Preeclampsia subtypes: Clinical aspects regarding pathogenesis, signs, and management

Placental estrogens, relaxin, and progesterone stimulate endothelial nitric oxide (NO) and prostacyclin (PGI2) production, however, other smooth muscle relaxing agents, e.g. endothelium derived hyperpolarizing factor (EDHF), and possible other gasotransmitters (carbon monoxide and dihydrogen sulfide) also contribute to vascular capacity increment.

Central hemodynamic examinations support both the missing of gestational blood volume augmentation and water retention beyond the given vascular capacity can lead to potentially serious consequences during pregnancy.

Preeclampsia (PE) is defined as the de novo development of hypertension (blood pressure ≥ 140/90 mm Hg, four hours apart) and any sign(s) of organ deficiency, including proteinuria (daily urinary protein loss ≥ 0.3 g), liver function deterioration (high transaminase levels), thrombocytopenia (platelet count ≤ 150.000/ml), neurologic symptoms (visual sensations) and/or fetal growth restriction appearing during the second half of pregnancy.

Hypovolemic, "classic" or placental PE

Fetal growth restriction is a hallmark regarding PE. Growth factors are essential for normal placenta development. High levels of antiangiogenic agents, such as soluble fms-like tyrosine kinase 1 (sFlt-1), and soluble endoglin diminish the functions of placenta growth factor (PlGF) and transforming growth factor β during the first phase of placental PE.

The essential etiologic role of antiangiogenic agents is shown in which the examination of PlGF/sFlt-1 ratio, especially combined with examination of serine protease corin, serves as a good diagnostic tool in the case of suspected PE. In consideration of these placental abnormalities, the development of normal wide and low-pressure placenta-supplying vasculature is insufficient. Blood supply, ensured by this placenta, is not enough for normal fetal development. As a result, fetal weight gain will not achieve normal growth, and there is a distinct potential fetal hypoxia will likely develop.

Agents from this malperfused placenta, primarily antiangiogenic factors and, among others, several types of cytokines, fetal and placental cell debris, all entering the maternal bloodstream result in generalized endothelial cell lesions, generating two important outcomes. One is the activation of platelets and adhesion to the vascular wall. This phenomenon can lead to a serious consequence at the level of microcirculation. Distinctively, erythrocyte aggregability consistently increases by slowing down the blood flow. Additionally, erythrocyte deformability shows a decrease in PE, possibly due to altered plasma to red blood cell interactions. These complex alterations lead to the development of thrombotic microangiopathy (TMA) in this subtype of PE.

Capillary occlusions obviously elevate systemic vascular resistance and decrease tissue blood supply. Some entrapped red blood cells suffer breakage, elevating lactate dehydrogenase enzyme levels, and can be detected as fragmentocytes in a peripheral blood smear. In the final stage, hypoxic capillaries become more transparent and a large extent of the vascular content enters to the extravasal compartment. Endorgan failures, such as anuria or eclampsia are terminal features of collapsing tissue blood supply.

The other consequence in reference to endothelium damage is the development of a complex mechanism regarding vasoconstriction, resulting in hypertension. Injured endothelium cells fail to produce vasorelaxant agents (NO, EDHF, PgI2), however, release a long-lasting, potent vasoconstrictor endothelin-1 (ET-1). Additionally, activated platelets release thromboxane A2 (TXA2), another vasoconstrictor. Due to contracted vasculature blood volume is considerably low in this type of PE, confirmed through classic hemodynamic examinations.

In the accumulation of relevant and convincing data allows one to state hypertension and symptoms of organ failures, such as proteinuria, can develop in pregnancy through another means, which is essentially characterized by high blood volume.

Hypervolemic, maternal or term PE

This subtype of PE is more common than when compared with the "classic" type. The important hemodynamic feature of this PE, the high blood volume, detected as CO above normal range, is experienced already in its latent phase.

Increased blood volume is in accordance with increased placental perfusion and high fetal birth weight reported in preeclamptic pregnancies. Notably, a positive correlation between maternal CO and fetal birth weight has been demonstrated in both normal and preeclamptic pregnancies.

