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Review Article

Blood laboratory testing for early prediction of preeclampsia: chasing the finish line or at the starting blocks?

Martina MontagnanaSezione di Biochimica Clinica, Dipartimento di Neuroscienze, Biomedicina e Movimento Università di Verona, Italy; Correspondence[email protected]
,
Elisa DaneseSezione di Biochimica Clinica, Dipartimento di Neuroscienze, Biomedicina e Movimento Università di Verona, Italy;
,
Giuseppe LippiSezione di Biochimica Clinica, Dipartimento di Neuroscienze, Biomedicina e Movimento Università di Verona, Italy;
&
Cristiano FavaSezione di Medicina Interna C, Dipartimento di Medicina, Università di Verona, Italy
Pages 240-253 | Received 22 Jul 2016, Accepted 26 Oct 2016, Published online: 29 Nov 2016

Abstract

Preeclampsia (PE) affects 2–8% of pregnancies worldwide, thus representing an important cause of maternal and neonatal morbidity, up to death. Many studies have been designed to identify putative biomarkers for accurate and timely diagnosing PE, but only some of them were focused on specific and sensitive biomarkers for early prediction of this life-threatening condition. In particular, some prospective studies aimed to investigate the predictive role of circulating biomarkers before 20 weeks of gestation in the general pregnant population yielded conflicting results. This article is hence centered on results obtained in studies investigating the predictive performances of angiogenic, anti-angiogenic, inflammatory, endocrine, and epigenetic biomarkers. The available evidence suggests that angiogenic and anti-angiogenic molecules, in particular the sFlt1:PlGF ratio, may be considered the biomarkers with the best diagnostic performance in the second trimester. However, doubts remain about their use in clinical settings before the 20th gestational week. Even lower evidence is available for other biomarkers, due to the fact that some positive results have not been confirmed in ensuing investigations, whereas unresolved analytical issues still contribute to make their clinical reliability rather questionable. Differential expression of microRNAs seems also a promising evidence for early prediction of PE, but additional research and well-designed prospective studies are needed to identify and validate routine predictive tests.

    KEY MESSAGES

  • Preeclampsia affects 2–8% of pregnant women worldwide, thus remaining one of the leading causes of maternal and neonatal morbidity and mortality.

  • Several studies have investigated the predictive role of circulating biomarkers before 20th week of gestation with conflicting results.

  • Additional research and well-designed prospective studies are needed to identify and validate predictive tests in clinical practice.

Introduction

Hypertensive disorders complicate 10–20% of pregnancies, are implicated in 20% of maternal deaths, and ultimately cause nearly 10% of preterm birth (Citation1). Preeclampsia (PE) affects 2–8% of pregnant women worldwide, thus remaining one of the leading causes of maternal and neonatal morbidity, up to death (Citation2,Citation3). In 2010, the National Institute for Health and Care Excellence (NICE) has released a definition of PE based on the presence of systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥90 mmHg in two different occasions accompanied by proteinuria (i.e., ≥300 mg of protein in 24-h urine collection or ≥1 + protein on an urine dipstick) observed after the 20th gestational week (GW) (Citation4). More recently, the American College of Obstetricians and Gynecologists has released new guidelines, which have considerably modified the diagnostic criteria for PE (Citation1). According to these guidelines, the diagnosis of PE can be made, even in absence of proteinuria, on the basis of new-onset hypertension occurring after the 20th GW associated with one of the following criteria: thrombocytopenia (platelet count <100,000/μL), impaired liver function as mirrored by abnormally elevated blood concentrations of liver enzymes (more than double the normal concentration), progressive renal failure (i.e., serum creatinine concentration >1.1 mg/dL or a doubling of serum creatinine concentration with no evidence of other renal diseases), new onset of cerebral or visual disturbances or pulmonary edema (Citation1).

