical findings either with intrauterine growth restriction, and decreased amniotic fluid volume [1]. PE starts after 20 weeks of pregnancy with vascular dysfunction. Delivering both the fetus and placenta has been the only method of treatment so far, however, this causes more premature births and stunted child growth [2].

Compared to developed countries, women in developing nations had 14 times higher risk of dying from maternal complications. Around 289,000 women globally perished in 2013 as a result of pregnancy problems, and 99% of them were residents of underdeveloped nations. PE alone claims the lives of roughly 12% of mothers worldwide [3]. According to World Health Organization (WHO) estimates, PE occurs seven times more frequently in underdeveloped nations than in wealthy nations. PE is more common in developing nations than in developed ones, with rates ranging from 1.8 to 16.7% [3].

Even though the cause of PE is yet unknown, it is believed that factors such as poor decidualization, inadequate cytotrophoblast invasion, endothelial dysfunction, and unsuitable immunological responses to the allogenic fetus may play a role in the illness [4]. If left untreated, PE involves conditions like stroke, kidney damage, hypoxemia, liver failure, and eclampsia [5]. These processes are linked by an excess release of various biochemical factors, into the maternal circulation, and a common downstream impairment of spiral artery remodeling [4]. This chapter will describe the molecular pathways involved in the pathophysiology and complications of PE.

2. Pathogenesis of PE

The pathogenesis of PE is caused by a variety of causes, including the shallow invasion of cytotrophoblasts, restricted spiral artery remodeling, involvement of immunologic factors, genetical, involvement of microRNAs, etc.

2.1 PE’s placental roots

2.1.1 Differentiation of trophoblasts

About 6 days after conception (a.c.)., at the stage of the blastocyst, the trophoblast is the first cell lineage to differentiate Two distinct trophoblast pathways, the villous and the extravillous pathway, are formed as a result of further differentiation processes. The early syncytiotrophoblast is created at the moment of implantation and grows in size as a result of a mechanism that continuously supplies it with mononucleated cytotrophoblast cells [6]. Villous trophoblast cells begin to form at around day 12 post-conception when the cytotrophoblast cells begin to break through the syncytiotrophoblastic mass and move in the direction of the first branches that extend into the intervillous space. The cytotrophoblast cells have reached the mother’s side of the syncytiotrophoblast mass only at day 15 a.c. Mononucleated trophoblast cells make their initial contact with the maternal decidual stroma at this stage. Therefore, the subtype of extravillous trophoblast cells is only developed in week 5 post menstruation [7].

The trophoblast lineage develops in week 1 post-conception, whereas the differentiation of the two paths (villous and extravillous) takes place in week 3 post-conception. Regarding the placental origins of prenatal diseases like PE and Intrauterine growth restriction (IUGR), this time variation may be significant [2, 7].

The very early changes in the serum marker concentrations show that PE appears to start developing at the beginning of placentation, possibly even around implantation [8].

1. The trophoblast cell lineage may suffer a serious deficit if the very first differentiation of the lineage is compromised during development from morula to blastocyst. This could lead to IUGR and PE or even more serious consequences including spontaneous abortions.

2. The same dramatic effect as stated above may occur if the insult occurs a little while later when the blastocyst trophoblast divides into the first cytotrophoblast and syncytiotrophoblast

3. If only the development of the extravillous trophoblast pathway is subsequently impacted, this may lead to pure IUGR, which has all the hallmark features such as unsuccessful invasion and aberrant uterine artery Doppler.

4. PE, which has its classic symptoms such as the production of syncytiotrophoblast membrane fragments and a maternal inflammatory response, may occur if only the villous route is impacted.

PE has been well recognized as a result of the realization that early-onset and late-onset PE have different pathophysiologies. Early pregnancy maternal spiral artery transformation was reduced in early-onset, commonly known as placental PE [9]. This is linked to the gross and molecular diseases of the placental tissues as well as placental malperfusion. Increased soluble fms-like Tyrosine kinase-1 (sFLT-1) production and decreased Placental growth factor (PlGF) are caused by the placenta being under oxidative stress, which reflects the biomarker patterns. There is little indication of decreased arterial conversion in late-onset PE, also known as maternal PE, and placental perfusion is maintained or even improved. As a result, there is only a minor degree of placental stress, and the placenta secretes sFLT-1 and PlGF at levels that are close to the normal range [10].

