Pre-eclampsia and maternal health through the prism of low-income countries

Introduction

Countries in transition, burdened by the past with an imposed irrational and dysfunctional organizational system, must imperatively solve the model of health insurance and health care protection. The development of all democratic societies in the world tends to regulate social systems, not only through laws but also by using other methods. Modern health care always includes a four-member relationship with interaction (patient, doctor, service provider institution, and the one who pays). Indeed, the health insurance model is a fundamental social issue.

Essentially, an ideal healthcare system does not exist. The aim is to find an optimal mode in each health system to promote the satisfaction of the user and the provider of health services. Although there is a lot of talk about the concept of health rights and the quality of health care, knowledge of the patient’s rights as part of mandatory health insurance is still debatable.

The health care system is a pillar of the functioning of society as a whole. The level of development of the health care system directly indicates the level of development of a country. Health reform (capacity, profiling of groups of health workers, faster recruitment, as well as faster orientation, better organizations of primary, secondary, and tertiary care, better coverage of insurance, and better connection with the economy) is probably a step that is already delayed in most low-income countries. Prevention programs should go toward the prevention of basic pathology of the population. For instance, when it comes to pregnant women, there is a problem of arterial hypertension.

Hypertensive syndrome in pregnancy complicates up to 15% of pregnancies, and preeclampsia (PE) occurs in about 3–10% of pregnant women [1, 2]. Given that delivery is the only treatment for PE, it presents the leading cause of iatrogenic preterm birth and low birth weight [1]. Inadequate prenatal care is associated with higher mortality from PE, possibly due to reduced monitoring, detection, and missed opportunities for early intervention. Preeclampsia is defined as hypertension (systolic pressure ≥140 mm Hg or diastolic pressure ≥90 mm Hg) after the 20th week of gestation and with at least one of the following symptoms: proteinuria, organ dysfunction (including kidney and liver, followed by hematological or neurological complications), with sometimes the presence of fetal growth restriction [1, 3]. In the event of a grand mal seizure in a patient, we refer to eclampsia. In contrast, HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome is identified when hemolysis (with microangiopathic blood smear), elevated liver enzymes, and thrombocytopenia prevail over hypertension, central nervous system, or renal dysfunction [1, 4]. The imperative of the clinician’s work is monitoring the symptoms and clinical signs of PE. Also, stratification of patients in relation to the risk of PE is essential. The definitive treatment of PE is childbirth, and the management of PE presents the treatment of high blood pressure and seizure prevention, with timely delivery and adequate postpartum follow-up [1, 5]. The question of the effect of PE on long-term maternal health is raised.

Preeclampsia and its effect on the cardiovascular system

During pregnancy, the organism adjusts primarily with blood volume, which begins to increase in the sixth week, increases in the second trimester, and stabilizes in the last eight weeks. Due to blood volume expansion, the increase in red cell mass values ​​(even in the late stages) is not so discernible (hematocrit values ​​are around 33–34%, and hemoglobin is 11–12 g/dL). At the same time, it should be noted that an increase in hemoglobin in the first and second half of pregnancy can be one of the predictors of preeclampsia [6].

In the last trimester, due to physiology, sodium may increase because of the effect of aldosterone, while in patients with PE, decreased sodium values ​​are verified [7].

Additionally, cardiac output increases by up to 40% due to increased stroke volume and heart rate (from 10 to 20% from resting heart rate values), though the opposite happens if intrauterine growth restriction occurs [8]. The appearance of tachyarrhythmias is possible primarily due to the secretion of catecholamines [9]. Low-resistance uteroplacental circulation causes a drop in mean aortic pressure, affecting the mother’s peripheral and pulmonary vascular resistance, which is reduced; in PE, however, the opposite happens, and resistance in the uteroplacental circulation will increase [10].

PE is an indicator of maternal susceptibility to develop some cardiovascular pathology (the possibility of the influence of PE on organ damage should be taken into account) [11].

It is also considered that the frequency of major coronary events (MCE) is higher in women with a history of PE [12].

Patients with PE experience twice the rate of cardiovascular (CVD) events and have a 2.2-fold increased rate of chronic hypertension, an 80% increased rate of type 2 diabetes, and a 30% increased rate of elevated cholesterol [13]. PE is related to future incident heart failure and a 2-fold increased risk of coronary heart disease, stroke, and death due to coronary heart or cardiovascular disease [14].