The early identification of pregnant women at risk of developing PE is an essential aspect to prevent acute and chronic consequences for both the mother and the fetus (Citation5). Thus, the importance of having a sensitive test to detect PE in early pregnancy, derives from the possibility to program a more intensive antenatal surveillance, to avoid delivery in emergency conditions and to eventually institute preventive interventions such as low dose aspirin to prevent the onset of PE (Citation6,Citation7). In particular, a recent meta-analysis showed that the administration of low-dose aspirin is effective to reduce the rate of PE in high-risk pregnant women (Citation8), a therapeutic intervention whose efficacy is higher the earlier is established (Citation9).

Several studies, especially published in the past few years, have been focused on identifying specific and sensitive circulating biomarkers, used either alone or in combination, for prediction and early diagnosis of PE (Citation10,Citation11) (). Most of these biomarkers were chosen to target specific pathophysiological abnormalities characterizing PE (Citation5). Nevertheless, the limited predictive value, the elevated costs and the need for validation in larger population samples have prevented or delayed their introduction in clinical practice (Citation12,Citation13).

Table 1. Diagnostic performance of blood circulating biomarkers for early prediction of PE (<20th GW).

PE is a multi-systemic disorder characterized by abnormal placentation (Citation14), endothelial dysfunction, exaggerated inflammatory and deranged immunity response (Citation5,Citation15). According to recent studies, epigenetic mechanisms such as modulation of microRNAs (miRs) expression or DNA methylation may also be involved in transition from physiologic to pathologic pregnancy (Citation16).

Although some biomarkers may have an important role in the pathophysiology of PE, in this review we will focus especially on their performance as predictors of this condition, to dissect whether or not their use can be proposed in clinical practice. Thus, our aim is to provide an overview of the most interesting results obtained in studies investigating the role and predictive performance of angiogenic, anti-angiogenic, inflammatory, immunological, endocrine, and epigenetic circulating blood biomarkers, measured before the 20th GW.

However, our search has been hampered by the fact that not all the measures of the performance of diagnostic tests, were reported in the retrieved studies. Rather, some studies report AUC and eventually sensitivity and specificity, but many do not calculate or estimate positive and negative predictive values (PPV and NPV), and a few report likelihood ratios, positive and/or negative (LR + and LR–): this makes the results of single studies difficult to compare between each other. Moreover, the populations which were analyzed are different in terms of the a priori probability of PE. Since the major aim of a screening test for the prediction of PE, early during pregnancy, is to avoid false negative results (it is preferable to include in a closer monitoring follow-up women who did not need it rather than exclude from it women who needed it), we think that probably tests that maximize sensitivity should be preferred at cost of a lower specificity. On the other hand, similar PPV can be associated with really different scenarios starting from an unselected population at low risk for pre-eclampsia rather than from a selected sample where the incidence of PE is expected to be higher (Citation17).

When possible we tried to explicit these problems and, in , we have also presented an estimate of PPV based on the possible prevalence of PE of 1%, 2%, 5%, 10%, or 20%, starting from Bayes theorem.

Table 2. Estimated positive predicted values according to a hypothesized prevalence of PE of 1, 2, 5, 10, and 20%, in the screened population.

There are also many reports about combination of different biomarkers and especially about the sum of biomarkers with Doppler ultrasound and, as expected, the combination usually reinforces the prediction (Citation18–26). Nevertheless, we would like to focus our attention especially on blood biomarkers separately, so that a comparison between their capabilities of prediction is easier to dissect. Moreover, Doppler ultrasound is informative especially in the second trimester of pregnancy. Finally, urine biomarkers, which can be particularly useful in low-resource settings, are not addressed in the present review but the interested reader can refer to another recent review article (Citation27).

Angiogenic and anti-angiogenic biomarkers

Abnormal angiogenesis in placenta is certainly implicated in the pathophysiology of PE, by causing impaired remodeling of maternal spiral arteries, placental dysfunction, and low perfusion (Citation28). In particular, some members of the vascular endothelial growth factor (VEGF) family, especially VEGF-A and its tyrosine kinase receptors (Flt1 and KDR), are thought to be important factors in both fetal and placental angiogenic development (Citation28). Serum placental growth factor (PlGF) is another member of the VEGF sub-family. Although VEGF and PlGF are angiogenic modulators, sFlt1 and soluble endoglin (sEng), a novel placenta-derived soluble TGF-beta co-receptor, mainly act as anti-angiogenic factors (Citation29,Citation30).