The pathogenesis of early-onset PE begins with aberrant blood vessel development in the mother’s spiral arteries. Major adaptive changes, such as spiral artery remodeling in the uterus of the pregnant woman, occur throughout a typical pregnancy to lower maternal blood vessel resistance and subsequently raise uteroplacental perfusion [11]. The placenta receives high-capacitance, low- pressure blood flow as a result of these changes in the spiral arteries, which are crucial for embryonic nourishment [12]. Through trophoblast invasion and the removal of the smooth muscle in the blood vessel wall, spiral artery remodeling is accomplished.

2.2 Immune maladaptation

The PE clinical syndrome, a systemic inflammatory response, and malfunction of maternal peripheral endothelium cells are all caused by placental stress. Reduced blood flow to maternal organs is accompanied by physiological findings such as vasospasm, activation of the coagulation cascade, and decreased plasma volume before the onset of clinical illness [10]. Although there may be hyperplasia of the underlying cytotrophoblast cells, some of them also go through apoptosis or cellular aging. These lesions are connected to the release of trophoblastic debris, which is not surprising [10].

The development of hypertension is facilitated by the excessive release of placental factors such as syncytialtrophoblastic knots/debris, sFlt-1, and the soluble receptor for a vascular endothelial growth factor (VEGF) into the maternal circulation as a result of placental ischemia. These factors together increase oxidative stress. These angiogenic factors are also important inflammatory mediators that support PE-related maternal inflammation (Figure 1). Villous cytotrophoblasts secrete inflammatory cytokines such as interleukins (ILs)-1, -2, -4, -6, -8, -10, -12, and -18, transforming growth factor (TGF)-1, IFN- inducible protein 10/IP-10, tumor necrosis factor (TNF)-, interferon (IFN)-, monocyte chemotactic protein (MCP)-1, intercellular adhesion molecule [8, 13], which contribute in the development of PE.

Figure 1.

The diagram depicts the distinct pathways leading to PE. Placental tension causes a release of various placental factors and inflammatory cytokines.

2.3 Endothelial dysfunction

Endothelial dysfunction is the cause of the clinical sign of mother such as impairment of the hepatic endothelium causing HELLP (Hemolysis, Elevated Liver enzymes, and Low Platelet count) syndrome to develop, impairment of the cerebral endothelium causing refractory neurological problems, or even eclampsia [14]. Vascular endothelial growth factor depletion in podocytes increases the ability of endotheliosis to obstruct the basement membrane’s slit diaphragms, contributing to decreased glomerular filtration and proteinuria. The promotion of microangiopathic hemolytic anemia by endothelial dysfunction leads to edema, especially in the lower limbs or lungs, while vascular hyperpermeability brought on by low blood albumin induces edema [9].

2.4 Role of matrix metalloproteinases

Matrix metalloproteinases (MMPs) comprise a group of zinc in the catalytic field of enzyme and calcium-dependent endoproteases, it is well-known to degrade several components of the extracellular matrix (ECM) at physiological pH. It is categorized into collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and others according to their structure, unique substrate, and subcellular localization [15]. MMPs have numerous tissue distribution, secreted specifically with the aid of pro-inflammatory, uteroplacental tissue including lymphocytes, fibroblasts, vascular smooth muscle, endothelial cells, cytotrophoblasts, neutrophils, and osteoblasts [14]. It is actively involved in extracellular matrix remodeling in physiological and also in some pathological conditions like vascular disorders, cancer, rheumatoid arthritis, neurological, cancer, reproductive changes as well as in chronic inflammation [11, 16].

MMPs are differentially expressed as a result of the trophoblast invasion’s distinct temporal features. Early in the gestational period, MMPs create the conditions for the ensuing incursion to the placental bed. MMP-2 has a major function during implantation and MMP-9 during the invasion. In PE, the trophoblast will generate less MMP-9 and MMP-9 inhibition or gene silencing, which will impair trophoblast invasion in vitro. As a result, dysregulated secretion of these enzymes may interfere with physiological trophoblast invasion [15]. Studies demonstrate that during the first trimester of pregnancy, a low concentration of placental MMPs may have an impact on the remodeling of the spiral arteries, leading to a poorly perfused fetoplacental unit. The vasoconstriction, altered vascular reactivity, and endothelial damage caused by various MMPs may be the cause of the vascular dysfunction seen at the late stage of PE [11, 14, 15]. Due to these factors, MMPs have emerged as potent indicators for identifying pregnant women at risk for PE and as viable biological targets for the treatment of this disease.

