Preeclampsia is a multi-system, progressive disorder complicating 2% to 8% of pregnancies with regional variations.1 It contributes to a large percentage of both maternal and fetal morbidity and mortality. Maternal morbidity occurs in 1.4% of deliveries, specifically when the disease progresses to preeclampsia with severe features or eclampsia.2 Currently, research is directed at detecting biomarkers of preeclampsia in the first trimester since early identification will enable clinicians to take preventative steps and offer close monitoring to this high-risk pregnancy group, thereby minimizing adverse perinatal events. In this review, we aimed to review the literature on the pathogenesis of preeclampsia and summarized all prediction modalities that have been studied so far.
Preeclampsia is defined as new onset hypertension in previously normotensive women (systolic blood pressure (SBP) ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) on at least two occasions, at least four hours apart and proteinuria after 20 weeks of gestation.1 Proteinuria is defined as 300 mg/dL of protein or more in a 24-hour urine collection, a protein-to-creatinine ratio of 0.3 or more, or 2+ proteinuria on urine dipstick.1 Recent guidelines allowed the diagnosis of preeclampsia even in the absence of proteinuria, provided that signs or symptoms of significant end-organ dysfunction accompany the new onset hypertension.1 These include thrombocytopenia (platelet count of less than 100 × 109/L), renal insufficiency (serum creatinine more than 1.1 mg/dL or doubling of creatinine in the absence of renal disease), liver dysfunction (liver transaminases at least twice the upper limit of the normal concentrations), pulmonary edema, and new onset headache or visual disturbances.1
Risk factors of preeclampsia are important for its early detection. A prior history of preeclampsia is the most predictive factor for the development of subsequent preeclampsia, and is associated with 8.4 times the risk compared to women with a previous uncomplicated pregnancy.3 Maternal preexisting comorbidities such as preexisting chronic hypertension (relative risk (RR) = 5.1), pre-gestational diabetes (RR = 3.7), anti-phospholipid syndrome and systemic lupus erythematosus (RR = 2.5) play a role as well.3 Preeclampsia is 2.9 times more likely to develop in multifetal pregnancy.3 Other risk factors are nulliparity, increasing maternal age beyond 35 and assisted reproductive techniques.
The pathophysiology of preeclampsia remains not fully understood. Many studies have suggested the presence of two elements implicated in the disease: abnormal placentation and maternal inflammatory response leading to the development of the preeclampsia syndrome.4,5
In a normal pregnancy, the placenta develops from trophoblasts. By the end of the third week of fertilization, trophoblasts surround the embryo and form the interface with maternal tissue.4 The cytotrophoblasts then leave the placenta proper and develop into extra-villous cytotrophoblasts.4 A subset of these cells differentiates from epithelial to endothelial cell type, and further invades the endometrial stroma between glands and capillaries.4 This invasion causes physiological changes in the myometrial spiral arteries characterized by destruction of arterial muscles and elastic tissues, and replacement of endothelium by trophoblasts and internal elastic lamina by fibrin.4 These cause the myometrial vessels to increase by four to six times their initial size, rendering them large tortuous vessels that accommodate the increased blood flow to the placenta.6 These processes appear to be missing in preeclampsia, or at least limited to the decidual vessels rather than extending to the myometrium, resulting in placental hypoperfusion and ischemia.5 Microscopically, these vessels are small in caliber, exhibit medial hypertrophy, fibrin deposition and aggregation of small lymphocytes.7
Defective trophoblast differentiation
When trophoblasts differentiate, they express stage-specific antigens that serve as adhesion molecules.8 They are integrin cell-extracellular matrix receptors, matrix metalloproteinase-9 (MMP-9) and human leukocyte antigen-G (HLA-G). MMP-9 regulates the uterine invasion, and HLA-G regulates immune interactions.8 Analysis of placental specimens of women with preeclampsia showed that trophoblast expression of integrin cell-matrix was altered, namely α1, MMP-9 and HLA-G, hence, leading to dysregulation of the differentiation and invasion process.8