VEGF and PlGF expression is induced in response to tissue hypoxia and endothelial cell damage (Citation30). Some studies found that the circulating values of these angiogenic mediators were higher in patients with PE compared to healthy pregnant controls (Citation31–33). However, in the nested case-control study of Odibo et al. (Citation32), recruiting women in a first-trimester screening program, predictive performance evaluated by means of receiver-operating characteristic (ROC) curves, demonstrated that none of the biomarkers were clinically useful for prediction in the first trimester of PE. As regards the most representative investigations, Levine et al performed a nested case-control study by measuring the serum concentrations of total sFlt-1, free PlGF and free VEGF throughout pregnancy in 120 pairs of healthy nulliparous women (Citation34), and observed that biologically active free PlGF levels between the 13 and 16 GWs were significantly lower in women who later developed PE than in those who did not. However, a later increase of sFlt-1 values was observed, with statistical significance being reached in PE cases after the 33th GW. The VEGF concentrations remained low throughout the pregnancy and did not differ between PE cases and controls.

Despite the fact that these angiogenic and anti-angiogenic modulators can be easily measured by using automated immunoassays (Citation35,Citation36), the real clinical usefulness for predicting PE remains a matter of debate (Citation37). More informative data has emerged from the serum sFlt1:PlGF ratio, wherein its diagnostic performance exhibited a diagnostic accuracy (area under the curve, AUC) greater than 0.90 in large observational studies including pregnant women in second or third trimesters of pregnancy (Citation38,Citation39) or carried out in selected population at higher risk of PE (Citation40–42). In particular, Zeisler et al. (Citation28) performed a prospective, multicenter, observational study on 1050 pregnant women (500 included in the development cohort and 550 in validation cohort) at 24–36 GW at the first visit, by demonstrating that an sFlt-1:PlGF ratio cutoff of 38 had important predictive value. The predictive performance of sFlt-1 and PlGF, used separately, was not superior to the predictive performance of the sFlt-1:PlGF ratio (Citation38).

Notably, the limited number of prospective studies which investigated the predictive role of angiogenic factors before 20th GW yielded rather contradictory results (Citation18,Citation19,Citation24,Citation25,Citation43,Citation44). Crovetto et al. (Citation45) studied 9462 pregnant women undergoing first-trimester screening, and observed that the inclusion of angiogenic factors (PlGF and sFlt-1) measured at 8–11 GW in combined algorithms substantially improved PE prediction. More recently, Andersen et al prospectively studied an unselected cohort of 1909 pregnant women, and showed that PlGF and the sFlt-1/PlGF ratio measured at 20–34 GWs had a good predictive value for PE, displaying and AUC of 0.704 and 0.755, which remarkably increased to 0.901 and 0.883 for severe early-onset PE (Citation46). Importantly, both PlGF and the sFlt-1/PlGF ratio were not found to be significant predictors of PE when assayed between 8 and 14 GWs. As clearly highlighted by the results of these studies, the values of angiogenic biomarkers appears to be not sufficiently early modified in women with PE, so that their assessment in the first half of pregnancy has not acceptable performance for predicting the later development of PE (Citation44).

