Section 3 Cellular Function

#### **Chapter 3**

## Cellular Functions of ER Chaperones in Regulating Protein Misfolding and Aggregation: An Emerging Therapeutic Approach for Preeclampsia

*Janaranjani Murugesan, Ajithkumar Balakrishnan, Premkumar Kumpati and Hemamalini Vedagiri*

#### **Abstract**

Proteinuria is one of the hallmarks of preeclampsia (PE) that differentiates other hypertensive disorders of pregnancy. Protein misfolding and aggregation is an emerging pathological condition underlying many chronic metabolic diseases and neurodegenerative diseases. Recent studies indicate protein aggregation as an emerging biomarker of preeclampsia, wherein several proteins are aggregated and dysregulated in the body fluids of preeclamptic women, provoking the multisystemic clinical manifestations of the disease. At the cellular level, these misfolded and aggregated proteins are potentially toxic interfering with the normal physiological process, eliciting the unfolded protein response (UPR) pathway activators in the endoplasmic reticulum (ER) that subsequently augments the ER quality control systems to remove these aberrant proteins. ER resident chaperones, folding enzymes and other proteins serve as part of the ER quality control machinery in restoring nascent protein folding. These ER chaperones are crucial for ER function aiding in native protein folding, maintaining calcium homeostasis, as sensors of ER stress and also as immune modulators. Consequently, ER chaperones seems to be involved in many cellular processes, yet the association is expanding to be explored. Understanding the role and mechanism of ER chaperones in regulating protein misfolding and aggregation would provide new avenues for therapeutic intervention as well as for the development of new diagnostic approaches.

**Keywords:** ER stress, ER chaperone, protein misfolding, aggregation, preeclampsia

#### **1. Introduction**

Hypertensive disorders are a most common medical problem encountered during pregnancy, affecting 6–8% of all pregnancies. Approximately 70% of hypertensive disorders in pregnancy are mainly due to gestational hypertension, adding up further complications. Preeclampsia (PE) is a multi-systemic disease diagnosed by the presence of new onset hypertension accompanied by proteinuria,

#### *Preeclampsia*

renal insufficiency, pulmonary edema, liver failure, neurological complications and fetal growth restriction [1]. The progression of the disease is unpredictable mainly leading to fetal damage associated with other clinical manifestations such as thrombocytopenia, oxidative stress, vascular endothelial dysfunction, systemic inflammation and aberrant angiogenesis, which invariably necessitates early diagnosis of the disease condition so as to prevent further pathogenesis [2].

Proteinuria is one of the hallmarks of preeclampsia that differentiates it from other hypertensive disorders of pregnancy. Recent studies have indicated that protein aggregation as an emerging biomarker of PE, providing insights for therapeutic intervention and development of new diagnostic approaches. Notably, endoplasmic reticulum (ER) stress has recently emerged as a major pathological condition underlying chronic metabolic diseases such as diabetes, cancer, neurodegenerative diseases including PE. At the cellular level, misfolded proteins in the ER significantly lead to ER stress by activating the unfolded protein response (UPR) pathway and molecular chaperones [3–8]. Mis-folded or aggregated proteins are potentially cytotoxic, and consequently cells possess quality control systems to remove these aberrant proteins. These aberrant proteins will expose hydrophobic regions, free cysteines and tend to aggregate, molecular chaperones play key roles in ER quality control because they recognize mis-folded and aggregation-prone proteins [9, 10]. ER chaperones, folding enzymes and other proteins involved in ER stress would serve as a valuable tool in the investigation of disease pathogenesis, prediction of early diagnostic markers and development of targeted therapies. Hence, exploring the structure and functions of ER chaperones would provide new insights in reducing the cellular stress underlying preeclampsia.

#### **2. Regulation of ER stress**

Endoplasmic reticulum (ER) is a cellular organelle involved in multiple cellular processes required for cell survival and physiological functions. These processes include intracellular calcium homeostasis, protein secretion and lipid biosynthesis [11–13]. ER constantly monitors the level and conformational status of secreted and membrane-related proteins and rapidly activates multiple signaling pathways in response to changes in the quality and quantity of the proteins it processes, levels of reactive oxygen species and metabolic changes. The ER has a specialized environment, including complexes of chaperones and foldases, as well as high fidelity quality controlling mechanisms to ensure the crucial maintenance of ER homeostasis in cells. ER homeostasis is a unique equilibrium between the cellular demand for protein synthesis and the ER folding capacity to promote protein transportation and maturation.

The ER lumen is a one-of-a-kind biological environment, wherein cells are flooded with calcium inorder to mediate the active transport of proteins by calcium ATPases. In addition, ER is also concentrated in calcium-dependent chaperones such as glucose-regulated protein, 78 kDa (GRP78), GRP94 and calreticulin, which help in stabilizing protein-folding intermediates. The oxidative environment in the ER lumen is crucial for disulphide bond formation mediated by protein disulphide isomerase (PDI). The di-sulfide bond formation helps in the proper folding of many proteins intended for secretion as well as those expressed on the cell surface. Different post-translational modifications, including glycosylation and lipidation of proteins too occur in the ER [14, 15].

Disparity in ER function leads to a state known as ER stress, which activates a series of evolutionarily conserved signaling pathways collectively referred to as the unfolded protein response (UPR). Triggering of UPR pathways results in three *Cellular Functions of ER Chaperones in Regulating Protein Misfolding and Aggregation… DOI: http://dx.doi.org/10.5772/intechopen.101271*

effector functions: adaptation, alarm and apoptosis [16]. Initially the UPR pathway intends to recover the homeostasis and normalize the ER function. The adaptive mechanism is primarily involved in the activation of transcriptional pathways responsible for enhancing the protein folding capacity and ER-assisted degradation (ERAD). Both of these pathways reduce the load of misfolded proteins in ER by refolding the proteins or exporting them to cytosol for degradation. Initial to this, translation of mRNA is inhibited to prevent the entry of the new protein into ER until the activation of genes encoding UPR pathways [17].

#### **3. Unfolded protein response pathway**

Accumulation of unfolded proteins trigger an evolutionarily conserved signaling pathway designated as UPR [18, 19]. Three major proteins: inositol requiring enzyme 1α/β (IRE1), PKR-like ER kinase (PERK), and activating transcription factor 6α/β (ATF6) are the key UPR signaling activators [20–22]. These activators are capable of retrotrafficking from ER membrane to cytosol by their unique domain organization. They contain 3 domains: an ER luminal domain (LD), a membrane spanning domain and a cytosolic domain. The LD, either directly or indirectly involved in sensing the misfolded proteins [23]. Type 1 transmembrane proteins PERK and IRE1α possess the domain structure that is similar as ER luminal domain structures and a cytosolic Ser/Thr kinase domain, whereas type II transmembrane protein ATF6α contains a cytosolic cyclic AMP response element-binding protein (CREB)-ATF basic leucine zipper domain. UPR pathway activation involves a reduction in protein synthesis, increased protein folding and transport in the ER, an increase in ER-associated protein degradation and autophagy.

After ER is loaded with unfolded proteins, UPR signaling pathways are not simultaneously activated. Primarily ATF6α and IRE1α activation occurs, with subsequent activation of PERK during chronic ER stress [5, 6]. ATF6α and IRE1α are responsible for the activation of transcriptional pathways that increases the cell's capacity for protein folding, transport and degradation. Adaptive response to the protein misfolding is achieved by ATF6α, which is synthesized as an inactive precursor. The N-terminus is located in cytoplasm and serve as an effector portion which possess DNA-binding and transcriptional activation regions. On the accumulation of unfolded protein in ER, ATF6α travels to the Golgi, and the N-terminal effector portion present in cytosol-bZIP transcription factor is fragmented by S1P and S2P [24]. The fragment induces the genes encoding protein chaperones such as binding immunoglobulin protein (BiP), ER protein 57 (ERp57) and glucoseregulated protein 94 (GRP94), proteins involved in ERAD pathway.

X-box binding protein 1 (XBP1), a transcription factor regulating UPRassociated genes is activated by IRE1 [25, 26]. IRE1 acts as an endonuclease and selectively cleaves the 26-nucleotides from the XBP1u mRNA producing XBP1 spliced mRNA (XBP1s). Activated XBP1s enhances the expression of ER chaperone GRP78, increases the phospholipid biosynthesis and also promotes degradation pathways. Regulated IRE1-dependent decay (RIDD) is also mediated by the activation of IRE1α when the ER protein-folding load is intolerable [27–29]. PERK-eIF2α-ATF4 mediated pathway attenuates the non-essential protein synthesis and increases the antioxidant defense system. PERK phosphorylates eIF2α at Ser51 which temporarily stops the initiation of global mRNA translation. In irony, phosphorylated eIF2α upregulates the translation of mRNA's such as ATF4 to increase the protein transport capacity in the ER [30]. Genes encoding ER chaperone protein, folding enzymes and genes encoding ERAD system are activated by p-eIF2α. The collective activation of the genes leads to revive the ER homeostasis

#### **Figure 1.**

*ER chaperones mediate Protein folding, Quality control, and signaling during ER Stress.*

and at saturation, the misfolded proteins are degraded by ERAD system assisted by proteasome mediated degradation and pro-apoptotic protein C/EBP homologous protein (CHOP) [31, 32]. Aforementioned pathways are activated based on the severity of the stress condition (**Figure 1**) [18, 33].

#### **4. Protein misfolding and aggregation**

Protein misfolding, aggregation and tissue deposition of fibrous protein aggregates are the critical etiological manifestations of many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, etc. Recent

#### *Cellular Functions of ER Chaperones in Regulating Protein Misfolding and Aggregation… DOI: http://dx.doi.org/10.5772/intechopen.101271*

studies report that numerous aggregated proteins considerably contributes to the heterogeneous clinical manifestations in preeclamptic women, indicating that protein aggregation and misfolding does have a correlation with the disease pathogenesis. Numerous proteomic profiling studies of urine, serum and placental samples from preeclamptic women based on MS analysis, has revealed that aggregation of proteins significantly contributes to the PE associated pathogenesis. Several proteins, including amyloid beta peptide, transthyretin, alpha-1 antitrypsin, albumin, IgG k-free light chains, and ceruloplasmin are aggregated in PE, resulting in toxic deposition of amyloid-like aggregates in the placenta and body fluids [34, 35]. In addition, many extracellular chaperones like casein, clusterin, pregnancy zone protein are implicated to be dysregulated in pregnancy, leading to the accumulation of misfolded proteins and disease manifestation. Probably, these aggregated proteins in the early stages of pregnancy induces defective trophoblast invasion, placental ischemia, ER stress thereby promoting PE manifestation. Insights into the molecular mechanisms of formation of these aggregated proteins and understanding the role of molecular chaperones in regulating the misfolded proteins will open new avenues for pharmacological intervention and therapeutic targeting of PE.

Disruption of ER homeostasis as a result of excess accumulation of unfolded/ misfolded proteins due to prolonged or severe ER stress is involved in several pathologies that induce endometriosis and endometrial/ovarian cancers as well as various pregnancy complications that result in preeclampsia, fetal growth restriction and preterm birth. Depending on the severity of ER stress, UPR behaves as sort of binary switch between life and death. Initially, the UPR aims to restore ER homeostasis, but if these attempts fail then the apoptotic cascade is activated. These pathways are now recognized as playing a central role in the pathophysiology of chronic diseases, which contributes to the placental pathology in early-onset PE [36].

The ER has tremendous intracellular store of Ca2+ necessary for regulating a variety of cellular functions both in the ER lumen and cytosol. Inside the ER lumen, huge reserves of Ca2+ are important for proper protein folding assisting disulfide bond forming chaperone, protein disulfide isomerases (PDI). To maintain the ER calcium levels, sarcoendoplasmic reticulum calcium transport ATPase (SERCA) pumps in the ER membrane actively transport Ca2+ from the cytosol into the ER lumen. These pumps are specifically regulated based on the proportion of Ca2+ in the ER lumen to the cytosol. Alteration in SERCA pumps blocks the movement of Ca2+ into the ER, decreasing the function of molecular chaperones and PDI, thereby increasing the burden of misfolded proteins in the ER [37].

#### **5. Pathophysiology of PE**

Impaired placentation mainly contributes to the manifestation of systemic symptoms in PE, which may be preceded or followed by protein misfolding and aggregation along with subsequent placental release of inflammatory cytokines, anti-angiogenetic factors, placental debris and particles as well as protein aggregates into the maternal circulation. This pre-clinical dysregulation causes endothelial dysfunction, excessive thrombin generation, systemic inflammation and as a result, elicits multiorgan syndromes of PE [38–41]. During early stages of pregnancy, several proteins such as transthyretin, may be transported to the placenta from maternal circulation. These aggregation-prone proteins easily undergo misfolding and aggregation in the microenvironment of non-compatible conditions, such as acidic pH, ischemia/hypoxia, amino acid fluctuation, inflammation, and hormonal dysregulation [10, 42]. Protein aggregates induce ER stress and may eventually overwhelm the capacity of the unfolded protein response (UPR) and clearance

#### *Preeclampsia*

machineries, leading to deposition and accumulation of these aggregates in trophoblasts, extracellular domains and subsequently causing placental toxicity, poor trophoblast invasion, differentiation, superficial endometrial invasion and failure of spiral artery remodeling. Continuous accumulation of protein aggregates may aggravate ER stress and cause cell apoptosis, leading to release of aggregates into maternal circulation and excretion through injured glomerulus into urine.