Hypoxia and placental hypoperfusion
Early placental development in normal pregnancies occurs under hypoxic conditions, followed by an abrupt increase in oxygen levels between 8 and 12 weeks of gestation.9 This results in an upregulation in hypoxia-inducible factor (HIF)-1α and HIF-2α in the placenta, two molecular markers of oxygenation which regulate the expression of hypoxia-induced genes including erythropoietin, vascular endothelial growth factor (VEGF) and nitric oxide (NO) synthase.5 Oxygen tension is one of the factors that regulate trophoblast proliferation, differentiation and invasion.10 Under normal circumstances, HIF-1α and HIF-2α upregulate and downregulate when oxygen levels decrease and increase, respectively.10 However, in preeclampsia, they fail to downregulate appropriately.10 This could be an indicator of placental stress.10
Imbalance in angiogenic and anti-angiogenic factors
VEGF is an important angiogenic factor, which acts on endothelial cell growth.11 This action is promoted by NO and vasodilatory prostacyclins, thus resulting in overall decrease of vascular tone and blood pressure.11 Therefore, VEGF antagonism may have a role in hypertension and proteinuria.12 Soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), secreted by the placenta, is upregulated in preeclampsia.5,13
Historically, it was suggested that the maternal immune system does not react to the fetal antigens due to a state of immunosuppression occurring during pregnancy. However, over the years, HLA-G was detected on the surface of invasive trophoblasts.14 This is important because HLA-G protects the trophoblasts from the action of natural killer cells found in the decidua.15 HLA-G expression is absent on trophoblasts in preeclampsia, thus reducing the ability of trophoblast invasion, and causing placental hypoperfusion; it is the hallmark pathology of preeclampsia.16
On the other hand, the cause of hypertension in preeclampsia is attributed to the presence of anti-angiogenic factor and autoantibodies to the angiotensin II type 1 receptors (AT1-AAs), rather than a defect in the renin-angiotensin-aldosterone system itself.17 These autoantibodies can increase the secretion of sFLT1, which is an antiangiogenic factor.18
Another immunological aspect that occurs with normal placentation to prevent rejection of the fetus is the predominance of type 2 T-helper cells (Th2) cytokines such as interleukins 4, 5, 6, and 13, which subsequently suppress type 1 T-helper cells (Th1) by cytotoxic T-cells. In preeclampsia, this balance seems to be disrupted, with predominance of Th1 cytokines such as interferon-gamma (IFNγ) and tumor necrosis factor (TNF).5,19
Placentation is not only controlled by immune cells. Complement activation, especially through the alternative pathway, has been linked to the pathogenesis of the disease.5,16 Activation of the complement, specifically C5a, is an important event that occurs in the pathogenesis of some placental diseases as shown in a mouse model. This activation causes dysregulation in angiogenic factors, namely deficiency of VEGF, and a subsequent defective placental development.20 A study in 2019 showed a correlation between complement activation and increase in levels of sFLT1, without being able to show activation of which factor precedes the other.21 It has also been shown that levels of factor H, which helps regulate the alternative complement pathway, and complements C1q, C3 and C4 are significantly decreased in preeclamptic patients when compared with a control group, probably because of the consumption of these factors. In the same study, the complement activation factor Bb levels were significantly elevated in preeclampsia.22 Patients with elevated levels of fragment Bb are at four-fold risk of developing preeclampsia.23
The two-stage preeclampsia model
Lately, it has been proposed that preeclampsia pathophysiology is best explained by a two-stage process whereby the first stage is dominated by shallow invasion of the trophoblast that leads to inadequate remodeling of the spiral arteries.24 The effect of this stage depends on the degree of inflammation of the maternal vasculature, potentially leading to the second stage, which involves the maternal response to endothelial dysfunction with an imbalance between angiogenic and antiangiogenic factors, that culminates in the clinical characteristics of the disease.