According to many decades' worth of clinical observations, the first symptom regarding this future PE is low extremity edema, which frequently evolves into a generalized form. In some cases, following several days or weeks, blood pressure begins to elevate. In the case of hypervolemic edema, hypertension is volume-derived; specifically, the reason for hypertension is primarily also due to the pathologically increased water retention.

Obesity (BMI ≥ 30 kg/m2) is associated with increased water retention and is known as a precursor to hypertension, among nonpregnant females. However, it is not only augmented gestational weight gain but high pre-pregnancy weight which also is associated with the development of this type of PE.

The minor increase of plasma sodium levels in hypertensive individuals is well documented. Na/K-ATPase (Na+ pump) inhibitors, including digitalis-like cardiotonic steroid marinobufagenin (MBG), have been recognized as one of the classic agents seen in elevating blood pressure in response to sodium loads. The potent endogen steroid MBG, also produced by the placenta, is included in the pathogenesis in reference to PE.

Volume overload per se can deteriorate endothelial function in nonpregnant individuals during hemodialysis. A similar effect is seemingly supported by levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, which depicts incremental increase, not only in early onset, but also in late onset PE, when compared with normal pregnancy levels.

By increasing water retention, venous congestion of parenchyma can develop which may cause tissue hypoxia and signs of various organ dysfunctions, ranging from proteinuria to eclampsia.

Prediction and prophylaxis of PE

Early identification of females who are considered at increased risk regarding PE may experience the opportunity to decrease an adverse perinatal outcome.

In "classic" PE, the placenta and the vessels (endothelium) are the most affected tissues in the latent phase of the disease. Therefore, the usefulness of markers regarding placental function, such as PlGF, sFlt-1, pregnancy-associated plasma protein-A (PAPP-A), and placental protein 13 and characteristics of endothelial function, such as ADMA, ET-1, and vascular cell adhesion molecule 1 for PE prediction all have been intensively studied.

On the other hand, the Doppler velocimetry assessment of flow characteristics regarding uterine artery (UtA) (pulsatility or resistance) has been considered a suitable non-invasive method for evaluating placental perfusion. Examinations for PE screening are standardized for the 11 to 13 + 6-week. Abnormal UtA flow velocimetry reflects the incomplete spiral arteries remodeling and contributing placental insufficiency characteristically aligned to PE.

Identification of novel potential biomarkers may likely improve PE prediction. Promising biomarkers include placental messenger RNAs, placental and endothelial micro RNAs and cell-free RNA. Evaluation of changes in maternal plasma proteome represents another new method deemed beneficial in predicting early onset PE and helps to distinguish PE phenotypes.

It has been widely accepted, in cases of increased probability of PE development, administration of aspirin is suggested to prevent or at least to decrease the severity of the disease. Aspirin inhibits platelet aggregation by altering the balance between the platelet inhibitor PGI2 and platelet aggregator and vasoconstrictor TXA2 through an irreversible inhibition of the platelet cyclooxygenase enzyme. Consequently, TXA2 synthesis declines in platelets.

According to prophylaxis, a salt-restricted diet may decrease the effect of MBG, supporting the antihypertensive therapy. In the case of low calcium intake, Ca supplementation was found to reduce the incidence and serious complications of PE but fails to decrease recurrent PE. Noteworthy, effects of Ca supplementation may be different in different PE subtypes. A mild diuretic, e.g. phytotherapy, in gestational edema among obese patients is a questionable issue.

Management of PE

An effective examination of maternal CO in PE is seemingly the key method for improved management since it allows a principal segregation of hypo- or hypervolemic types, which obviously need different managements.

In the absence of opportunity regarding a hemodynamic examination, clinical signs may help in differentiating PE subgroups. The gestational week, when cardinal symptoms of PE are manifested, accurately differentiating various PE subgroups may prove daunting. As prenatal care appointments are usually organized at 3–4 weeks, PE can be diagnosed as late onset, however, hypertension and proteinuria will have likely have already developed several weeks ago. In contrast, fetal growth restriction, in the absence of congenital fetal anomalies, refers to "classic", hypovolemic PE. On the other hand, high pre-gestational BMI and high gestational weight gain with generalized edema and normal or high estimated fetal weight are referred to as a hypervolemic type.