ER stress is intricately linked to oxidative stress and inflammation, indicating the co-existence of these pathways in major pathologies particularly early on-set PE, through feed-forward mechanisms [43]. ER stress induction and UPR activation was insignificantly evident in both intra uterine growth retardation (IUGR) and IUGR associated early-onset pre-eclampsia (IUGR + PE) placentas. However, increased apoptosis, higher levels of eIF2α phosphorylation, GRP94 and CHOP in the syncytiotrophoblast and endothelial cells of the foetal capillaries was evident in IUGR + PE placental samples and not in IUGR alone [44]. ER stress associated proteins such as GRP78, GRP94, p-PERK, eIF2α, p-eIF2α, XBP1, CHOP, IRE1, p-IRE1 and inducible nitric oxide synthase (NOS) expression where high in preeclamptic placentas compared to control placenta [45]. Overexpression of placental UPR pathways including IRE1, ATF6 and XBP-1 was significantly observed in early-onset PE compared to that of late-onset of PE and normotensive controls [33]. Preeclamptic placentas feature higher levels of ER stress with prominent activation of pro-inflammatory pathways that contributes to maternal endothelial cell activation. These complexity of cellular responses to ER stress emphasizes the need for a holistic approach for designing potential therapeutic interventions for PE. Antioxidants, ER chaperones, NO donors, statins and H2S donors display pleitropic antioxidant, anti-inflammatory, and proangiogenic effects on the signaling pathways involved in the pathophysiology of PE, exhibiting potential strategies for therapeutic intervention [46].

#### **6. ER chaperones**

The transcriptional up-regulation of ER chaperones is the hallmark of the ER stress response and occurs in all eukaryotic organisms. The primary function of ER resident chaperones and their cofactors involved in the ER quality control system is to monitor the error-prone steps in protein synthesis and assembly [13, 47]. Three major chaperone families exist in the ER that interact with a wide variety of clients: the lectin chaperones, which generally recognize incompletely folded glycosylated proteins, the heat shock proteins (HSPs) family, which interacts with both nonglycosylated as well as glycosylated proteins and the thiol oxireductases, that aids in the disulphide bond formation [48].

#### **6.1 Heat shock proteins (HSPs)**

HSPs are a large family of evolutionarily conserved molecular chaperones, first observed as a group of proteins upregulated in heat-stressed *Drosophila melanogaster* [49], that are well-known for their roles in protein maturation, re-folding and degradation. These molecular chaperones of this HSP family are critical effectors of the UPR adaptive response. They protect intracellular proteins from misfolding or aggregation, inhibit cell death signaling range and preserve the intracellular signaling pathways that are essential for cell survival. HSPs classified according to their molecular weight as proteins of approximately 84 and 70 kDa (HSP84 and HSP70), are amongst the most prominent chaperones in the ER [50]. HSPs are constitutively expressed, inducibly regulated to prevent aggregation of misfolded polypeptides and assists in refolding, besides being crucial modulators of neurotoxicity in Alzheimer's

*Cellular Functions of ER Chaperones in Regulating Protein Misfolding and Aggregation… DOI: http://dx.doi.org/10.5772/intechopen.101271*

disease [51]. Placental ischemia, oxidative stress, maternal systemic inflammatory response are major elements in the pathogenesis of PE that induces the expression of HSP70 which in-turn is associated with cytokine aggravation, oxidative stress and hepatocellular injury [52].

Binding immunoglobulin protein (BiP)/glucose-regulated protein 78 (GRP78), belongs to the HSP70 family, is a well known ER chaperone that binds to the hydrophobic region of unfolded proteins. GRP78 binds through substrate-binding domain and assists protein folding through a conformational change, achieved through the hydrolysis of ATP by the ATPase domain. Another chaperone, oxygenregulated protein (ORP)150/GRP170 belonging to the HSP110 family (a HSP70 subfamily), assists the protein folding similar to that of BiP. The group of ER DnaJ proteins-ERdj1, ERdj3/HEDJ, ERdj4, ERdj5, SEC63 and p58IPK belonging to the HSP40 family acts as co-chaperones, mediating the acitivity of BiP by regulating its ATPase activity [53, 54].

Hsp90 is an essential component of cytoplasmic Hsp90-Hsp70 chaperone network, responsible for protein folding. Protein emerging from ribosome is initially folded in nascent polypeptide by Hsp70 and then passed to the Hsp90 for later folding. GRP94, the hsp90 family chaperone, hydrolysis the ATP, facilitates protein folding and liable for the maturation of certain oligomeric proteins including Tolllike receptors (**Table 1**) [58].


#### **Table 1.**

*Classification of ER chaperones and their functional roles.*

#### **6.2 Lectin chaperones**

A unique aspect of the ER involves glycosylation-assisted folding which is largely mediated by ER resident lectins. There are two calcium-activating chaperones in the ER - calnexin (CNX) and calreticulin (CRT), that associates with glycoproteins and completes the protein folding process [55, 59]. The CNX/CRT cycle is critical part of the ER quality control machinery in monitoring the glycosylation and sugar chain structures in protein folding and assembly. When one glucose residue is attached to the client protein, ER lectins bind to initiate the folding process and later release the protein to UDP-glucose-glycoprotein glucosyltransferase. The disulfide bond isomerase ER protein 57 (ERp57) majorly involved in the CNX/CRT cycle, catalyzes the oxidation and isomerization of the disulfide bonds in glycoproteins. Further, CRT elicits an immune response through the assembly of major histocompatibility complex (MHC) class I molecules for eventual antigen presentation on the cell surface, intended for apoptosis [60].

#### **6.3 Thiol oxireductases**

Formation of transient disulfide bonds in the protein folding process are mediated by thiol oxidoreductases and are essential for the activation of the PERK pathway [56]. These are the major proteins that redox control by utilizing catalytic cysteine residues for oxidation or reduction of their substrates. Protein disulphide isomerase (PDI), ERp72, ERp61, GRP58/ERp57, ERp44 and ERp29 are enzymes that mediate the formation of disulphide bonds through oxidizing cysteine residues of nascent proteins. However, most of the thioloxidoreductases act as oxidants [61] and in certain cancer models, ERp57 as well as PERK gets activated in a PDI dependent manner, reducing cancer cell proliferation and sensitizes cancer cells to ionizing radiation [62].

Hsp47 (Serpin H1) is an ER-resident collagen-specific molecular chaperone that is essential for molecular maturation of collagen. Hsp47 binds Yaa-Gly-Xaa-Arg-Gly in triple-helical procollagen in the ER via hydrophobic and hydrophilic interactions. The binding of Hsp47 stabilizes procollagen by preventing unfolding of the triple helix and aggregate formation. Thus, Hsp47 is indispensable for efficient secretion, processing, fibril formation, and deposition of collagen in the extracellular matrix [63]. The chaperone function of Hsp47 is also involved in the deterioration of fibrosis, suggesting Hsp47 as a therapeutic target for fibrotic diseases, including liver, lung and spleen fibrosis. Lipase maturation factor 1 (LMF1) is an ER chaperone that affects ER lipid metabolism through the activation of lipoprotein, hepatic and endothelial lipases [64]. Mutations in LMF1 are associated with severe hypertriglyceridemia caused by deficiency of these lipases.

#### **7. Conclusion**

Preeclampsia is the most frequently encountered medical complication in pregnancy that affects 3–7% of pregnant women worldwide, characterized by de novo on-set of hypertension, proteinuria after 20 weeks of gestation, entailing the heterogeneous etiological disease manifestations. Placental dysfunction due to reduced perfusion, trophoblast remodeling, oxidative stress, ER stress and exaggerated inflammatory response are the major factors that contributes to early on-set preeclampsia. Numerous reports substantiate that ER stress, protein misfolding and aggregation are the major inducers behind the etiological manifestations of PE, leading to disease pathogenesis [65, 66]. Furthermore, amyloid fibrous protein

*Cellular Functions of ER Chaperones in Regulating Protein Misfolding and Aggregation… DOI: http://dx.doi.org/10.5772/intechopen.101271*

aggregates are an emerging biomarker of PE representing amyloid aggregation of amyloid β, transthyretin, immunoglobulin light chains and alpha-1 antitrypsin. These aggregated proteins mediate defective trophoblast invasion and abnormal remodeling of spiral arteries leading to the onset of PE. This unveils new strategies to identify novel biomarkers as well as targets for therapeutic intervention, to alleviate the underlying pathological conditions and decrease the risk of preeclampsia.

### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Janaranjani Murugesan1 , Ajithkumar Balakrishnan1 , Premkumar Kumpati2 and Hemamalini Vedagiri1 \*

1 Department of Bioinformatics, Bharathiar University, Coimbatore, Tamil Nadu, India

2 Department of Biomedical Science, Bharathidasan University, Tamil Nadu, India

\*Address all correspondence to: hemamalini@buc.edu.in

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## Section 4 Organ Dysfunction

#### **Chapter 4**

### Preeclampsia: From Etiopathology to Organ Dysfunction

*Nissar Shaikh, Seema Nahid, Firdous Ummunnisa, Ifrah Fatima, Mohamad Hilani, Asma Gul, A. Al Basha, W. Yahia, F. Al Hail, H. Elfil, E. Abdalla, M.M. Nainthramveetil, M.A Imraan, Muhammad Zubair, Sibghatulla Khan, N. Korichi, S. Alkhawaga, H. Ismail, S. Yaqoob and Mashael Abdulrahman M.S. Al Khelaifi*

#### **Abstract**

Preeclampsia is a hypertensive disorder of pregnancy affecting 6–12% of the population. There are various risk factors for the development of preeclampsia, ranging from advanced maternal age to genetics. The proposed etiologies for preeclampsia are abnormal placentation, immunological intolerance, endothelial damage, and genetic inheritance. The pathogenesis includes endothelial activation and dysfunction leading to vasospasm. Preeclampsia is divided into two stages: asymptomatic and symptomatic stages. Preeclampsia causes multiple organ involvement, namely central nervous system, respiratory, cardiovascular, hematological dysfunction, HELLP (hemolysis elevated liver enzymes, low platelets) syndrome, endocrine, renal, hepatic, and uteroplacental dysfunction. These organ dysfunctions increase morbidity and mortality in preeclamptic pregnant patients.

**Keywords:** abnormal placentation, etiology, endothelial dysfunction, epidemiology, hypertensive disorders of pregnancy, HELLP syndrome, long-term impact, multiple organ dysfunction, preeclampsia, risk factors, uteroplacental malfunction

#### **1. Introduction**

Hypertension is a common pregnancy-specific medical disorder, which is a significant cause of maternal and perinatal mortality [1]. There is disproportionate risk to the mother and fetus for further complications and long-term sequelae.

Preeclampsia is a hypertensive disorder of pregnancy causing multi-organ dysfunction syndrome with placental dysfunction occurring in the latter half of pregnancy, with major cause of maternal morbidity, maternal intensive care admissions, Cesarean section, end-organ damage, and fetal complications.

#### **2. Definition**

Preeclampsia is defined as new onset of hypertension with or without proteinuria or new onset hypertension with evidence of end organ dysfunction after 20 weeks gestation or postpartum in a previously normotensive woman [2].

Classification of hypertension in pregnancy by ACOG (American College of Obstetrician and Gynecologist) 2013 task force:

	- Preeclampsia without severe features
	- Severe preeclampsia with severe features

Progress of preeclampsia is divided into two stages:

#### **2.1 Asymptomatic first stage**

It occurs early in pregnancy with impaired remodeling of the spiral arteries and abnormal placentation. This failure of normal angiogenesis results in superficial placentation.

#### **2.2 Symptomatic second stage**

It presents in late second or third trimester and is characterized by signs and symptoms distinguished by the release of excess of antiangiogenic factor from intervillous space into the maternal circulation, which causes widespread maternal endothelial dysfunction and accentuated systemic inflammatory response specific to each organ system.

#### **3. Epidemiology**

It affects 6–12% of all pregnant women worldwide, with preeclampsia in 5–8% of pregnancy [3, 4]. The WHO (World Health Organization) has identified hypertension as the second most common cause of maternal death among the triad of hemorrhage and sepsis [5]. It is responsible for 70,000 maternal deaths (major cause of maternal morbidity and mortality) and 500,000 fetal deaths worldwide every year [5]. Nulliparous women are prone to develop preeclampsia, while older women are at higher risk of chronic hypertension with superimposed preeclampsia.