Pulmonary edema is a condition that usually occurs in severe forms of PE and occurs more often in older preeclamptic pregnant women [15], [16], [17]. PE that develops in pregnant women with multifetal gestation is a special risk compared to single pregnancy [15]. Clinical characteristics are difficulty breathing, cough, psychomotor restlessness, chest pain, palpitations, and excessive sweating [15]. The severity of these symptoms is related to the outcome, while the etiological basis of pulmonary edema in PE is multifactorial [17]. A decrease in oncotic pressure, which is potentiated by hypoproteinemia with an increase in pulmonary vascular hydrostatic pressure, is one of the pathophysiological mechanisms [15, 17]. Endothelial dysfunction with heart failure and malignant hypertension can directly lead to pulmonary edema. Volume load caused by the treatment of patients with PE can be one of the causes of pulmonary edema [15], [16], [17].

Preeclampsia and venous thromboembolism

PE is considered to be associated with 3-to-12-fold increases in risks of pulmonary embolism and stroke [18]. Endothelial dysfunction of blood vessels leads to increased permeability of blood vessels, which leads to hypercoagulability and reduced blood viscosity. The appearance of proteinuria, which leads to hypoproteinemia, further worsens the condition of hypercoagulability. The need for hospitalization of patients with PE, along with the described pathophysiological changes, additionally provokes the occurrence of thrombosis and thromboembolic incidents [18]. Acute pulmonary embolism affects circulation and gas exchange and is followed by hypoxia, hypocapnia, and disturbance in the acid-base status. Moreover, right heart failure due to acute pressure overload is regarded as the primary cause of death in severe PE [19]. Complications of pulmonary embolism include sudden death, respiratory failure, pulmonary infarction, heart failure, and pulmonary hypertension [19].

Preeclampsia and previous cardiac pathology

Maternal risk assessment is critical if the mother has previous cardiovascular morbidity. High-risk patients should be treated in specialized centers. Pregnancy is contraindicated if there is pulmonary arterial hypertension for any reason, if there is left ventricular systolic dysfunction [ejection fraction of left ventricle (EFLV) <30%, New York Heart Association (NYHA) III and IV], if there is previous peripartum cardiomyopathy with residual left ventricular dysfunction, if there is severe mitral or severe aortic stenosis, dilatation of the aorta (generally >5.0 cm, in Marfan syndrome or aortopathy >4.5 cm), in Ehlers-Danlos syndrome, in coarctation of the aorta (or recoarctation), in right heart failure, or in Fontan with complications [20].

Volume load can additionally lead to the progression of the previous valvular defect, and echocardiography should take into account volume overload in pregnancy when interpreting the grade of the valvular pathology [21]. During pregnancy, the mitral and tricuspid valves are subjected to increased hemodynamic stress, rendering the patient at increased risk of rhythm disturbances, acute heart failure, and major adverse cardiac events (MACE) [21, 22]. There is no clear data that PE is associated with a higher risk of the acute coronary syndrome, although it is a fact that it can often be missed [22]. Also, in the case of the acute coronary syndrome, coronary angiography and percutaneous coronary intervention will be performed, if necessary, as quickly as possible, and the pregnant uterus should be protected from direct radiation, while cardiac surgery is performed if the mother’s life is threatened [21]. All of this has an effect on the increased risk of MACE for the rest of life. It is believed that patients with PE will be complicated with increased levels of angiotensin II (ANG-II) sensitivity and elevated levels of the pro-fibrotic factors interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), triglycerides and free fatty acids, while in the postpartum period is followed by increased levels of leptin and decreased levels of the anti-fibrotic factor adiponectin, which represents etiological factors that could lead to systolic dysfunction [23].

Preeclampsia and liver enzymes

Increased activity of liver enzyme systems can be expected in 3% of pregnant women [27], while increased values are associated with PE and represent a characteristic of HELLP syndrome. Acute liver failure itself generally occurs in HELLP syndrome ≥20 weeks of gestation, whereas acute fatty liver of pregnancy (AFL) occurs at the end of the third trimester or in the early postpartum period (maternal mortality is approximately 18%) [28]. It is considered that fatty liver infiltration is also a characteristic of PE [29], [30], [31].