Endocrine and immunological biomarkers

The placental production and secretion of several hormones seem tightly coordinated and regulated during physiological pregnancy. Low values of Pregnancy-Associated Plasma Protein-A (PAPP-A) and placental protein 13 (PP13), along with and elevated level of α-fetoprotein (AFP), β-human chorionic gonadotropin (hCG), activin-A and inhibin-A were found to be significantly associated with development of PE in several studies which measured these biomarkers during the first trimester (Citation47–52). However, when the data of eight studies totaling 115,290 pregnancies where pooled in a meta-analysis, no combination of these serum biomarkers was found to be acceptable for early diagnosis of PE (Citation53). Comparable data were reported by a more recent meta-analysis based on 103 studies which evaluated the accuracy of PAPP-A, hCG, PlGF, and PP13 measured during the first trimester for predicting PE and secondary end-points such as small for gestational age (SGA) and preterm delivery (Citation54). PlGF was found to be the best predictor of PE, displaying positive and negative likelihood ratios of 4.01 and 0.67, respectively. Nevertheless, this diagnostic performance remains still far from being considered clinically useful. Allen et al also performed a meta-analysis of 30 studies totaling 65,538 women, with the aim to define the diagnostic role of several putative biomarkers of PE. When evaluating only those measured in the first trimester the study included PAPP-A (nine studies), PlGF (four studies), PP13 (foyr studies), β-hCG (four studies), sEng (two studies), inhibin-A (five studies), sFlt-1 (four studies), p-selectin (one study), pentraxin (one study), and VEGF (one study) (Citation55). Interestingly, PAPP-A (odds ratio [OR], 2.1; 95% CI, 1.6–2.6), PP13 (OR, 4.4; 95% CI, 2.9–6.8), sFlt-1 (OR, 1.3; 95% CI, 1.02–1.65), pentraxin (OR, 5.3; 95% CI, 1.9–15.0), and inhibin-A (OR, 3.6; 95% CI, 1.7–7.6) were found to be significant predictors of PE.

A number of studies which measured PP13 between 5 and 7 GWs in healthy women and PE cases concluded that the concentration of this biomarker may be significantly lower in PE, but then considerably increases in parallel with the severity of PE (Citation56–58). However, a very recent study published by Schneuer et al., (Citation59) measured first trimester PP13 in an unselected maternal cohort of 2989 women, and concluded that the diagnostic performance of this biomarker was only marginally useful (AUC, 0.73; 95% CI, 0.69–0.77) for purposes of early diagnosis or risk stratification of PE.

Spencer et al measured activin-A and inhibin-A between the 11 and 14 GWs in 64 women and observed that serum values of these biomarkers was not useful for early identification of pregnancies at risk of PE (Citation60). More specifically, the AUC was 0.64 (95% CI, 0.55–0.72) for inhibin-A and 0.59 (95% CI, 0.51–0.67) for activin-A, respectively, yielding an overall diagnostic efficiency at the 90th percentile cut-off value of 20% and 35% for activin-A and inhibin-A, respectively. And the same low diagnostic performance, apart from studies with a limited number of cases (Citation24,Citation61), were shown also in other studies (Citation25,Citation51,Citation62).

Corin is an atrial natriuretic peptide-converting enzyme which promotes trophoblast invasion and uterine spiral artery remodeling. Interesting evidence about the potential role of corin in the pathogenesis of PE emerged from the study of Cui et al. (Citation63), who showed that this protein promotes trophoblast invasion and spiral artery remodeling. Notably, it was also shown that corin-deficient pregnant mice were prone to develop some typical features of PE such as hypertension and proteinuria. An additional important aspect was the observation that Corin mRNA and protein serum levels were found to be significantly lower in PE patients than that in women with normal pregnancies. Opposite results were obtained in a subsequent case-control study published by Zaki et al. (Citation64), who showed that plasma values of corin mean were significantly higher in pregnancy-induced hypertensive patients than in a control group of healthy pregnant women. Further doubts about the potential usefulness of corin in PE emerged from the study of Khalil et al. (Citation65), who measured this biomarker every four weeks until delivery in 122 women, 85 who concluded a healthy pregnancy, 12 who developed gestational hypertension, 13 who developed term PE and 12 who developed preterm PE. At variance with the previous two studies, a significant difference was observed in corin serum levels only between normotensive group and preterm PE (p = 0.001) requiring delivery before 37 weeks’ gestation, but not between normotensive and term PE women (Citation65).