Hypertension is well known in pregnancy worldwide, including chronic, gestational, and possible dangerous preeclampsia [6]. It is considered as high-risk pregnancy when unfavorable conditions prevail for the well-being of mother, fetus, or both.

Effective antenatal care with good surveillance minimizes the risk of complications. Hypertensive disorders of pregnancy can result in life-threatening multisystem pathology, affecting nervous, hematological, renal, hepatic, and respiratory systems.

Preeclampsia presents with maternal features of hypertension, proteinuria, and systemic dysfunction with or without fetal syndrome. Thus, proteinuria is an objective marker and reflects the system-wide endothelial leak that characterizes the preeclampsia syndrome.

There has been an alarming 30% increase in incidence of hypertensive disorders of pregnancy [7], which is explained by the demographics of increase in maternal age, obesity, and increase in use of assisted reproductive techniques, which alters the maternal-fetal immune response. It is also influenced by genetic predisposition, race, and ethnicity.

#### **4. Risk factors**

Numerous preconceptional and pregnancy-related risk factors are identified and classified in development of preeclampsia.

#### **4.1 Advanced maternal age**

There has been variation of maternal age of pregnancy from teenage to women who are 40 years or older, as compared with women between 20 and 29 years [8] of age, with approximately twofold increase in risk of preeclampsia. Hispanic ethnicity may be at increased risk of developing preeclampsia [9]. Women with advancing age and delayed childbirth show a substantial increase in chronic hypertension during pregnancy and are at increased risk of preeclampsia.

#### **4.2 Genetic factors**

Maternal and fetal genetic factors carry strong risk for preeclampsia, with one-third attributable to maternal genetic factors [10]. Women are twice as likely to develop the disorder if they have a family history of preeclampsia, [11] and the risk increases with multiple affected pregnancies [12], potentially carrying high-risk outcomes of placental abruption and fetal growth restriction. Women with history of preeclampsia in previous pregnancy are at increased risk in subsequent pregnancy, particularly in the early onset of preeclampsia.

Partner-related risk factors are long considered a disease of primigravida in women due to limited paternal sperm antigens exposure before conception, which suggests an immunological role in pathophysiology of preeclampsia, with its incidence approximately threefold higher as compared to parous women [13]. A significant contribution of paternal genes (in the fetus) was identified as risk, with one-fifth of the variance in liability conferred through fetal genes in preeclampsia [14].

#### **4.3 Metabolic factors**

With worldwide increase in prevalence of obesity, risk of preeclampsia escalates with increasing body mass index (BMI) [15]. A systemic review found that an increase in BMI of 5–7 Kg/m was associated with a twofold increased risk of preeclampsia; it also has strong association with insulin resistance and chronic hypertension, elevating the risk of preeclampsia [16].

Other maternal medical conditions with recognized risk factors for preeclampsia are chronic renal disease, antiphospholipid antibody syndrome, and systemic lupus erythematosus [17] and pregnancy-related conditions with increased placental mass, including multiple fetal gestation and hydatidiform mole, are associated with higher rates of preeclampsia as well [18].

Associated metabolic syndrome, chronic disorders hypertension, preexisting diabetes, and renal diseases that cause endothelial injury are risk factors for preeclampsia. This explains the similar tendency of endothelial dysfunction and common factor for association of preeclampsia with increased future cardiovascular diseases [19].

#### **4.4 Behavioral factors**

Cigarette smoking during pregnancy decreases the risk of preeclampsia [20] by 30–40% as compared to women who do not smoke although biological mechanism remains unknown but probable mechanism may include nicotine inhibition of thromboxane A2 synthesis [21], simulation of nitric oxide release, or combination of both.

#### **4.5 Recreational physical activity**

Physical activity during pregnancy is associated with decreased risk for preeclampsia in non-obese women [22]. This occurs by decreasing oxidative stress, enhancing endothelial function, and modulating the immune and inflammatory response.

#### **5. Evtiology**

The exact cause of initiation and progress of the disease process is not known, with placenta being the focus in pathogenesis.

Following theories have been proposed to explain mechanics causing preeclampsia.


#### **5.1 Abnormal placentation**

In physiological pregnancy, embryo-derived endovascular cytotrophoblast invades the decidual (10–12 weeks) and myometrial (16–18 weeks) segment of spiral arterioles of uteroplacental bed, replacing endothelial lining [23] and causing remodeling of vascular smooth muscles and inner elastic lamina (**Figure 1**). These physiological changes lead the maternal spiral arterioles to distend the luminal diameter fourfold, resulting in creation of tortuous and funnel-shaped flaccid [23] tubes that provide a low-resistance, low-pressure, high-capacitance, high-flow pathway into intervillous space, which gets further remodeled and unresponsive to vasoactive stimuli. These alterations in maternal vasculature ensure adequate blood flow to nourish the growing fetus and placenta.

In preeclampsia, endovascular cytotrophoblast invasion may be incomplete [24] and only the decidual vessels undergo change, while the deeper myometrial arterioles do not lose their endothelial lining and musculoelastic tissue, resulting in narrowing of maternal spiral arterioles (**Figure 1**), thus impairing placental blood flow and remaining hyperresponsive to vasomotor stimuli. Inadequate spiral arteriolar remodeling leads to narrowing of maternal vessels and relative placental ischemia.

*Preeclampsia: From Etiopathology to Organ Dysfunction DOI: http://dx.doi.org/10.5772/intechopen.101240*

#### **Figure 1.**

*A-Normal pregnancy uterine spiral arteries are wide open and remodeled by endovascular trophoblast, thereby increasing blood flow B-Preeclampsia women spiral arteries fail to remodel due to defective trophoblast invasion.*

The severity of the disease correlates with the magnitude of defective trophoblastic invasion [25]. Atherosclerotic changes in maternal radial arteries that supply decidua are observed in preeclampsia. Decidual vasculopathy lesions have high association in preeclampsia with placental insufficiency, including intrauterine growth restriction and small for gestational age [26]. These changes correspond to symptomatic second stage of the preeclampsia syndrome with systemic inflammatory response [27].

In association with defective remodeling of uteroplacental vasculature, there may be presence of agonistic autoantibodies to the angiotensin receptor-1 (AT1) [28]. These autoantibodies activate AT1 receptors, endothelial cells, and vascular smooth muscle cells [29]. The autoantibodies appear to block trophoblastic invasion and may induce the production of reactive oxygen species that plays a significant role in the pathogenesis of preeclampsia at several different stages [29].

#### **5.2 Immunological factors**

Maternal immune tolerance to parentally derived placental and fetal antigens is lost at maternal-placental interface, which is suggestive of acute graft rejection. The abnormal uteroplacental development is not clearly understood but is likely due to complex interaction of immunologic, vascular, environmental, and genetic factors. The theory of immune maladaptation may play a central role in predisposition to abnormal placentation and subsequent preeclampsia, suggesting that long-term exposure to paternal antigens in sperm is protective.

In preeclamptic women, extravillous trophoblast in early pregnancy expresses reduced amounts of immunosuppressive non-classic human leukocyte antigen G (HLA G). These changes contribute to defective placental vascularization in stage 1 of preeclampsia syndrome [30].

Excess macrophages in the decidua are associated with impaired trophoblast invasion and impaired placentation, signifying excess inflammation. NK cells interact with fetal trophoblast cell markers *via* killer immunoglobulin receptors (KIR) to influence trophoblastic invasion. Specific genotypic combinations of maternal KIR and trophoblastic human leukocyte antigen C (HLA-C) may increase the risk for preeclampsia. Systemic review of 22 studies examining association between HLA type and risk of preeclampsia suggests that HLA-DR correlates with preeclampsia, but it is unclear if this or any other HLA genotype is casually related to preeclampsia risk; further large sample size studies are called to examine maternal-fetal HLA combinations and risk of preeclampsia [30].

Etiology of preeclampsia is summarized in **Figure 2**.

#### **6. Pathogenesis**

#### **6.1 Endothelial activation or dysfunction causing vasospasm**

Inflammatory changes are said to be a continuation of stage 1 alternation. Placental factors are released in response to ischemia, and a cascade of events is provoked in response to antiangiogenic and metabolic factors and other inflammatory leukocyte mediators, commonly called endothelial cell activation or dysfunction. Systemic endothelial cell injury with intense vasospasm is from imbalance of vasodilators (PGI, NO), vasoconstrictors (Angiotensin-II, Thromboxane A2, and Endothelin-II), oxidative stress, and inflammatory mediators (**Figure 3**). Vasospasm exerts a damaging effect on blood vessels and causes endothelial cells to contract and, together with hypoxia, leads to hemorrhage, necrosis, and compromised end-organ function.

In preeclampsia, inflammatory mediators contributed by systemic oxidative stress are tumor necrosis factor [31] alpha (TNF-Alpha) and interleukins that in turn lead to formation of lipid peroxidases [32], producing toxic radicals that injure systemic vascular endothelial cells.

Mechanisms are precisely understood but proposed theory discussed are as follows:

• Increase in circulatory pressor substances.

#### **Figure 3.**

*A: In normal pregnancy. B: Vasoconstriction in preeclampsia.*

	- Genetically predisposed to hypertension developing during pregnancy.
	- Imbalance of angiogenic and antiangiogenic proteins.

#### **6.2 Endothelial cell injury**

Injury to systemic endothelial cell is crucial in pathogenesis of preeclampsia and likely secretes placental protein factors into maternal circulation, which provokes activation and dysfunction of systemic vascular endothelium, producing less nitric oxide contributing to vasoconstriction, and promotes coagulation and greater sensitivity to vasopressors.

#### **6.3 Increased pressor responses**

Normal pregnant women develop blunted vascular pressor response selectively to pressor agent angiotensin II, mediated by synthesis of endothelial prostaglandin and nitric oxide, which is a potent vasodilator. Following preeclampsia, angiotensinase activity is depressed, and the presence of autoantibodies to angiotensin AT1 receptor increases the vascular sensitivity to pressor agent angiotensin-II (**Figure 4**).

**Figure 4.**

*Imbalance of increased thromboxane and decreased prostacyclin in preeclampsia.*

#### **Figure 5.**

*Normal pregnancy: signaling of vascular hemostasias is maintained by physiological level of Vascular endothelial growth factor (VEGF) and Transforming growth factor (TGF). (B) In preeclampsia: excess secretion of Sflt1 (soluble fms- like tyrosine kinase) and sENG (soluble endoglin protein) inhibits VEGF (Vascular endothelial growth factor) and TGF (transforming growth factor) signaling of vasculature.*

#### **6.4 Angiogenic and antiangiogenic proteins**

There is an imbalance of proangiogenic (VEGF) [33] and antiangiogenic (soluble fms-like tyrosine kinase sFlt-I) proteins in placental vascular bed. Soluble fms-like tyrosine kinase 1 (sFlt-1) has a receptor for VEGF (**Figure 5**).

With the progress of pregnancy, the placenta becomes relatively hypoxic at uteroplacental interface and results in an overexpression and release of placentally derived antiangiogenic peptide factors from the trophoblastic tissue, including sFlt-1 and soluble endoglin protein (sEng) into the maternal circulation, which appears to be important in pathogenesis of preeclampsia and remains the underlying theory [34]. Endothelin-I is synthesized by endothelial cells and is a potent vasoconstrictor causing hypertension (**Figure 5**).

In preeclampsia, sFlt-1 is a soluble antiangiogenic protein that is elevated, which binds and inactivates or reduces biological activity of free-circulating proangiogenic proteins, vascular endothelial growth factor (VEGF), and placental growth factor (PIGF), causing endothelial dysfunction [35].

### **7. Systemic organ dysfunction and complications**

Severe manifestations of preeclampsia occur in all body systems because of widespread endothelial dysfunction, making diagnosis difficult due to similar clinical presentation despite complex differences in their underlying pathophysiology and prognosis.

Numerous factors combine to exert vasoactive effects in preeclampsia [36], causing resistance to blood flow and accounts for the development of arterial hypertension. Systemic organ dysfunction is explained in **Figure 6**.

#### **7.1 Central nervous system dysfunction**

Two marked cerebral pathologies are gross hemorrhage and ischemia, with other common variable lesions noted are edema, hyperemia, and thrombosis.

Manifestations of the central nervous system are severe headache, hyperexcitability, hyperreflexia, and coma attributable to hypoxia. Reversible vasogenic cerebral edema occurs commonly due to endothelial dysfunction of the brain in preeclampsia and eclampsia. Failure of autoregulation with reduced global cerebral blood flow and hyperperfusion commonly occurs in posterior circulation, such that the changes in the brain of patients with preeclampsia/eclampsia result in posterior reversible leukoencephalopathy syndrome (PRES) [37].

Intense ocular arteriolar constriction may cause visual disturbances, and may include blurred vision, scotoma, amaurosis [38], and retinal detachment (**Figure 7**).