2.5 Angiogenic and antiangiogenic markers

PE can be described as a two-stage process, with the preclinical phase beginning early in pregnancy (first trimester) and being defined by aberrant placentation, and the symptomatic phase following (occurring after 20 weeks gestation) and being characterized by the maternal syndrome of hypertension and multiorgan dysfunction [17]. In a healthy pregnancy, the placental bed and uterine circulation dramatically vascularize to allow for the circulation of blood between the mother and the fetus. Uterine vasculature includes vasculogenesis, angiogenesis, and maternal spiral artery remodeling [9]. The molecules that control angiogenesis and vessel remodeling must be carefully balanced for these processes to occur. Ischemia and damage to the placenta are caused by deficiencies in appropriate vascularization and vascular remodeling [2]. When a placenta is aberrant, more antiangiogenic substances, such as sFLT1 and soluble endoglin (sENG), are created and released into the maternal system [4].

3. Indicators of PE risk

National Institute for Health and Care Excellence (NICE) recommendations 2019 [18] classify a woman at high risk of PE if there is a history of hypertensive disease during a previous pregnancy or a maternal disease including chronic kidney disease, autoimmune diseases, diabetes, or chronic hypertension (Table 1). Women are at moderate risk if they are nulliparous, ≥40 years of age, have a body mass index (BMI) ≥ 35 kg/m [2], have a family history of PE, a multifoetal pregnancy, or have a pregnancy interval of more than 10 years [3]. These risk factors are echoed in the largest meta-analysis of clinical risk factors to date conducted by Bartsch et al. [8], who analyzed over 25 million pregnancies from 92 studies. The presence of one high-risk factor, or two or more moderate risk factors, is used to help guide aspirin prophylaxis, which is effective in reducing the risk of PE if administered before 16 weeks of pregnancy [9, 10]. There are additional clinical factors that significantly increase PE risk, including raised mean arterial blood pressure before 15 weeks gestation [11], polycystic ovarian syndrome [12, 13, 14], sleep-disordered breathing [15], and various infections such as periodontal disease, urinary tract infections [16], and Helicobacter pylori [17, 18]. In terms of obstetric history, vaginal bleeding for at least 5 days during pregnancy increases PE risk [11], as does the use of oocyte donation, which has a higher risk of PE in comparison to In Vitro Fertilization (IVF) without oocyte donation or natural conception [19, 20, 21].

High-risk factors	Moderate risk	Other clinical factors
Previous history of PE	>40 years of age	Increased mean arterial
Chronic kidney disease	BMI ≥35 kg/m	pressure before 15wks of
Autoimmune diseases	Family history of PE	gestation
Diabetes	Multifoetal pregnancy	Polycystic ovarian
Chronic hypertension	Lengthy	syndrome (PCOD)
Pre-gestational diabetes	interconceptional period	Sleep-disordered
	(> 5 years)	breathing
	Assisted Reproduction	Infections (H. Pylori,
		Urinary tract infections
		(UTI)
		Vaginal bleeding

Table 1.

Risk factors of PE [10, 18, 19].

4. Screening and early diagnosis of PE

PE frequently has no symptoms, making it challenging to predict the syndrome. A terminal crisis, such as eclampsia or HELLP syndrome, which necessitates an immediate termination of pregnancy, is frequently heralded by symptoms like epigastric discomfort or excruciating headache [10]. Circulating biomarkers or a Doppler ultrasonography analysis of the uteroplacental circulation can both identify PE that is either impending or already present [2]. This may be helpful for the early-onset form of the condition but not the late-onset form. To allow for therapies like aspirin prophylaxis, which must be started early to be effective, it is crucial to screen for PE in the first trimester of pregnancy [20]. In the Fetal Medicine Foundation (FMF) approach, the additional evaluation of biochemical and biophysical parameters, including monitoring the mean arterial blood pressure, the uterine artery Doppler analysis, as well as assessing biomarkers like the placental protein A (PAPP-A) and PlGF, can identify up to 75% of women who are destined to develop PE, requiring delivery 37 weeks of gestation [20].