Like corin, controversial data also emerged from studies which measured copeptin, a 39-amino acid C-terminal component of prepro-vasopressin (Citation66). Yeung et al measured serum copeptin values in samples longitudinally drawn throughout pregnancy in 136 healthy controls, 169 PE women, 92 women with gestational diabetes mellitus, 101 with gestational hypertension, and 86 with preterm birth (Citation67). It was hence observed that copeptin values measured at the 16th GW were significantly associated with the risk of PE (OR, 1.55; 95% CI, 1.03–2.31). This association was found to be stronger when PE was diagnosed before the 37th GW (OR, 1.86; 95% CI, 1.08–3.20). Despite the serum value of copeptin levels increased in parallel with gestational age in PE cases and controls, the difference remained statistically significant. At variance with these results, Birdir et al. (Citation68) measured serum copeptin levels during 11–13 gestation weeks in 35 women with PE and 100 health pregnant controls, failing to find any significant difference between the two groups. Like corin, the clinical usefulness of measuring copeptin for early identification of PE remains hence rather questionable.

Inflammatory biomarkers

An abnormal maternal inflammatory response due to inadequate trophoblast invasion has been implicated in the onset of PE, probably mediated by an interplay between inflammation and activation of maternal endothelium (Citation69,Citation70). In different studies the concentration of a large number of vascular inflammatory biomarkers was found to be variably increased or decreased in PE patients compared to healthy pregnant controls. These markers basically included C-reactive protein (CRP), leukocytes, neutrophils, pentraxin-3, tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and interleukin-8 (IL-8), and anti-inflammatory biomarkers (omentin-1, nesfatin-1, and lipoxin A4) (Citation69,Citation71–79). Nevertheless, only few studies investigated the clinical usefulness of measuring these biomarkers in the first trimester for predicting the following development of PE.

Hamai et al. (Citation71) measured IL-2 and TNF-α in 32 pregnant women between the 11 and 13th GWs, and found that the values of both cytokines were significantly higher in women who developed PE compared to those who did not. The diagnostic accuracy was 81% for IL-2, using a cut-off of 0.4 U/mL and 75% for TNF-α using a cut-off of 7 pg/mL, respectively. Freeman et al studied 34 women who developed PE and 34 age- and parity-matched controls without adverse pregnancy outcome, and observed that IL-6 values were slightly but not significantly higher in women who later develop PE than in those who did not (1.58 versus 1.19 pg/mL, p = 0.051) (Citation72). Interestingly, in this same study the concentration of other biomarkers including CRP, IL-10, sVCAM, sICAM, and TNF-α was found to be virtually identical in PE cases and controls.

Siljee et al. (Citation73) used a pre-targeted proteomics approach with 41 bead-based multiplexed immunoassays to investigate serum samples collected at the end of the first trimester, and observed that only IL-1 beta among the various inflammatory biomarkers resulted significantly increased in PE. Unlike this previous study, Tangerås et al. (Citation80) studied 548 pregnant women who were either nulliparous or multiparous with previous gestational hypertension or PE, and showed that women who developed gestational hypertension had increased serum values of IL-1β, IL-5, IL-7, IL-8, IL-13, basic fibroblast growth factor and VEGF than those who subsequently developed PE. Compared to normal pregnancy, women who developed PE had also increased serum levels of both IL-5 and IL-12.

Chemerin, also known as tazarotene induced gene 2 (TIG2) and retinoic acid receptor responder 2 (RARRES2), is a pro-inflammatory adipokine which acts recruiting and activating immune cells (Citation81). Xu et al. (Citation82) studied 518 pregnancy women, and showed that the first trimester serum values of chemerin were independent predictors of PE.

Even after excluding the presence of infectious diseases, high-sensitivity C-reactive protein (hs-CRP) was found to be increased in patients with PE, and its concentration was found to increase in parallel with the severity of the disease (Citation74). CRP is actively produced and released into maternal circulation by placental tissue (Citation83). Kashanian et al. (Citation84) measured hs-CRP during 8–13 GWs in 394 pregnant women, and observed that the concentration of this biomarker in the PE group (n = 42) was higher than in normotensive pregnant women (7.1 ± 2.6 mg/L versus 3.6 ± 2.3 mg/L, p = 0.001). The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy at the cut-off value of 4 mg/L were 0.78, 0.72, 0.25, 0.96, and 0.73, respectively. Interestingly, the use of a slightly higher cut-off value (i.e., 7 mg/L) allowed to accurately diagnosed 74% cases of severe PE (relative risk [RR], 9.3; 95% CI, 4.5–19.5). Unlike this study, Karinen et al. (Citation85) observed no differences in hs-CRP levels measured during first trimester between women with PE and those with healthy pregnancy.