Airway: In normal healthy pregnancy, the internal diameter of the trachea is reduced because of mucosal capillary engorgement, which can be exaggerated with narrowing of upper airway, resulting in pharyngolaryngeal edema, and subglottic edema with signs of airway obstructions such as dysphonia, hoarseness, snoring, stridor, and hypoxemia; these changes may compromise visualization of airway landmarks during direct laryngoscopy making intubation difficult [39].

**Figure 6.** *Etiopathogenesis of preeclampsia.*

**Figure 7.** *PRES syndrome.*

#### **7.2 Respiratory system dysfunction**

Pulmonary edema occurs in approximately 3% of preeclamptic women [40]. It is relatively infrequent in young healthy women than multiparous women. Decreased colloid osmotic pressure, in combination with increased permeability and the loss of intravascular fluid and protein into the interstitium, increases the risk for pulmonary edema [41]. Endothelial activations lead to extravasation of intravascular fluid into the extracellular space and, importantly, into the lungs. Excess intravenous fluid administration is an important risk factor for pulmonary edema in preeclampsia patients [42].

#### **7.3 Cardiovascular system dysfunction**

Common cardiovascular disturbances in preeclampsia syndrome are increased afterload caused by hypertension and reduced preload by pathologically diminished volume expansion during pregnancy.

Preeclampsia is a hyperdynamic state with increased vascular tone and increased sensitivity to vasoconstrictor, resulting in clinical manifestation of hypertension, vasospasm, and end-organ ischemia [43]. Hemodynamic response to circulatory catecholamine is exaggerated and characterized by severe vasospasm. Typically, blood pressure and systemic vascular resistance are elevated.

The majority of preeclamptic women show increased cardiac output [44], mildto-moderate increased systemic vascular resistance [45], and hyperdynamic left ventricular function.

In summary, aggressive fluid administration in severe preeclampsia substantially elevates left-sided filling pressures and cardiac output to hyperdynamic levels. This elevates pulmonary capillary wedge pressure, causing pulmonary edema despite normal ventricular function.

#### **7.4 Hematologic system dysfunction**

Increase in blood volume is not evident in severe preeclampsia due to vasospastic state that follows endothelial activation and worsens with increased vascular permeability, and leakage of plasma into the interstitial space, resulting in increased hemoconcentration and hematocrit values that signify preeclampsia. These women with severe hemoconcentration are unduly sensitive to blood loss at delivery than normal [45].

#### **7.5 Maternal thrombocytopenia**

Thrombocytopenia is the most common hematologic disorder with platelet count of less than 100,000/mm3 in severe preeclampsia disease or HELLP (hemolysis elevated liver function low platelets) syndrome [46] that creates a hypocoagulable state correlating with the severity of the disease process.

In preeclampsia [47], platelets are activated, subsequent degranulation accounting for decrease in platelet function, and aggregation appears to account for the decrease in platelet count.

HELLP syndrome: It is characterized by hemolysis, elevated levels of liver enzymes, and low platelet count. It is associated with increased rates of maternal and perinatal morbidity. Weinstein coined the acronym HELLP. Women who do not reveal one or more of the clinical features is called partial HELLP syndrome [48].

Clinical presentation of maternal signs and symptoms vary from right upper quadrant or epigastric pain, nausea and vomiting, headache, hypertension, and proteinuria, and 12–18% of women may be normotensive and 13% may be without proteinuria. Clinical management has to prioritize maternal stability, particularly, hypertension and Coagulation abnormalities, and assess the fetal condition *via* FHR monitoring. Risk of postpartum hemorrhage is significantly increased in HELLP patients [48].

#### **7.6 Hemolysis**

Severe preeclampsia is frequently accompanied by microangiopathic hemolysis that manifests as elevated lactate dehydrogenase, reduced haptoglobin levels, hemolytic anemia, and abnormal peripheral blood smear with schistocytes, spherocytes, and reticulocytosis [49].

#### **7.7 Coagulation changes**

Disseminated intravascular coagulation is a syndrome secondary to microthrombi formation in severe preeclampsia with liver derangement [50]. Activation of coagulation system is marked by consumptions of procoagulants, increased levels of fibrin degradation products, and end-organ dysfunction. In advanced stages of DIC (disseminated intravascular coagulation), it may cause spontaneous hemorrhage, intrauterine fetal demise, placental abruption, or postpartum hemorrhage.

#### **7.8 Endocrine and hormonal alternations**

Plasma levels of renin, angiotensin I & II, aldosterone, deoxycorticosterone, and atrial natriuretic peptide (ANP) are substantially increased during normal pregnancy, which is further enhanced in preeclampsia women.

#### **7.9 Fluid and electrolyte alterations**

Extracellular fluid manifests as edema with pathological fluid retention in women with severe preeclampsia due to endothelial injury. In addition to generalized edema and proteinuria, these women have reduced plasma oncotic pressure, which creates a filtration imbalance and further displaces intravascular fluid into the surrounding interstitium, creating intravascular dehydration and extravascular overhydration. Electrolyte concentration does not differ grossly in preeclampsia patients.

#### **7.10 Renal dysfunction**

Defining component of preeclampsia is proteinuria, with its renal manifestations of persistent proteinuria, changes in glomerular filtration rate, renal blood flow, and hyperuricemia. In preeclampsia serum markers, blood urea nitrogen BUN, creatinine, and uric acid reflect a decrease in renal functions. Hyperuricemia (elevated uric acid levels) is one of the recognized early predictors of preeclampsia, with the primary mechanism of decreased renal clearance [51]. High level of serum uric acid correlates with the severity of the disease. Glomerular endotheliosis is the main feature of the preeclamptic kidney defined by endothelial swelling and glomerular capillary narrowing.

Oliguria is a probable late manifestation and parallels the severity of preeclampsia. Persistent oliguria (< 500-mL urine output in 24 hours) requires immediate attention for evaluation of intravascular volume status.

Major pathological process of acute renal failure in preeclampsia (83–90%) is from prerenal and intrarenal pathology (most commonly acute tubular necrosis), which resolves completely after delivery.

#### **7.11 Hepatic dysfunction**

Reduced blood flow to the liver may lead to periportal necrosis and are at risk of periportal hemorrhage, fibrin deposit, subcapsular bleeding, and hepatic rupture.

Hepatic involvement frequently presents as right upper quadrant or epigastric pain and accounts for 32% maternal mortality rate [50].

Rupture of a subcapsular hematoma of the liver is a life-threatening complication that can manifest as abdominal pain, which worsens over time and becomes localized to the epigastric area or right upper quadrant associated with nausea, vomiting, and headache. Alarming hypotension and shock develop with enlarged and tender liver. Diagnosis of liver subcapsular hematoma is confirmed by ultrasonography, computerized tomography (CT), or magnetic resonant imaging (MRI). The most common cause of death is coagulopathy. Conservative management is recommended for subcapsular hematoma or intraparenchymal hemorrhage without capsular rupture in stable women with an important component to avoid all potential trauma to the liver.

#### **7.12 Uteroplacental malperfusion**

Uteroplacental perfusion can be impaired in pregnancies complicated by preeclampsia with increased downstream resistance in the uteroplacental bed, decreased diastolic flow velocity, and increased systolic-diastolic flow velocity ratio [51]. Reduced uteroplacental malperfusion is considered one of the major causes of fetal compromise (IUGR, premature birth, and perinatal death). Risk of placental abruption is increased threefold with increased perinatal morbidity and mortality in preeclampsia women [51].

#### **8. General principles and management**

• Definite treatment of preeclampsia is termination of pregnancy to prevent disease progression and reduce maternal complications and neonatal morbidity. Time of delivery is based on gestational age, severity of preeclampsia, and maternal and fetal condition.


#### **9. Long-term consequences**

**Table 1** describes long-term complications of preeclampsia syndrome.


**Table 1.**

*Long-term impact of preeclampsia.*

#### **10. Conclusion**

Preeclampsia is one of the hypertensive disorders of pregnancy with increased morbidity and mortality. It occurs in up to 12% of pregnancies. Advanced maternal age, genetic factors, obesity, and chronic renal impairment increase the risk of preeclampsia in pregnant patients. Abnormal placentation, immunological changes, endothelial injury and activation, and increased pressor response are the pathogenesis of preeclampsia.

Due to these generalized endothelial changes, the preeclampsia patients develop multiple organ dysfunction, including PRES (posterior reversible encephalopathy) syndrome, pulmonary edema, HELLP syndrome, acute kidney injury, and uteroplacental insufficiencies.

Management of preeclampsia is supportive therapy, blood pressure control, and seizures prevention and delivery of the fetus. Long-term effects of preeclampsia are chronic hypertension, stroke, and chronic kidney disease.

*Preeclampsia*

#### **Author details**

Nissar Shaikh1 \*, Seema Nahid2 , Firdous Ummunnisa3 , Ifrah Fatima4 , Mohamad Hilani4 , Asma Gul4 , A. Al Basha4 , W. Yahia2 , F. Al Hail4 , H. Elfil1 , E. Abdalla1 , M.M. Nainthramveetil<sup>2</sup> , M.A Imraan2 , Muhammad Zubair2 , Sibghatulla Khan2 , N. Korichi4 , S. Alkhawaga4 , H. Ismail4 , S. Yaqoob4 and Mashael Abdulrahman M.S. Al Khelaifi4

1 Surgical Intensive Care Unit: Hamad Medical Corporation, Doha, Qatar

2 Department of Anesthesia/ICU and Perioperative Medicine: Hamad Medical Corporation, Doha, Qatar

3 Dr. Halima Al Tamimi, Obstetrics and Gynaecology Centre, Doha, Qatar

4 Women Wellness and Research Center: Hamad Medical Corporation, Doha, Qatar

\*Address all correspondence to: nissatfirdous99@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Preeclampsia: From Etiopathology to Organ Dysfunction DOI: http://dx.doi.org/10.5772/intechopen.101240*

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[28] Saftlas AF, Beydoun H, Triche E. Immunogenetic determinants of preeclampsia and related pregnancy disorders: A systematic review. Obstetrics and Gynecology. 2005; **106**:162-172

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Section 5

## Gestational Endothelialpathy

#### **Chapter 5**

## Gestational Endotheliopathy as Trigger Disorder of Haemodynamics Pregnancy Supply

*Dmytro Konkov, George Belkania, Levon Dilenyan, Victor Rud, Liana Puchalska, Alina Piskun and Larisa Klimas*

#### **Abstract**

The idea for this study is based on endothelial-dependent adaptation of hemodynamic circulation in pregnancy. The optimization of the circulatory component of the cardiovascular system (CVS) during pregnancy via blood pressure (BP), especially in physiological pregnancy (PhP), is accompanied by a clear overall increase in systolic characteristics of the pumping function of the heart. This orientation in cardiac output (CO) is unambiguously manifested throughout all three trimesters as with PhP—in a prone and standing position in total according to 24 characteristics out of 24 (*P* < 0.01), while for gestational endotheliopathy (PaP)—by 18 out of 24 (*P* < 0.05) clear restructuring of the dynamic organization of the circulatory state according to the anthropophysiological ratio to the hyperkinetic state according to CO in a standing position (type III) was noted with all blood pressure (BP) regimes. If the manifestation of type III under hypotonic, normotonic, and hypertonic regimes in BP was 8, 12, and 6%, respectively, then in the case of PhP, it was 21, 36, and 50%, respectively (*P* < 0.01), and for PaP, it was 48, 66, and 76% (*P* < 0.01). Hemodynamically identified heart failure (HF) syndrome, as the earliest preclinical circulatory endothelial-dependent form, is examined as a trigger of formation of perinatal pathology corresponding to preeclampsia.

**Keywords:** pregnancy, gestational endotheliopathy, perinatal pathology, cardiovascular system, circulation, pumping function of heart, cardiac output, cardiac index, heart failure

#### **1. Introduction**

In early gestational age, the decidua has been extensively studied to define the spiral artery remodeling process that occurs during pregnancy. The remodeling results from a complex interaction between maternal decidual immune cells in the uterine wall and invasive trophoblasts. During remodeling the arterial muscular layer is replaced by fibrinoid material, and the arterial diameter increases 4–12-fold [1, 2]. The process of optimal trophoblast invasion is often defective in preeclampsia, particularly in early-onset preeclampsia, affecting the endothelium (gestational endotheliopathy) but not the interstitial invasion pathway; the remodeling of

myometrial spiral artery segments is particularly affected. However, defective remodeling is also seen in other cases of perinatal pathology and even rarely in normal pregnancy. The resulting abnormal uteroplacental flow is associated with placental oxidative stress, probably from ischemia reperfusion injury of the placenta. It is not known why some woman with gestational endotheliopathy develop preeclampsia, while others do not [3–6].