This revised two-stage model of preeclampsia can better account for the disparity in the clinical presentation of this syndrome and stress that the placenta is a key player in all forms of preeclampsia.
Early predictors of preeclampsia
Uterine artery doppler
The use of uterine artery Doppler is based on the fact that preeclampsia is a result of abnormal placentation and hypoxia which causes placental hypoperfusion. Low end-diastolic velocities and an early diastolic notch characterize the waveforms of uterine artery flow in early first trimester. Persistence of this diastolic notch beyond 24 weeks of gestation or abnormal velocity ratios are associated with abnormal trophoblastic invasion.25 Several studies showed no difference in uterine artery Doppler studies in the first trimester. The mean pulsatility index (PI) and presence of early diastolic notch in pregnant women at 11 to 13 weeks of gestation was similar in women with and without preeclampsia.26 Other studies demonstrated that the use of uterine artery Doppler for the prediction of preeclampsia was more effective in the second rather than the first trimester. A systematic review in 2008 studied 15 uterine artery Doppler indices used in the prediction or preeclampsia. It showed that preeclampsia was best predicted in the second trimester with an increased PI accompanied with bilateral notching with 19% sensitivity and 99% specificity25 with each unit increase in the uterine artery PI being associated with a 37-times fold risk of preeclampsia. The combination of both uterine artery PI and umbilical peak systolic velocity index predicted 80.3% of the cases of severe preeclampsia.27 The use of uterine artery Doppler alone for the prediction of preeclampsia has not been standardized, especially because studies have used different indices. Its use may be more predictive if combined with maternal risk factors, mean arterial pressure and serum biomarkers.28
Vitamin D Levels
A meta-nalysis in 2017 showed that the risk of preeclampsia was reduced upon introduction of calcium and/or vitamin D, although this reduction was not statistically significant compared with the placebo group. Vitamin D regulates calcium homeostasis, which in turn decreases the tone of vascular smooth muscles, causing vasodilation, and hence, lowers the risk of preeclampsia.29 It also appears to play a role in regulating the genes responsible for placental invasion, implantation and angiogenesis.30 Vitamin D levels have also been studied in different autoimmune disease, suggesting its role in regulating T-cells and inflammatory cytokines.31 Therefore, studies were directed to determine the effect of vitamin D on preeclampsia. A systematic review in 2019 showed that vitamin D supplementation was associated with a reduced risk of preeclampsia (odds ratio (OR): 0.37, 95% confidence interval (CI):0.26–0.52).32 A maternal 25-hydroxy-vitamin D (25(OH)D) concentration less than 37.5 nmol/L at less than 22 weeks of gestation was associated with a 5-fold increase in the risk of development or preeclampsia, independent of maternal characteristics.30 This risk is significantly decreased with supplementation of vitamin D.30 A randomized controlled trial showed that women with vitamin D levels above 30 ng/mL had significantly lower incidence of preeclampsia (2.25%) compared with women who had lower levels at the same point in time (11.92%). The risk reduction of preeclampsia was directly proportional to the levels of vitamin D.33
VEGF, PlGF, sFLT-1, and sFLT1/PlGF ratio
The concept of imbalance between angiogenic and antiangiogenic factors in the development of preeclampsia has become widely accepted. Of interest are the two angiogenic factors VEGF and PlGF, and the antiangiogenic factor sFlt-1. In pregnancies complicated with preeclampsia, sFLT-1 is increased, thus decreasing the levels of VEGF and PlGF and disrupting the normal process of angiogenesis.34–36 The study by Chen et al. showed that the levels of sFLT-1 were higher in preeclamptic women compared with normal ones.37 The levels also predicted the severity of the disease.37 In the same study, the levels of sFLT-1 were significantly higher in patients with late-onset severe preeclampsia vs. those with early-onset severe preeclampsia.37 Patients with low levels of sFLT-1 (< l26.8 μg/L) had a systolic blood pressure (SBP) of (152.9 ± 1.64) mm Hg while that of those with