A known risk factor for PE is being overweight or obese. According to much research, PE potentiates the normal disruption of the connection between adiposity and serum leptin concentrations, which is then furthered by rising BMI [21, 22, 23]. In response to hypoxic conditions, the levels of leptin rise in the vascular compartment and are used as an indicator of placental ischemia. The under-perfused placenta may receive more nutrients as a result of this feedback mechanism [23].

5. Complications of PE

Hypertension during pregnancy increases the risk of PE with unfavorable maternal, fetal, and neonatal consequences [24]. Moreover, the risk of PE needs to be separated from the patient’s inherent risk, which could only be shown when PE is under stress. To enhance the health of women around the world, this information will help create new treatments, interventions, and screening suggestions [12]. There are several placenta-related consequences of the diseases, including placental insufficiency, placental abruption, intrauterine growth restriction, premature birth, and intrauterine fetal death (Table 2). Thrombocytopenia disseminated intravascular coagulation, acute pulmonary edema, cerebrovascular diseases, and chronic hypertension were additional systemic complications of the disorders whose risk increases by three to twenty-five times compared to women without hypertension (Table 2) [28]. Short-term maternal problems of PE include HELLP syndrome, eclampsia, retinal detachment, and cerebrovascular hemorrhage. However, as was already said, PE is now known for its long-term effects, which can appear up to 15 years after childbirth [12].

Maternal outcome	Fetal outcome
Hypertension	IUGR
Diabetes mellitus	Respiratory distress
Antepartum and postpartum	Preterm delivery
hemorrhage	Stillbirth
Pulmonary edema	Necrotizing enterocolitis
Placental abruption
Coagulopathy
Future cardiovascular risk
Renal disorder
Hepatic failure
CNS damage
Seizure
Death

Table 2.

Maternal and fetal outcome due to adverse effects of PE [9, 25, 26, 27].

Worldwide, PE and eclampsia are responsible for 10–15% of maternal mortality. Eclampsia is the primary cause of death in underdeveloped nations, but PE-related complications are more common in industrialized nations. In as many as 3% of severe PE instances, pulmonary edema, a rare but dangerous issue, leads to problems [25]. Eclampsia case fatality ratios range from 0 to 1.8% in high-income countries to 17.7% in middle-income nations like India, which reflects the disparity in maternal healthcare quality. In Sweden, there were no maternal deaths attributable to eclampsia in a year, whereas an Indian hospital reported 11 eclampsia-related fatalities [28].

A prospective cohort study in 2022 found a higher level of unfavorable maternal outcomes was seen in the PE group in the Sidama region compared to the normotensive group [29]. PE patients experienced greater rates of maternal death, ICU admission, postpartum hemorrhage, antepartum hemorrhage, and blood transfusion than normotensive patients, also an Indian study reported placental abruption and coagulopathy were the most frequent consequences [25]. The commonest perinatal outcome is preterm birth followed by IUGR, stillbirth, and newborn ended up with early neonatal death [24, 25, 26, 30].

6. Conclusions

A complex clinical condition called PE harms nearly all of a pregnant woman’s essential organs. The early and late-onset variants are currently the most likely ends of the spectrum. The early onset form is mostly caused by faulty placentation in the first few weeks of pregnancy, which shares an underlying pathophysiology with other placental abnormalities, including reduced fetal growth. In contrast, late-onset PE causes increased oxidative stress followed by maternal malperfusion and demand in fetal-placental function. The last 10 years have seen significant progress in the study of preeclampsia as evidenced by the discovery of a wide array of novel biomarkers that allow early diagnosis of the disease and prediction of the outcome after a half-century of struggling to understand the molecular basis of the disease.

Acknowledgments

To make this study possible, the authors would like to thank Prof. S. Seetesh Ghose, Dean-MGMCRI, Prof. N. Ananthakrishnan, Dean-Faculty, Prof. S.R. Rao, Vice President-Research, Sri Balaji Vidyapeeth, and Prof. SC Parija, Hon’ble Vice-Chancellor, Sri Balaji Vidyapeeth.

Conflict of interest

The authors declare that there is no conflict of interest.