It is important to understand that all organism mechanisms providing pregnancy depend, foremost, on the hemodynamic system and the priority role of the perfusion complex (volume–tube–pump–pressure–blood flow)—pumping function of heart. More research assures that preeclampsia is examined not so much as the first event in subsequent development for women with cardiovascular diseases [7], but rather as a special circulatory state due to not insufficient, in our view, but tense adaptation of the CVS [8–10] in women, as straight-walking creatures, in pregnancy. However, a faithful a faithful parcel in determination of relations reason-result determines the necessity of establishment of certain factor or terms, according to which such adaptations show up in the CVS in pregnancy, and also determination of hemodynamic structure of perfusion mechanisms lying in and defining the orientation of this adaptation at physiological and pathological pregnancy. Such synergy substantially impacts tension of adjusting of blood circulation on a gravitational factor, especially in the upright position. In turn, antigravity tension of the CVS affects the blood circulation of pregnant women, which is critical for maintenance and development of fetoplacental circulation of blood. The real influence of formed biophysical terms related to pregnancy shows up from the second half of pregnancy, on circulation of blood and in the lying position [10–12].

Some studies have shown an association that displays growth of circulatory tension and gestational endotheliopathy of typology alteration of dynamic organization of CVS with growth of hyperkinetic state of circulation of blood in position straight standing-type III of antropophysiological correlation (upright/lying, %), minute volume of blood (MVB), system resistance of arterial vessels, especially on circulatory responsible regions (abdominal and pelvic circulation of blood), often combining with the ischemic state, together with the increase of hemodynamically identified [13, 14] circulatory syndromes of heart failure (HF). Obtained data suggest that antigravity tension of the CVS is a circulatory basis for both early and late preeclampsia. It is thus necessary to mean that blood pressure (BP) in pregnant, to that attention is brought over its determination of the state of preeclampsia, is the external display (a result, but not reason) of adaptation changes of all difficult complex of maternal circulation of blood, especially its basic mechanisms of perfusion, in the hemodynamic fetoplacental complex and, actually, organism of pregnant. Orthostatic proteinuria, which in preeclampsia is associated with arterial high BP, reflects tension of kidney link in the adaptation of the CVS to the gravitational factor of circulation of blood and out of pregnancy [15, 16].

*The aim of this study is antropophysiological analysis of the circulatory state of the CVS in PhP and pregnancy with gestational endotheliopathy as a trigger, in the development of hemodynamic supply disorder in pregnancy and perinatal pathology (PaP).*

#### **2. Materials and methods**

The study was performed at the National Pirogov Memorial Medical University, Vinnytsya, Ukraine, under budget grant No. 0121 U109141. Observational clinical studies were undertaken on 114 women with physiological pregnancy (PhP) and 131 pregnant women with perinatal pathology (PaP). The former group consisted of 23 women in their first trimester, 38 women in their second trimester, and 55

#### *Gestational Endotheliopathy as Trigger Disorder of Haemodynamics Pregnancy Supply DOI: http://dx.doi.org/10.5772/intechopen.100737*

women in their third trimester, whereas the latter group consisted of 20 women in their first trimester, 36 women in their second trimester, and 75 women in their third trimester. A control group was formed by 115 healthy nonpregnant women. General age of pregnant women was 17–36 years (*n* = 245); only four pregnant women were older than 30 years.

We enrolled pregnant women with gestational endotheliopathy, who were diagnosed when microalbuminuria was more than 5.0 mg/mmol (screening test) and endothelium-dependent vasodilation was less than 10% (approving test).

Multicentral description of "hemodynamic model" of the examined conditions (not pregnant and pregnant women) was made basis on antropophysiological research [6] of the circulatory state of the CVS, using the diagnostic system ANTROPOS-CAVASCREEN [17], which is an innovative diagnostic complex for analyzing the performance of various blood circulation sections using noninvasive methods (thoracal and regional tetrapolar rheography, electrocardiography, BP measurement, electrometrial features of skin).

According to basic criteria and syndromal analysis of multicentral complex of hemodynamic characteristics [18–21] of the "hemodynamic model" of providing of pregnancy [22] was held special antropophysiological analysis of showing up (part in % on a selection) of the different modes is conducted on middle blood pressure (BPm) hypo-, normo- and hypertensive on positions of body upright and lying. For determining raised and lowered BPm, we used general normative descriptions of systolic BP (<140 and > 90 mmHg) and diastolic BP (<90 and > 60 mmHg). According to our special diagnostic scale, [23] group normative descriptions for BPm = BPd + 0.32\*(BPs-BPd) in the lying position were well associated with the accepted diagnostic criteria; for women up to age 35 years, BPm was 79–105 mmHg. In standing position, there have been used connected to antropophysiological characteristics correlations of BPm to its criteria in position lying (in %), that allowed to identify the adaptive orientation of adjusting on the mode of BP in position upright, in that influence of gravitational (hydrostatical) factor of circulation of blood maximally impact circulatory state of the CVS. According to used criterion and by syndromal analysis [24, 25], criteria of raised and lowered BP were identified, as well as normotensive state.

With the examined modes for BP was analyzed expression of circulatory syndromes of HF at them hemodynamically identified by diagnostic algorithm worked out by us [26], as a system estimation of pumping function of heart (PFH) in the circulatory state of the CVS. PFH additionally was estimated by trimester measuring of cardiac output (CO, ml) and cardiac index on body weight (CI, ml/kg) separately in standing and lying positions. By antropophysiological ratio of CO upright/lying (APR, %) typological description of dynamic organization of the circulatory state of the CVS was made [27]. The last was presented by three types of blood circulation: type I or hypokinetic state, with the decrease of BP in standing position (93% and less) comparing to it's size in a prone position; type II or eukinetic state, with BP of 94-106% from standing to lying position; and type III or hyperkinetic state, with increase of BP up to 107% or more in the upright position.

For the integral estimation of the analyzed condition of the CVS we additionally used system characteristics, including syndrome of greater biological age (aging, age-related depreciation) and syndrome of hemodynamic risk [5, 17] on the index of hemodynamic non-optimality (IHU > 30%), as well as regional and system estimation of syndrome of resistance (vasoconstrictions) of the arterial vessels of the head, lungs, stomach, pelvis, femur, and calf [13, 14], and increases of the systolic post-loading (post+) on the left (LV) and right (RV) ventricles of the heart.

For statistical description of obtained data methods of variation and nonparametric analysis were used with Microsoft Excel 2010. Evaluation was performed by variations of criteria of student, non-parametric to the criteria of signs and rule

of specificity of predominating of bigger part of a selection or compared sub-groups (part) in selections of "control-pregnant" and "physiological pregnancy vs pathological pregnancy" [28] with the accepted level of probability no less than 95%.

#### **3. Results and discussion**

Data on mBP for nonpregnant (control) and pregnant women were analyzed on general and actual selections on the BP mode. General selections were formed on correlation of BP "upright or lying." Decreased BP "upright or lying" is hypotonic mode ("−" marks), increased BP "upright or lying" is hypertensive mode (it marks "+"), and accordance of BP to normative limits "lying and upright" is the normotonic state ("0" marks). The actual modes were formed on the real combination of the modes for BP upright/lying with corresponding marks (−0+/−0+) (see **Figures 1** and **2**). It should be noted that in the normotonic mode—general ("0") and to the variants actual (0/−+) normative description of changes of BP upright there is however a primary increase of pressure, pressure orientation in adjusting of CVS in position upright.

#### **Figure 1.**

*Distribution of stake of people (in %) with the general modes of cardiovascular system according to BP (normotonic—Upright and lying, high blood pressure and hypotension—Upright or lying) for women of reproductive age (control) and in the first, second, and third trimesters of PhP and PaP.*

*Gestational Endotheliopathy as Trigger Disorder of Haemodynamics Pregnancy Supply DOI: http://dx.doi.org/10.5772/intechopen.100737*

It is necessary to mean that in position upright taking into account expression of the hypertensive state totally with a normative increase of BP the stake of the states of CVS of pressor orientation for women arrives at 90–92%, demonstrating actuality of the tense of pressor adjustment in adaptation of CVS to the gravitational

#### **Figure 2.**

*Distribution of types of circulation (numbers on a diagram are a stake in % on a selection) in antropophysiological ratio of cardiac output (CO) upright/lying—Hypokinetic (I), eukinetic (II), and hyperkinetic (III) at the general modes of BP (hypotension, normotension, hypertension) of the circulatory state of CVS for nonpregnant women (control), PhP, and PaP. Authenticity of distinction (D) on the types of circulation is brought between control and PhP, by control and PaP (first row), and between PhP and PaP (second row).*

(hydrostatical) factor of circulation of blood for a human as straight-walking creature. There is a background to examine it as physiological basis of forming of the hypertensive state [3, 4], including, for pregnant.

**Figure 3** shows the subsequent dynamics of this setting for pregnancy in the first and second trimesters of PhP. It shows a clear reduction of the hypertensive states to their absence in the lying position, and it is especially shown in the upright position up to the third trimester. Such dynamics at PhP demonstrate optimization of the circulatory state of the CVS, at least on the mode of BPespecially it's important for maturing of pregnancy in terms of straight-walking (sitting, upright, at walking). Clear growth of expression of hypotonic states is thus marked in the lying position, with 10% for nonpregnant women (control group) to the first (39%) and the second trimesters - 32% (*P* < 0.01).

**Figure 1** shows less expressed marked orientation in distribution of the modes for BP in the upright position determined at PaP. The hypertensive state is absent only in the first trimester. It appears in the second and third trimesters, though at lower levels (3–5%; *P* ≤ 0.05) compared to nonpregnant women (10%). For PaP, the hypertensive states are present in the lying position during all three trimesters, increasing three times (from 5% for nonpregnant women to 15% in PaP; *P* < 0.05).

#### **Figure 3.**

*Dynamics of the hemodynamic providing of physiological pregnancy (PhP) and pathological pregnancy (PP) on a cardiac index (CI = CO/kg body weight) in the lying and upright positions (marked by figures) and on antropophysiological correlation (APR = CO upright/lying, in %)—Index of typology alteration of dynamic organization of the CVS.*

*Gestational Endotheliopathy as Trigger Disorder of Haemodynamics Pregnancy Supply DOI: http://dx.doi.org/10.5772/intechopen.100737*

It should be noted, that according to optimization of the state of the CVS on the mode of BP for pregnant raising of systolic function of heart, especially clearly expressed at physiological pregnancy, was marked. **Table 1** presents the data on MBV, on positions lying SI and APF and upright in the first, second, and third trimesters of pregnancy. For analysis, we used an average (*X* ± *m*x) and nonparametric statistical descriptions of hemodynamic parameters: median (*Me*) and percentile range. The *k*-value of percentile was determined with 95% probability


*Statistical parameters of selection: the first row of digital data is a median (Me) of selection, second row is a percentile range (k0–k1) with 95% probability (P* ≤ *0.05), and the third row is an average by the c error of middle (X ± mx).*

#### **Table 1.**

*Cardiac output for nonpregnant women in control group and for pregnant women (first, second, and third trimesters).*

(*P* ≤ 0.05) taking into account a sample size, percentile with *k* ≥ 0 was determined as the lower limit of the percentile range, and *k* ≥ 1 was determined as the higher limit. For convenience, shorthand signs will be used for -lower (*k*0) and overhead (*k*1) percentile.

MVB (minute volume of blood), APR (antropophysiological correlation), and CI (cardiac index) are homogeneous hemodynamic indexes and therefore they are taken for systole descriptions (parameters) of the hemodynamic providing of pregnancy on the pumping function of heart. A non-standard approach was used to estimate the differences of these descriptions in nonpregnant women (CG) and between PhP and PaP. Each one, of the estimated hemodynamic parameters (MBV, APF, and SI), as marked higher, on one or another condition (trimester, lying, upright) used, four descriptions, that is driven in **Figure 1** in order of their placement—*Me*, *k*0–*k*1, *X*.

Analyzing of the dynamics generally in all trimesters, was conducted by three hemodynamic criteria – MBV, CI (in a prone and standing position) and APR, in every separate trimester; a total number makes 20 descriptions. In comparison with a control group, and also PP and PaP, on non-parametric criteria; the amount of the descriptions is taken to the account with unidirectional difference (anymore, less than, absent).

Optimization of the circulatory state of the CVS during pregnancy accompanied by the clear increase of systolic descriptions on the pumping function of heart and shows up on all three trimesters, especially at PP (**Table 1**). On MBV such orientation simply shows up during all three trimesters as at PhP—lying and upright totally for 24 descriptions from 24 (*P* < 0.01) and at PaP—also for 18 from 24 (*P* < 0.05). However at development of pregnancy substantially, that the pumping function of heart provided increasing pregnant body and fetus weight, therefore the calculation of SI is oriented not to the surface of body of pregnant, but on its weight. Consideration of SI demonstrates clear weakness of systolic possibilities of the heart during PhP—in position lying on all 12 from 12 descriptions of SI lower as compared to nonpregnant, and for 11 from 12 descriptions lower as compared to PaP (see a **Table 1**). Unlike PhP at PaP the clear and increasing decline of SI was marked during all pregnancy (**Figure 3**), as compared to both nonpregnant women and PhP.