Management of "classic", hypovolemic PE

Since precise pathogenesis and development of the first phase regarding "classic" PE remains obscure, the management, in general, is limited to close observation, including blood pressure, laboratory markers, and fetal well-being, promotion of fetal pulmonary maturation, and delivery induction in preventing the most severest complications.

The prescribed antihypertensive treatment in PE remains a controversial issue. Extremely high, uncontrolled hypertension and serious complications regarding PE, including eclampsia, pulmonary edema or placental detachment are also associated with high blood pressure, requiring urgency (intravenous or sublingual) antihypertensive treatment. In the case of imminent eclampsia, intravenous MgSO4 medication is prescribed, which also effective in lowering levels of blood pressure. However, large scale and sudden drop in blood pressure could be harmful to the fetus.

Careful antihypertensive medication is indicated once blood pressure persists at 160 mm Hg systolic or 110 mm Hg diastolic pressure, or above. In hypovolemic PE, when hypertension is caused due to vasoconstriction, vasodilator agents (e.g. nifedipine) are the most logical choice, however, methyldopa and labetalol show similar affectivity in unselected cases. Additionally, calcium dobesilate (CAD) may have favorable effects on microcirculation by promoting NO synthesis, improving diminished erythrocyte deformability, reducing platelet aggregation, and decreasing vascular permeability. CAD and other agents, such as pravastatin, metformin, and ezomeprazole, primarily through decreasing sflt-1 production, may favorable influence the outcome of placental PE, however, further studies are necessary for the clinical application.

In promoting fetal pulmonary maturation, corticosteroid (betamathasone or dexamethasone) administration is recommended prior to gestational week 34. In general, following gestational week 34, delivery induction serves a better outcome, however, individual evaluation, including fetal wellbeing, proves essential in each serious preeclamptic case.

Management of maternal, hypervolemic PE

In hypervolemic PE, organ perfusion is excellent at the beginning of the disease, manifesting in increased placental perfusion and normal/ high fetal weight.

Maternal co-morbidities are strongly associated with hypertensive disease in pregnancy. Therefore, effective management of predisposing diseases can result in a favorable effect in emerging PE.

Once vasculature is relaxed, vasodilator blood pressure depressors fail to improve cardiovascular function. Instead, agents with negative effects on CO, alpha- and beta blocker (labetalol) or centrally acting alpha-methyldopa can be a far better choice if and ones blood pressure decrease manifests.

Diuretics (thiazides or loop diuretics) are frequently applied agents to decrease hypertension, by reducing CO, in non-pregnant patients. Thiazides promote diuresis by inhibiting the N/Cl co-transporter located in the nephron of kidney. Thiazides decline Na reabsorption which increases urinary fluid loss, which in turn decreases extracellular fluid and plasma volume.

During pregnancy, diuretics can increase also fetal urination, detected as polyhydramnios. In consideration of PE with contracted blood volume, a further decrease of CO by diuretics can prove harmful. Therefore, guidelines for managing gestational hypertension or PE, without distinguishing hypo or hypervolemic cases, do not recommend the use of diuretics. Therefore, studies with diuretics during pregnancy are limited primarily to prophylaxis or the postpartum period of PE.

In consideration of hypertension, increased gestational weight gain, remarkable levels of edema, and even proteinuria, which all can be explained by water retention beyond the given vascular capacity in hypervolemic PE, the use of diuretics seems to be fully justified.

Additionally, non-pharmacological methods can improve the effectiveness in antihypertensive management during pregnancy. According to pregnancy termination, in early late hypervolemic PE (gestational weeks: 34–37), planned delivery is associated with improved maternal yet with less favorable neonatal outcome, compared with expectant management.

Currently, the clinical relevance of this novel PE consideration implies the following. Considering CO or clinical features, the separation of PE cases as either placental or maternal type, is indicated. In the case of placental type, a vasodilator is the preferable drug to a careful decrease of blood pressure, if it is deemed beneficial. In maternal PE, diuretic therapy is a worthy consideration following delivery. In an adipose patient afflicted with generalized gestational edema, with or without hypertension, diuretic management is recommended. On the other hand, in following up regarding the issue of new guidelines of PE management is highly suggested.

Source: P. Tamas ´ et al.; European Journal of Obstetrics & Gynecology and Reproductive Biology 274 (2022) 175–181