Preeclampsia and renal status

Renal plasma flow and glomerular filtration rate are expected to be reduced in PE (increased afferent arteriolar resistance or reduced ultrafiltration coefficient) [30, 36]. Neutrophil gelatinase-associated lipocalin (NGAL) levels increase in preeclampsia, indicating acute kidney injury [31]. Decreased serum albumin levels affect hemostasis but also the pharmacokinetics of other pharmacological agents [37]. Transient oliguria (less than 100 mL over 4 h) is common in PE, but it often occurs during labor or passes 24 h after it. True oliguria occurs in severe forms of PE (<500 mL of urine/24 h) [36]. The glomerular filtration rate can drop by more than 25 percent. Oliguria, together with anuria, can be associated with renal cortical necrosis and can lead to hematuria.

Preeclampsia and brain status

Seizures are a sign of eclampsia, and there is an opinion that women with a history of PE are susceptible to cognitive impairment later [38]. Eclamptic attacks are more common in patients with severe PE and occur in 1 in 50 patients with PE. The pathogenesis of PE includes changes in the brain that include hemorrhages, petechiae, edema, vasculopathy, ischemic damage, and the appearance of necrosis. PE has also been deemed a risk for vascular dementia, but recently there are more and more theories about the connection between PE and an increased risk of Alzheimer’s disease [39, 40]. It is also associated with a higher risk of stroke [41]. The presence of migraine before the onset of PE increases the likelihood of stroke in pregnancy [42, 43].

In more severe forms of PE, the appearance of visual symptoms emphasizes the severity of the disease [44]. They are associated with retinal blood vessel angiopathy, as well as changes in cerebrovascular autoregulation. In addition to pulmonary edema, cerebral edema is one of the complications in the pathophysiological mechanism of preeclampsia. Its presence also leads to visual outbursts [44]. The spectrum of symptoms is represented by blurred vision, the appearance of flickering and light sparks, scotoma, diplopia, or even blindness in one or both eyes. Disorders at the level of arterial blood vessels in the retina lead to its ischemia, so retinal ablation accompanied by damage to the optic nerve can often occur in such forms. Patients have a hard time bearing these symptoms [44]. Cerebral hemorrhage is also accompanied by visual symptoms, so a quick distinction is imperative.

Discussion

The incidence of PE is much higher in low and middle-income countries [45, 46]. Early stratification of patients with early detection of factors that can be predictors of PE is essential [47]. There are numerous tests or markers but with limited sensitivity. Prevention of PE has not given adequate results so far. The time from the initial pathophysiological processes to the clinical manifestation of the disease is often very long. Adaptation of patients to the pathological condition often leads to a delay in appearing for an examination. PE is a condition that affects both the fetus and the pregnant woman. PE represents an entity with metabolic abnormalities (including dyslipidemia and insulin resistance) with increased inflammatory response, hypercoagulable state, and endothelial dysfunction [48]. Hypertension, as the main cause of PE, appears primarily due to higher peripheral vascular resistance, which is the result of arterial and venous vasoconstriction [49]. The second hemodynamic marker is a lower minute volume compared to a normotensive pregnancy. The third hemodynamic change is reduced total plasma volume, resulting from increased endothelial permeability and transudation of the plasma [49]. In addition to hemodynamic changes, one of the main characteristics of preeclampsia is the insufficiency of the uteroplacental circulation. PE probably induces injury of all organs and impacts long-term maternal health. Endothelial dysfunction alone and vasoconstriction lead to systemic hypertension and peripheral hypoperfusion. As a result of the reduced perfusion and inadequate exchange of oxygen in the tissue of the placenta, a dysbalance occurs between the humoral factors which regulate vascular tone because the oxygen free radicals already present are released in larger quantities in the placenta, and their effect is inactivation of the endothelium-derived relaxing factor, as a result of damage to the endothelium and the consumption of thrombocytes [49]. Lipid infiltration in the walls of spiral arteries alone is an indicator of atherosclerosis [50].

Conclusions

PE is not a condition that passes through childbirth, and presents a condition that determines the health of the individual and in the rest of life, and represents etiological risk factor of a wide spectrum of pathologies of the entire organ systems. Individuals with a history of PE should be viewed through the prism of primary prevention of acute incidents.

In low-income countries, cheap screening programs are indicated, with a clear focus on education for both clinical workers and patients.