Unlike position of body lying—upright SI increases for 10 from 12 characteristics (totally for three trimesters) at PP (*P* < 0.05), while at PaP—only for 7 from 12 (*P*>). At this SI at PaP in position upright was for less comparing to PP—for 9 descriptions from 12 (*P* < 0.05). Should be noted clear change during pregnancy of correlation MBV upright/lying (in %) on the index of APF, which is the typological reflection of dynamic organization of the circulator state of CVS and demonstrated at pregnancy in position upright hyperkinetic alteration of pumping function of heart and circulatory state of the CVS. Thus, both on PhP and PaP—for 12 descriptions of APF from 12 (*P* = 0.01). However most expressed such alteration is in PaP, that totally during all three trimesters marked for 12 from 12 descriptions of APF (*P* < 0.01).

It should be noted that such alteration of typological structure of the circulator state of the CVS at pregnancy was marked at all general modes of BP (**Figure 2**). It's evident, that as compared to nonpregnant, stake of type III (in %) at PhP and PaP for increases at all three modes of BP (*P* < 0.01).

Thus at PaP it is greater comparing to PhP (*P* < 0.01), arriving at normotonic and hypertensive modes of BP of level of specific description on a selection accordingly 66 and 76%. It is necessary to underline that both these modes of BP, unlike the hypotonic mode, are the reflection of pressor adjusting of the CVS. From the data presented on **Figure 4**, its evident, that at these modes of BP pressor *Gestational Endotheliopathy as Trigger Disorder of Haemodynamics Pregnancy Supply DOI: http://dx.doi.org/10.5772/intechopen.100737*

orientation lowers representative hypokinetic state of the CVS (type I) with a decline MBV in position upright—to 10–12%.

It is necessary to mean that hemodynamic adaptation at pregnancy that was accompanied by increasing antigravity tension of CVS and that shows up in forming of the hyperkinetic state of MVB in position upright, from one side, directionally on the hemodynamic providing, increase of pumping function of heart; and, from another side, limits functional abilities of the CVS in type III.

In the conditions of such tension extreme depreciation of heart is real. Thus, there can be both the real clinical state developing during pregnancy (dystrophy, cardiomyopathy, ischemia, etc.) and hidden from standard diagnostic determination not clinically, and the hemodynamically identified transitory heart failure (tHF), as most early form of display of this state. Earlier we showed such possibility,

**Figure 4.**

*Expression (stake in %) of syndromes of transitory heart failure (tHF) at the general modes of BP for women of reproductive age (control) and in the first, second, and third trimesters of pregnancy in the upright position.*

including, in pregnancy [29], and also clear association of most expressive hemodynamic syndromes of insufficiency of circulation of blood is shown, including HF, exactly at type III of the circulatory state of CVS [30].

Thus it should be noted that at any modes of BP expression of hemodynamically identified HF for pregnant and nonpregnant women exactly in position upright maximal antigravity tension of CVS, as compared to position lying, certainly higher (**Figure 5**).

So, if nonpregnant in control group in position lying in hypotonic, normotonic and hypertensive mode of expression of HF (stake in %) made about 0, 3 and 0%, then in position upright it increased in all three modes, accordingly to 4% (*P* < 0.05), 15% (*P* < 0.01) and 24% (*P* < 0.05). In general, but even more distinctly marked correlations on primary expression of tHF in position upright determined for pregnant. Thus, clearly growing from I to III trimester (**Figure 5**). It should be noted that all trimesters did not have any fundamental distinctions of expression of HF. An exception was made only by the hypertensive mode, which made expression of HF (50%) in II trimester, comparing to III trimester (44%).

Out of antigravity tension of CVS in lying position certain features showed up on different general modes of BP. So, at normotonic general orientation is traced—from the clear display of optimization of the circulatory state of CVS in I trimester with absence of CH to the increase of its expression in III trimester to 7% (*P* = 0.05). Absence of tHF in position lying for pregnant of "general" hypertensive mode and in II and in III trimesters attracts attention.

Another feature in position upright and lying of the circulatory state of CVS on the analyzable "general" modes of BP is differentiation of display of tHF on a right and left heart, and also on basic circulatory syndromes—on the syndrome of decline of arterial perfusion and syndrome of venous stagnation and insufficiency. From data presented in **Figure 4**, clearly evident, what for nonpregnant and pregnant (totally PhP and PaP) in position upright shows up mainly HF on a perfusion type, growing from the hypotonic mode to normotonic and, especially increasing at the hypertensive mode.

When it comes to pregnant, het real increase of expression of tHF in position upright in I trimester marked at the hypotonic state (**Figure 4**). On the whole dynamics on expression of HF in I and II trimesters of pregnancy reflects to the noted optimization of the circulatory state of CVS. Especially distinctly it shows up on II trimester, that is reflected in the low level of expression of HF. Substantial feature of the circulatory state of CVS at pregnancy in position upright is a primary display of right-heart tHF of perfusion type—on **Figure 4** practically on all positions, except pregnant with the normotonic mode. It's a sign that antigravity tension of CVS for pregnant in position upright the weakest links a right heart, consequently, pulmonary hemodynamics. As a result—growing pressure in the pulmonary artery and increased post-tension on the right ventricle.

Especially meaningful is the increase of expression of tHF in position upright determined in III trimester of pregnancy, including, and mainly on a right heart. Exactly on this stage of development of pregnancy the well-known physical terms, related to the increase of the sizes of uterus and fetus, maximally strengthen their synergistic influence on adjusting of circulation of blood on a gravitational (hydrostatical) factor and corresponding antigravity tension of CVS, directed of hemodynamic providing of pregnancy and actually organism of pregnant. It is necessary to remember, that dualism is real in this biologically important adaptation—not all, that is positive for the hemodynamic providing of fetoplacental complex, is positive for pregnant women. Actually, solving such dualism determines success of physiological development of pregnancy or pathological consequences during or afterwards.

*Gestational Endotheliopathy as Trigger Disorder of Haemodynamics Pregnancy Supply DOI: http://dx.doi.org/10.5772/intechopen.100737*

#### **Figure 5.**

*General expression (stake in %) of syndromes of HF (total of left and right heart) for healthy nonpregnant women (control group) and on the general group of pregnant (total of PhP and PaP) at the "general" modes of the state of CVS for BP (hypotension, normotension, high blood pressure) in the upright and lying positions (marked by figures).*

Practically one level of expression of tHF in III trimester at all examined general modes of BP testifies to independent meaning fullness to the PFH and syndrome of tHF in expression of antigravity tension of CVS and as possible circulatory basis of insufficiency of hemodynamic adaptation in pregnancy. It gives certain grounds to suppose that it's not in the mode of BP, and in structural organization of the circulatory state of CVS, functional basis of that is made by the pumping function of heart, and actually the state of last. Actually certain mode is the result of such alteration. Thus the marker of tension of hemodynamic alteration is a transition on the cardiac output to the hyperkinetic state in position upright comparing to lying to type III of dynamic organization of the circulatory state of CVS, and by the predictor of insufficiency of adaptation of CVS, including, at pregnancy—results of hemodynamically identified by antropophysiological diagnostic algorithm of circulatory syndromes of HF. Last, as the most early circulator form of HF of perfusion type on preclinical level is a trigger of forming of dynamic organization of the

circulatory state of CVS, corresponding to the hypertensive state, including, one in pregnancy.

Therefore, there is a clear association between tHF and dynamic alteration of the circulatory state of the CVS to the hyperkinetic condition (type III) in the upright position. On **Figure 6** at the same orientation of such alteration it is clearly determined higher stakes of type III, both for nonpregnant and for pregnant, exactly in a group with the syndromes of HF. During postnatal ontogenesis in the process of adaptation to the gravitational factor of circulation of blood, a transition to III to the type of dynamic organization of the circulator state of CVS was marked, that was accompanied by general growth on CVS and the blocks of circulation of blood of syndrome of the age-related depreciation (greater biological age) of the hemodynamically risky states, especially expressed at type III. Thus clearly grew expression of syndromes of HF. There are reasons to suppose that these two constituents

#### **Figure 6.**

*Distribution of types of circulation (stake in % on a diagram) of blood on antropophysiological correlation of minute volume of blood (MVB) upright/lying—Hypokinetic (I), eukinetic (II), and hyperkinetic (III) in nonpregnant (control) women and pregnant women on the states with and without syndromes of tHF.*

#### *Gestational Endotheliopathy as Trigger Disorder of Haemodynamics Pregnancy Supply DOI: http://dx.doi.org/10.5772/intechopen.100737*

(typology alteration and HF) induce the features of dynamic organization of CVS at one or another somatic state.

Besides a trigger function, tHF was, as marked higher, by the display of antigravity tension of CVS, leading to functional depreciation of CVS and to increase of hemodynamic risk, both on the general state of circulation of blood and on the basic circulatory blocks of CVS.

At overlook of dynamic organization of the circulatory condition of CVS it is necessary to remember the state of the capacity making adjusting of CVS on the gravitational (hydrostatical) factor of circulation of blood, which is present in position upright, including for pregnant, in system vasoconstriction of arterial vessels, especially shown in vascular regions below level of heart [31]. It is necessary to notice, that in diagnostic algorithm as a syndrome of resistance, the state when indexes of arterial impedance (vascular resistance) exceed a normative increase, is fixed. Mentioned on **Figure 7** data clearly demonstrate the value of the state of heart in this system adjusting to pressor orientation, especially in position upright. Both for nonpregnant and pregnant those who have hemodynamically identified tHF, as a rule, perfusion type, in position upright marked more expressed (red blocks), as compared to the states without tHF (green blocks), system vasoconstriction. By grey color marked blocks of circulation of blood, on which distinctions are absent.

Optimization of the circulatory state of CVS during pregnancy by the regime of blood pressure, especially with FP, was accompanied by a clear overall increase in systolic characteristics of the PhP. This orientation in the cardiac minute volume (CMV, ml) unambiguously manifested itself during all three trimesters as with PhP—lying and standing in total according to 24 characteristics out of 24 (*P* < 0.01), while with gestational endotheliopathy—by 18 out of 24 (*P* < 0.05). If the manifestation of type III under hypotonic, normotonic, and hypertonic regimes in blood pressure was 8, 12, and 6%, respectively, then in case of PhP it was 21, 36, and 50%, respectively (for all *P* positions <0.01) and for PaP, 48, 66, and 76% (for all positions *P* < 0.01). For gestational endotheliopathy in all modes of blood pressure, the representativeness of the hyperkinetic state in the e pumping function of

#### **Figure 7.**

*Antropophysiological (upright and lying positions) characteristics of differences of expression (stake in %) of syndromes of hyperresistance of arterial vessels for nonpregnant (control) women and pregnant women at comparison on groups with syndromes of HF and without.*

the heart standing (type III) was significantly higher compared to PhP (*P* < 0.01). According to it, the marker of tension of hemodynamic alteration was a transition on the CMV to the hyperkinetic state in position from standing to lying—to type III of dynamic organization of the circulator state of CVS and system hyperresistance of arterial vessels, and by the predictor of insufficiency of adaptation of CVS was displayed mostly in the position upright by perfusion type, combining with circulatory syndromes limiting adaptive possibilities of arterial circulation.

For hemodynamic providing of pregnancy such system of vasoconstriction has a critical value, especially for circulatory blocks, directly responsible for hemodynamic providing of fetoplacental link—abdominal and pelvic circulation of blood. Placenta, volume of amniotic fluid, and self-weight of fetus in max decrease influence of gravitational (hydrostatical) pressure at straight-walking (sitting, upright, walking). However direct dependence of the hemodynamic providing of fetoplacental complex from maternal circulation of blood is saved, both from regional, especially abdominal and pelvic and the circulatory state of CVS in general and its central link—pumping function of heart [32].

Expression of autonomic "slipping out" of arterial vessels of abdominal and pelvic circulation from under system vasoconstriction, probably because of endothelium-depending humoral mechanism, determine phenomenon of optimization of the circulatory state of CVS at the beginning of pregnancy, especially expressed at PhP, and inhibition of pathological changes. And, vice versa, expressed vasoconstriction of abdominal and pelvic arterial vessels, along with hypoperfusion and decrease of pumping function of heart determine circulatory basis of PaP (in the first place preeclampsia). Therefore, estimating the circulatory state of CVS for pregnant, and nonpregnant, necessary to be oriented not on the mode of BP, but on condition of basic perfusion mechanisms a "volume of blood—pumping function of heart—vascular capacity—blood stream" and regulators of autonomic regional blood flow—endothelial function providing distribution of peripheral circulation of blood, and it explained that gestational endotheliopathy is the trigger component of disorder hemodynamics supply pregnancy and development of perinatal pathology. In fact, the state of perfusion mechanisms that form the basis of hemodynamic support of any somatic condition and especially pregnancy, taking into account the formation of a fetoplacental complex «above organism» and necessity of hemodynamic adaptation of CVS of pregnant as straight-walking creature, to formed exceptional organism situation not only in gestational feature, but also in aspect of adaptation.