high levels of sFLT-1 (≥l26.8 μg/L) was (162.37 ± 3.36) mm Hg, P < 0.001.37 Levine et al. studied the angiogenic factors in preeclampsia and normal pregnancies; sFLT-1 levels were approximately 2.5 times higher, VEGF levels 2 times lower, and PlGF levels almost 5 times lower in preeclampsia pregnancies.35 Moreover, a temporal relation existed between the alteration of the levels of these biomarkers and the development of preeclampsia. sFLT-1 and PlGF levels started to shift from normal 11 to 9 weeks before the actual onset of preeclampsia.35 VEGF levels however did not appear to vary in preeclampsia and normal pregnancies.35 Another study showed that the variations in the levels are more pronounced in early than late-onset preeclampsia.36 sFLT1 was 43 and 3 times higher and PlGF levels were 21 and 5 times lower in early and late onset preeclampsia, respectively compared with controls.36 In practice, sFLT1/PlGF ratios have been used to detect preeclampsia early. A study showed that this ratio was moderately elevated in participants with gestational hypertension and markedly elevated in those with preeclampsia. A cutpoint ratio of ≥ 85 in women less than 34 weeks, predicted more severe adverse outcomes.38 Comparing the ratio between the preeclampsia and control groups, the average of the preeclampsia group (354.5 ± 44.84) was significantly higher than that of the control group (19.43 ± 1.62). The ratio is a better marker than either one of the parameters alone, with a sensitivity of 82% and specificity of 95% when the cutoff of 85 is used.39 More recently, a low PlGF was found to correlate with preterm delivery independent of a diagnosis of preeclampsia or gestational age at presentation.40
Soluble endoglin (sEng)
Endoglin is a cell-surface receptor found on the cell membranes of vascular endothelium and syncytiotrophoblasts. It acts as an antiangiogenic factor by inhibiting the action of the angiogenic factors transforming growth factor (TGF)-β1 and TGF-β3. It also inhibits the role of endothelial NO synthase, thereby interfering with the vasodilatory effect of NO mediated by TGF.41 Several studies have shown that an association between endoglin and preeclampsia and its severity exists. Venkatesha et al. noted a four-fold increase in Endoglin mRNA and sEng in preeclamptic patients. Further analysis showed that the level of sEng serves as a prognostic marker as well. Concentrations of sEng were three-fold, five-fold and ten-fold higher in patients with mild preeclampsia, severe preeclampsia and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, respectively, when compared to controls.41 Another study assessed the variation of sEng levels at different gestational periods in normal pregnancies and in those complicated with preeclampsia. In controls, levels of sEng started to increase beyond 33 to 36 weeks of gestation. However, in women with term preeclampsia, these levels started to rise at the 25th through the 28th week of gestation, and for preterm preeclampsia, at the 17th through the 20th week. These levels started to vary 11 to 9 weeks before the onset of the disease in preterm preeclampsia and 14 to 12 weeks before term preeclampsia. The levels of sEng were significantly higher in preterm preeclampsia (10.2 ng/mL) and term preeclampsia (8.5 ng/mL) when compared to controls (5.8 ng/mL).42
Pregnancy-associated plasma protein A (PAPP-A) and alpha fetoprotein (AFP)
Low maternal serum levels of PAPP-A in the first trimester and high levels of AFP in the second trimester have been reflective of placental insufficiency complicating pregnancy as in small for gestational age, preterm birth and preeclampsia.43 These markers require correction for maternal weight and gestational age when used for aneuploidy prediction. Despite the perplexing evidence about their use for the prediction of preeclampsia,44,45 a recent study showed interesting results. Previous promising results of sFLT1/PlGF for preeclampsia prediction have led researchers to investigate the role of AFP/PAPP-A ratio. An uncorrected ratio of AFP/PAPP >10 in the first trimester was associated with a three- to five-fold risk of several placentally related adverse outcomes including preeclampsia, and two-fold risk of preeclampsia with preterm delivery and severe preeclampsia compared to a ratio ≤10.43 This uncorrected ratio was more predictive than when either of the biomarkers was corrected and used as a single indicator.43 Recently, combination of PAPP-A and PlGF was found to be similarly predictive of early-onset and preterm preeclampsia when performed before or after 11 weeks of gestation.46
The theory of altered immune response in the pathogenesis of preeclampsia has been described, with disruption of the balance of lymphocytic cells. The two main antagonistic lymphocytic cells are the T-regulatory CD4+ cells (Tregs) and T-helper cells (Th17). Tregs prevent the immune system's reaction to fetal tissue, and Th17 cells promote inflammation and autoimmunity. In normal pregnancies, Tregs increase and Th17 cells decrease. This balance seems to be disrupted in preeclampsia.47 Interleukin-17 (IL-17) is an inflammatory cytokine secreted by Th17 cells. It plays an important role in the induction of inflammation.48 Based on this, several studies have investigated the association between IL-17 and diseases of the placenta, one of which being preeclampsia. The median concentrations of IL-17 were noted to be significantly higher in the sera of preeclamptic (3.9 pg/mL) compared with normotensive women (2.4 pg/mL, P < 0.01).48 Many studies have described a relation between the levels of Treg cells and preeclampsia.49 Previously, it was thought that the immunological malfunction that occurs in preeclampsia is due to an altered function of Treg cells rather than a decrease in their level.50 However, recent studies contradicted this theory. The levels of Treg cells in patients with preeclampsia (median 3.1%) were found to be lower than those of patients with normal pregnancy (median 8%), range 4.4%–15%).51 Another study showed similar results, where the ratio of Treg cells (also known as CD4+CD25+T cells) in CD4+ lymphocytes were significantly lower in the preeclampsia group (6.76 ± 3.37)% compared with normotensive women (9.01 ± 2.18) %, P < 0.001.52
- The guidelines of the UK National Institute for Health and Clinical Excellence (NICE) and the American Congress of Obstetricians and Gynecologists (ACOG), continue to recommend the use of the traditional screening approach to evaluate women with high risk of developing preeclampsia.53,54 This is done through deriving risk factors from their medical histories and maternal demographic features.
- With the growing literature about early markers for the identification of preeclampsia, several multiparametric algorithms have been developed so far55–59 and some have been validated in Europe60,61 and China.62
- These models are derived from logistic regression analysis combining maternal characteristics and medical and obstetric risk factors with a combination of biophysical and biochemical markers. Although these algorithms seem to outperform the traditional risk-factor screening approach in the prediction of preeclampsia, their prediction performance is lower when applied to populations other than the original population from which they were derived.63
- With the availability of an effective pharmacological intervention namely low-dose aspirin to reduce the incidence developing preeclampsia and other pregnancy complications,64–66 early detection using a yet to be determined ideal combination of markers for routine screening seems to make more sense.
Preeclampsia remains one of the major causes of morbidity and mortality for both mothers and newborns worldwide. Efforts have been directed to understand the pathology underlying this disease to find strategies for prevention, early detection, treatment and prognosis. Several studies have shown promising results on the use of uterine artery Doppler and serum biomarkers such as vitamin D, sFLT1/PlGF ratio, sEng, and a subset of T-lymphocytes. It is unclear at this point whether one is superior to another, or whether the combination of any is superior to the use of a single marker. Large-scale, multicenter, multiethnic, prospective trials studies are required to improve screening strategies and evaluate the cost-effectiveness of any intervention. These new ways will possibly lead to new lines of treatment and possible targeted therapy for preeclampsia.
Conflicts of Interest
Anwar H. Nassar is an Editorial Board Member of Maternal-Fetal Medicine. The article was subject to the journal's standard procedures, with peer review handled independently of this editor and their research groups.
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