#### **4. Conclusions**


*Gestational Endotheliopathy as Trigger Disorder of Haemodynamics Pregnancy Supply DOI: http://dx.doi.org/10.5772/intechopen.100737*

3.Hemodynamically identified HF by perfusion type, as the earliest circulatory form at the preclinical level for gestational endotheliopathy, is considered a trigger for the formation of a dynamic organization of the circulatory state of the CVS corresponding to the hypertensive state, including during pregnancy (preeclampsia).

#### **Funding**

The authors received no financial support for the research, authorship, and/or publication of this article.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Author details**

Dmytro Konkov1 , George Belkania<sup>2</sup> , Levon Dilenyan3 , Victor Rud1 , Liana Puchalska4 , Alina Piskun1 and Larisa Klimas1 \*

1 National Pirogov Memorial Medical University, Vinnytsya, Ukraine

2 Expert Medical System Laboratory, Vinnytsya, Ukraine

3 Privolzhsky Research Medical University, Nizhny Novgorod, Russia

4 University of Warsaw, Department of Experimental and Clinical Physiology Warsaw, Poland

\*Address all correspondence to: lora@vnmu.edu.ua

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[2] Thilaganathan B. Pre-eclampsia and the cardiovascular–placental axis. Ultrasound in Obstetrics & Gynecology. 2018;**51**(6):714-717. DOI: 10.1002/ uog.19081

[3] Konkov DG, Belkania GS, Puchalska LG. The modern hemodynamic features of predictive diagnosis of preeclampsia. In: The Abstract Book of the 18th World Congress of the Gynecological Endocrinology; 7-10 March 2018; Florence, Italy; 2018. p. 214

[4] Borzenko I, Konkov D, Kondratova I, Basilayshvili O, Gargin V. Influence of endotheliopathy of spiral arteries on placental ischemia. Georgian Medical News. 2019;**11**(296):131-134

[5] Konkov DG, Piskun AO. The features of placental angiogenesis in early preeclampsia. Actual Questions of Modern Gynecology and Perinatology. 2018;**5**(4):25-29

[6] Konkov DG. The features of conversion of spiral arteries in pregnant women with the gestational endotheliopathy. Reports of Vinnytsia National Medical University. 2016; **20**(1):65-68

[7] Kalafat E, Thilaganathan B. Cardiovascular origins of preeclampsia. Current Opinion in Obstetrics and Gynecology. 2017;**29**(6):383-389. DOI: 10.1097/GCO.0000000000000419

[8] Coutinho T, Lamai O, Nerenberg K. Hypertensive disorders of pregnancy and cardiovascular diseases: Current

knowledge and future directions. Current Treatment Options in Cardiovascular Medicine. 2018;**20**(7):56. DOI: 10.1007/s11936-018-0653-8

[9] Thilaganathan B, Kalafat E. Cardiovascular system in preeclampsia and beyond. Hypertension. 2019;**73**(3):522-531. DOI: 10.1161/ HYPERTENSIONAHA.118.11191

[10] Konkov DG. The features of circulatory dynamics during physiological pregnancy. Reports of Morphology. 2012;**18**(2):317-321

[11] Konkov DG, Belkaniya GS, Dilenyan LR, et al. The multidisciplinary point of view on the condition of hemodynamic maintenance of pregnancy the anthropophysiological approach. Ohrana materinstva i detstva. 2017;**1**(29):5-13

[12] Belkaniya G, Konkov D, Dilenyan L, et al. The anthropophysiologic characteristics of circulatory model of haemodynamic pregnancy supporting. Reproductive Health. Eastern Europe. 2018;**8**(1):55-75

[13] Belkaniya GS, Dilenyan LR, Bagrii AS, et al. General approaches to anthropophysiologica of characterization of age-related changes in human circulation. Patogenez. 2017;**15**(4):24-31

[14] Belkaniya GS, Konkov DG, Dilenyan LR, et al. The anthropophysiological analisis of systemic vasoconstruction and endothelio-dependent vasodilation in the hemodynamic supplying of pregnancy. Actual Questions of Modern Gynecology and Perinatology. 2018;**5**(1):30-41

[15] Belkaniia GS. Funktsional'naia sistema antigravitatsii [Functional antigravitation system]. Problemy Kosmicheskoĭ Biologii. 1982;**45**:5-286 *Gestational Endotheliopathy as Trigger Disorder of Haemodynamics Pregnancy Supply DOI: http://dx.doi.org/10.5772/intechopen.100737*

[16] Belkaniia GS, Dartsmeliia VA. Priamokhozhdenie kak faktor razvitiia arterial'noĭ gipertonii u primatov [Upright walking as a factor in the development of arterial hypertension in primates]. Kosmicheskaia Biologiia i Aviakosmicheskaia Meditsina. 1984;**18**(3):14-19

[17] Belkaniya GS, Dilenyan LR, Bagriy AS, et al. Kardiodinamicheskie osnovyi i perspektivyi klinicheskogo ispolzovaniya reografii [The cardiodynamic basis and prospects for clinical use of rheography. Anthropophysiological aspect]. Nizhniy Novgorod: izd-vo Nizhegorodskoy gosudarstvennoy meditsinskoy akademi; 2016. p. 220

[18] Belkaniya GS, Dilenyan LR, Bagriy AS, et al. Antropofiziologicheskiy podhod v formirovanii diagnosticheskoy shkalyi gemodinamicheskih parametrov [The anthropophysiological approach in the formation of a diagnostic scale of hemodynamic parameters]. Meditsinskiy almanah. 2014;**2**(32): 152-156

[19] Dartsmeliia VA, Belkaniia GS. Tipologicheskaia kharakteristika gemodinamicheskikh sostoianiĭ v ortostatike u zdorovykh lits [Typological characteristics of hemodynamic states in the orthostatism of healthy persons]. Kosmicheskaia Biologiia i Aviakosmicheskaia Meditsina. 1985;**19**(2):26-33

[20] Dilenyan LR, Belkaniya GS, Bagriy AS, et al. Antropofiziologicheskiy podhod v sistemnom algoritme kriterialnogo analiza sostoyaniya serdechno-sosudistoy sistemyi [The anthropophysiological approach in the system algorithm of criteria analysis of the state of the cardiovascular system]. Meditsinskiy almanah. 2014;**5**(35): 170-174

[21] Dilenyan LR, Belkaniya GS, Bagriy AS, et al. Sindromalnyiy analiz krovoobrascheniya v sistemnom algoritme antropofiziologicheskogo isssledovaniya [The syndromic analysis of the state of the cardiovascular system]. Meditsinskiy almanah. 2015;**1**(36):125-130

[22] Belkaniya GS, Dilenyan LR, Ryzhakov DI, et al. Diagnostic informativity of hemodynamic identification of circulatory syndromes in heart failure. Patogenez. 2017; **15**(3):84-92

[23] Belkaniya GS, Dilenyan LR, Bagriy AS, et al. Osobennosti metodicheskogo obespecheniya antropofiziologicheskoy diagnostiki sostoyaniya serdechnososudistoysistemyi [The features of methodological support anthropophysiological diagnostics of the condition of cardio-vascular system]. Meditsinskiy almanah. 2013;**6**(30):208-214

[24] Dilenyan LR, Bagriy AS, Belkaniya GS, et al. Antro pogeneticheskaya model vozrastnoy dinamiki regulyatornoy ustanovki tsirkulyatornogo sostoyaniya serdechno-sosudistoy sistemyi [Anthropophysiological characteristics of«hemodynamic model»of age dynamics of circulation in humans]. Sovremennyie problemyi nauki i obrazovaniya. 2015;**6**:1-30

[25] Dilenyan LR, Belkaniya GS, Bagriy AS, et al. Antropofiziologi cheskaya harakteristika tipologicheskogo otrazheniya obschey sindromalnoy strukturyi tsirkulyatornogo sostoyaniya serdechno-sosudistoy sistemyi [Anthropophysiological characteristics of typological reflection of general structure of the cardiovascular system]. Sovremennyie problemyi nauki i obrazovaniya. 2016;**3**:1-34

[26] Belkaniya GS, Konkov DG, Dilenyan LR, et al. Novyiy vzglyad na krovoobraschenie u beremennyih antropofiziologicheskaya diagnostika gemodinamicheskogo obespecheniya beremennosti [A new look at the circulation in pregnant women anthropophysiligical diagnostics of hemodynamic support of pregnancy]. Sovremennyie problemyi nauki i obrazovaniya. 2017;**5**:1-18

[27] Belkaniya GS, Dartsmeliya VA, Galustyan MV, et al. Anthro pophysiological basis of species-specific stereotype of cardiovascular system reactivity in primates. Vestnik AMN SSSR. 1987;**10**:52-60

[28] Genes VS. Nekotoryie prostyie metodyi kiberneticheskoy obrabotki dannyih diagnosticheskih i fiziologicheskih issledovaniy [Some simple methods of cybernetic processing of diagnostic and physiological research data]. M.: Nauka; 1967. p. 208

[29] Belkaniya GS, Dilenyan LR, Konkov DG, et al. An anthropogenic model of cardiovascular system adaptation to the Earth's gravity as the conceptual basis of pathological anthropology. Journal of Physiological Anthropology. 2021;**40**(1):9. DOI: 10.1186/s40101-021-00260-2

[30] Dilenyan LR, Belkaniya GS, Martusevich AK. Role of systemic vasoconstruction in regulatory installation of blood circulation. Journal of Stress Physiology Biochemistry. 2018;**14**(4):35-45

[31] Belkaniia GS. Funktsional'naia sistema antigravitatsii i modelirovanie fiziologicheskikh éffektov ponizhennoĭ gravitatsii [Functional antigravitational system and modeling the physiological effects of reduced gravity]. Uspekhi Fiziologicheskikh Nauk. 1978; **9**(2):103-128

[32] Belkaniya GS, Dilenyan LR, Bagriy AS, et al. Antropofiziologi cheskoe obosnovanie tipologicheskogo opredeleniya optimalnosti i neoptimalnosti gemodinamicheskogo obespecheniya somaticheskogo sostoyaniya organizma [The anthropophysiological substantiation of the typological definition of the hemodynamic supply of the organism]. Meditsinskiy almanah. 2014;**1**(31): 119-122

Section 6

## Opthalamic Disorder

#### **Chapter 6**

## Ophthalmic Disorders in Posterior Reversible Encephalopathy Syndrome Associated with Preeclampsia

*Katarina Cvitkovic, Anita Pusic Sesar, Antonio Sesar and Ivan Cavar*

#### **Abstract**

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological entity presented with different symptoms such as visual disturbances, headaches, seizures, severe hypertension and altered mental status. It has been recognized in a different pathological conditions, although preeclampsia/eclampsia is the most common cause of PRES. The pathogenesis of PRES is still not fully understood, but it seems that failure of cerebrovascular autoregulation causing vasogenic edema, cerebral vasoconstriction, and disruption of the blood brain barrier plays an important role. Cortical blindness, hypertensive retinopathy, serous retinal detachment (SRD), central retinal artery and vein occlusions, retinal or vitreous hemorrhages, anterior ischemic optic neuropathy (AION) and Purtscher's retinopathy are ophthalmic disorders that may occur in PRES associated with preeclampsia. Among these, cortical blindness is the best documented complication of preeclampsia. Magnet resonance imaging (MRI) is a gold standard to establish the diagnosis of PRES because clinical findings are not sufficiently specific. Typically, there are bilateral cortical occipital lesions with hyperdensity on T2-weighted MRI. Blindness due to occipital lesions is reversible and the vision loss is usually regained within 4 h to 8 days.

**Keywords:** preeclampsia, eclampsia, posterior reversible encephalopathy syndrome, ophthalmological disorders, cortical blindness

#### **1. Introduction**

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological entity presented with different symptoms, such as headaches, seizures, visual disturbances, severe hypertension, and altered mental status [1]. Previously, it has been known by various names such as reversible posterior leukoencephalopathy syndrome, reversible posterior cerebral edema syndrome, and reversible occipital parietal encephalopathy [2, 3]. PRES was first described in 1996 by Hinchey et al. in patients with acute neurological symptoms and since then it has been recognized in different pathological conditions such as preeclampsia, eclampsia, hypertensive

encephalopathy, autoimmune diseases, renal failure, infection, and the use of cytotoxic or immunosuppressive drugs [1, 3–9]. Among these, preeclampsia and eclampsia are the most common causes of PRES. Preeclampsia is pregnancy-specific disorder clinically characterized by a new onset of hypertension and proteinuria that appear after the 20th week of gestation and up to 6 weeks postpartum in a previously normotensive woman [5, 6]. Preeclampsia and its variants affect approximately 5% of pregnancies and is the leading cause of both maternal and fetal morbidity and mortality worldwide [10]. It is characterized by impaired organ perfusion that occurs as a result of vasospasm and activation of the coagulation system [11]. Eclampsia is an acute cerebral complication of preeclampsia, presented with the occurrence of tonic-clonic convulsions in pregnant or recently postpartum women [12]. Severe intracranial vasospasm, local ischemia, intracranial hypertension, and endothelial dysfunction associated with vasogenic and cytotoxic edema are possible causes of seizures in PRES [11]. Rare cases of PRES in pregnant women with normal blood pressure and without preeclampsia have also been described in the literature [13]. Early recognition of PRES is essential in order to timely apply the medication, which typically includes drugs that lower blood pressure, act as antiedematous and interrupt tonic-clonic convulsions [7].

#### **2. Pathogenesis of PRES**

The exact pathophysiological mechanisms of PRES are not precisely known. Failure of cerebrovascular autoregulation, cerebral vasoconstriction, and disruption of the blood brain barrier due to endothelial disfunction are possible mechanisms involved in the pathogenesis of PRES [2]. Failure of cerebrovascular autoregulation causing vasogenic edema is the most accepted one. It seems that hyperperfusion plays a crucial role in disorders where hypertension is a key feature, such as in preeclampsia [14]. During fluctuations of systemic blood pressure, cerebrovascular autoregulation maintains cerebral blood flow, leading to vasodilation during systemic hypotension and vasoconstriction during systemic hypertension. The rapid development of hypertension can exceed the capacity of cerebral blood flow autoregulation leading to hyperperfusion [14]. It is supposed that posterior brain regions are more vulnerable to hyperperfusion, which is explained by better autoregulation of the anterior circulation due to better sympathetic innervations as compared to the posterior circulation [15]. Another theory suggests spasm of cerebral arteries in response to acute hypertension, thus resulting in decreased cerebral blood flow, intraarterial thrombosis, and cerebral ischemia leading to cytotoxic edema, especially in the border zones between arterial territories [16–18]. Breakdown of the blood brain barrier and endothelial dysfunction occurs in PRES with fluid and macromolecule extravasation into the interstitium. Further, increased concentrations of circulating cytokines activate endothelial cells and allow adhesion of circulating leukocytes. On the other hand, the tight junctions are disrupted and vascular endothelial growth factor expression is increased, leading to increased vascular permeability and vasogenic edema [19].

#### **3. Neuroimaging features of PRES**

The diagnosis of PRES cannot be established exclusively on clinical findings [1]. Brain lesions are usually located in the white matter, although rarely, overlying cortex may also be affected [20]. The parieto-occipital regions of the brain are main foci of changes, that are usually bilateral and symmetric. However, the lesions can

*Ophthalmic Disorders in Posterior Reversible Encephalopathy Syndrome Associated… DOI: http://dx.doi.org/10.5772/intechopen.101270*

also extend to other brain structures such as the frontal and temporal lobes, cerebellar hemispheres, basal ganglia, brain stem, and deep white matter [21]. A multislice computed tomography (MSCT) scan is often normal or shows cortical-subcortical hypodensities, predominantly in posterior brain regions. However, MSCT scans in PRES show lesions in only of about 50% cases [22]. Because of that, magnet resonance imaging (MRI) is a gold standard for the diagnosis of PRES and the follow-up of these patients. Neuroimaging studies showed hypointense or isointense signal changes on T1-weighted images. The typical neuroimaging feature is a high signal intensity on T2-weighted images predominantly in the posterior regions, which is caused by subcortical white matter vasogenic edema [1]. Abnormalities are more observable on fluid-attenuated inversion recovery imaging (FLAIR), which increases the ability to detect subtle lesions in PRES [15]. Supplemental diffusionweighted imaging (DWI) and apparent diffusion coefficient (ADC) map images are helpful in distinguishing vasogenic oedema from cytotoxic edema [15–19]. Cytotoxic edema appears hyperintense on DWI with a low signal intensity image on the corresponding ADC sequence. A predominantly low signal on DWI and a high signal on ADC image indicates vasogenic edema. Vasogenic edema and cytotoxic edema can also coexist in eclampsia [23].

#### **4. Ocular disorders in PRES associated with preeclampsia**

Visual disorders in pregnancy can be highly variable and range from mild symptoms such as transient blurred vision, photopsia, and different types of visual field defects to transient or permanent total blindness [24]. Vision loss during pregnancy has been documented in 1–3% of cases and a possible causes are cortical blindness, central retinal artery and vein occlusions, retinal detachment, ischemic optic neuropathy, retinal or vitreous hemorrhages, and Purtscher's retinopathy [24–26]. Approximately 25% patients with severe preeclampsia and 50% patients with eclampsia present different visual symptoms including blurred vision, homonymous hemianopsia, visual neglect, visual anosognosia, and cortical blindness [27, 28]. They seem to be a consequence of the cerebral edema located in the occipital cortex or in the temporal and parietal association cortices. In most patients, the visual impairment is reversible, but in rare cases, permanent blindness has been described [29].

#### **4.1 Cortical blindness**

Cortical blindness is among the best-documented complications of preeclampsia/eclampsia and affects almost 15% of eclamptic women [30, 31]. Cortical blindness is caused by a dysfunction in the visual pathway that conducts visual information from the lateral geniculate nucleus of the thalamus to the cerebral visual cortex [20]. Vasogenic edema is the main cause of cortical blindness. It appears that the primary visual cortex in the occipital lobes is more susceptible to the breakdown of cerebrovascular autoregulation and subsequent hyperperfusion than other brain regions [31]. Cortical blindness has been described to occur several hours before or after eclamptic seizures, rarely several days or weeks postpartum [32–34]. The bilateral vision loss often begins with blurry vision and progresses within a couple of hours to bare light perception [35]. Sometimes, the woman is unaware of her blindness and feels that she can see, which is known as visual anosognosia or Anton syndrome, indicating involvement of the visual association cortex [34, 36]. However, cortical blindness is associated with an intact pathway from the eye to the lateral geniculate body and therefore ophthalmological examination including the pupillary reflexes, ocular motility, and fundoscopic findings is normal in these patients [29]. Blindness due to occipital lesions is reversible and the vision loss is usually regained within 4 h to 8 days [27].

#### **5. Other ocular disorders in pregnancy complicated with preeclampsia**

#### **5.1 Hypertensive retinopathy**

According to some studies, the prevalence rate of hypertensive retinopathy in women with hypertensive disorders in pregnancy is 32.5% [37]. Generally, the retinal vascular changes correlate with the severity of systemic hypertension. At the pathophysiological level, increased blood pressure leads to focal or diffuse vasoconstriction. In addition, increased vascular permeability leads to the extravasation of fluid to the extravascular spaces. Clinically, the most common abnormality seen during fundoscopy is narrowing of retinal arterioles [38]. Other retinal changes that may be present are decreased retinal artery to vein ratio, cotton wool spots, hemorrhages and Elschnig spots [39]. Vasospastic manifestations are reversible, and the retinal vessels rapidly return to normal after delivery [38].

#### **5.2 Serous retinal detachment**

Serous retinal detachment (SRD) is a rare complication of hypertensive disease in pregnancy, affecting 1–2% of preeclamptic and 10% of eclamptic women [40]. It is characterized by separation of the neurosensory retina from the pigmented retinal epithelium and it is usually observed in the absence of significant retinal vascular abnormalities or retinal breaks [41]. It may be present either before or after delivery [42]. Clinically, patients report loss of visual acuity and visual field defects [42, 43]. The detachments are often bullous and bilateral [27]. The exact pathophysiology of SRD in cases of preeclampsia is not well known, but it seems to be related with choroidal ischemia, which is secondary to an intensive arteriolar vasospasm [27]. The choroidal vascular insufficiency can lead to lesions in retinal pigment epithelium, fluid transudation, and focal retinal detachment. The majority of women who manifest SRD during pregnancy have a gradually improvement of visual acuity in few weeks after delivery, ending with complete recovery of vision [31]. Management of SRD in preeclampsia is conservative and involves treating the underlying condition [27].

#### **5.3 Purtscher's retinopathy**

Purtscher's retinopathy is a rare cause of visual loss during pregnancy and has been mostly described in association with complicated labor [24]. However, isolated cases during normal spontaneous labor have also been described in the literature [44]. Clinically, it presents with decreased visual acuity and a different types of visual field defects such as central or paracentral scotoma. The retinal changes include ischemia at the posterior pole with white patches of edema known as Purtscher's flecken, which represent areas of capillary bed infarction. In the initial phase, the optic disc is normal, but in the later phases, disc pallor and optic atrophy occur [27]. According to some researchers, these fundoscopic changes may be caused by embolic occlusion of the precapillary arterioles of the retina by fat, air, platelets, and leukocyte aggregates [45, 46]. The diagnosis is established on the basis of clinical findings and confirmed by intravenous fluorescein angiography [47]. The majority of patients recover some of their visual function without

*Ophthalmic Disorders in Posterior Reversible Encephalopathy Syndrome Associated… DOI: http://dx.doi.org/10.5772/intechopen.101270*

treatment. Use of systemic steroids may improve visual outcome in some patients, but momentary specific medication is not available [47].

#### **5.4 Anterior ischemic optic neuropathy**

Anterior ischemic optic neuropathy (AION) is a rare ophthalmological disorder in preeclampsia that has been described to occur before and after delivery. Clinically, it is presented with sudden vision loss and unilateral or bilateral disc edema [48, 49]. The exact pathophysiology of AION in preeclampsia remains unclear, but it is suggested that uncontrolled hypertension leads to vasoconstriction or ischemia in the posterior ciliary artery circulation [49].

#### **5.5 Central retinal vein occlusion**

Central retinal vein occlusion (CRVO) is also described in preeclamptic women and was presented with bilateral vision loss up to 21 days postpartum. Ophthalmologic examination reveals multiple retinal hemorrhages in all 4 quadrants, venous dilatation, and macular edema. Improvement of visual acuity is significant but not complete [31]. The exact pathophysiological mechanism of CRVO in preeclampsia is not fully understood; however, it is proposed that central retinal artery thickening is thought to cause compression of the central retinal vein, thereby leading to venous occlusion [50, 51].

#### **5.6 Central retinal artery occlusion**

Central retinal artery occlusion (CRAO) is rare in young people, and it is usually associated with a predisposing pathological disorders such as cardiac valvular disease, systemic vascular disease, and hypercoagulable disorders. According to some studies, CRAO is rarely described in women with eclampsia [52, 53]. Clinically, it is presented with sudden, painless, and persistent vision loss. Fundoscopy shows typical changes such as pallor of posterior pole with cherry-red spot. It seems that the activation of coagulation system could be a cause of multiple emboli and vascular occlusion in these patients [53].

#### **5.7 Retinal and vitreous hemorrhages**

Retinal and vitreous hemorrhages are rare disorders that may precede the appearance of preeclampsia. They are presented as a sudden vision loss in a normotensive pregnant women, who usually develop preeclampsia within 2 weeks after labor [54, 55].

#### **6. Conclusion**

Preeclampsia and eclampsia are the most common conditions associated with PRES. Due to the high predilection of pathological lesions in white matter of the occipital lobes, PRES could be manifested with different types of ocular disorders. Some of these complications can be serious including cortical blindness, SRD, CRVO, CRAO, AION, and vitreal and retinal hemorrhages. Clinicians should be aware of these ocular manifestations, and careful ophthalmological, neurological, and neuroradiological evaluation should be carried out to ascertain the various causes of vision loss in pregnancy. In most cases, visual prognosis is usually good with permanent vision recovery. Effective treatment of preeclampsia/eclampsia along with termination of pregnancy is the mainstay of treatment.

*Preeclampsia*

#### **Conflict of interest**

The authors declare they do not have any conflict of interest.

### **Author details**

Katarina Cvitkovic1,2\*, Anita Pusic Sesar2 , Antonio Sesar2 and Ivan Cavar1,2

1 Department of Immunology, School of Medicine, University of Mostar, Mostar, Bosnia and Herzegovina

2 Department of Ophthalmology, University Hospital Center, Mostar, Bosnia and Herzegovina

\*Address all correspondence to: katarina.cvitkovic@mef.sum.ba

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Ophthalmic Disorders in Posterior Reversible Encephalopathy Syndrome Associated… DOI: http://dx.doi.org/10.5772/intechopen.101270*

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### *Edited by Hassan Abduljabbar*

Preeclampsia is a disorder of pregnancy characterized by high blood pressure, edema, and proteinuria that affects 2%–8% of pregnancies worldwide. Hypertensive disorders of pregnancy, including preeclampsia, are among the most common causes of death in pregnant persons. Over six chapters, this book examines the pathophysiology of preeclampsia, vitamin D deficiency as a risk factor for preeclampsia, the cellular changes that occur with preeclampsia, associated organ dysfunction, gestational endotheliopathy, and ophthalmic complications of preeclampsia.

Published in London, UK © 2022 IntechOpen © Avesun / iStock

Preeclampsia

Preeclampsia

*Edited by Hassan Abduljabbar*