Endothelial and coagulation activation biomarkers

Alterations of primary and secondary hemostasis, including platelet activation, hemodynamic and clotting abnormalities, and endothelial dysfunction, are common pathogenetic events that may sustain a hypercoagulability state in PE (Citation86). A variety of case-control and prospective studies were hence planned to investigate the role of platelet indices including immature platelet fraction (IPF), mean platelet volume (MPV) and P-selectin, or other indirect biomarkers of platelet activation (e.g., platelet-leukocyte and platelet-monocyte aggregates) in PE (Citation87–93).

Nearly 20 years ago, Konijnenberg et al. (Citation91) performed a prospective study including 244 pregnant women (17 of whom developed PE) aimed to assess the role of platelet activation biomarkers as putative predictors of PE. The expression of P-selectin (alpha-granule secretion), GP53 (lysosomal secretion) and GPIIa' (platelet endothelial cell adhesion molecule-1) was measured using flow-cytometric analysis. Among these platelet activation indices, only first-trimester GP53 resulted a possible predictor of PE (i.e., AUC >0.5) with a sensitivity of 47% and a specificity of 76% with use of a percentage of activated platelets above 2% as a positive test.

P-selectin expression not only is a reliable marker of platelet activation, but this receptor also plays an important role in both inflammatory and hemostatic reactions (Citation89,Citation94). Earlier evidence suggested that P-selectin was actively released from platelets after activation, but its concentration was not found to be significantly increased in women with PE compared to normotensive pregnant and non-pregnant controls (Citation95). At variance with this data, Bosio et al. (Citation96) performed a longitudinal study including 70 women who were followed up from the first trimester (11–14 GW) until delivery, and found that mean plasma P-selectin values were significantly increased by 10–14 GWs in women who later developed PE. P-selectin measurement was associated with 0.99 negative predictive value and 0.32 positive predictive value for predicting PE. These results were then confirmed in a case-control study including 56 women who developed PE and 168 healthy controls (Citation97). P-selectin was measured between the 11 and 15 GWs, and the overall predictive ability given a positive P-selectin value was found to be as high as 59%. However, in other studies P-selectin did not show the same diagnostic performance both in detecting early and late PE (Citation19,Citation98). Indeed, the main drawback of using this biomarker is represented by the cumbersome analytical technique and the poor standardization, thus seriously hampering the access to its measurement in many clinical laboratories.

Many platelet parameters can now be easily, inexpensively, and quickly measured by using modern hematological analyzers, thus opening interesting diagnostic perspectives for several human disorders, including PE. Dundar et al. performed a longitudinal study including 1336 pregnant women in the first trimester attending to the “GATA Haydarpasa Teaching Hospital Obstetric Outpatient Clinic” (Citation99), and found that MPV values in women who developed PE (n = 107) were significantly higher than in normotensive counterparts after the 24th gestational week. Interestingly, an increase of MPV value was found to anticipate the diagnosis of PE by approximately 4.6 weeks. In another study, Kanat–Pektas studied 200 healthy pregnant women who had MPV measured in the first trimester of pregnancy (11–14th GW) and were then prospectively followed until delivery. The MPV value was found to be significantly higher in PE pregnancies (p = 0.001) compared to physiologic pregnancies. Moreover, MPV values >10.5 fL predicted the development of PE with 0.67 sensitivity and 0.64 specificity (Citation88). More recently, Kirbas and colleagues retrospectively analyzed many parameters of the complete blood cell count (CBC) during the 11–14 GWs in 614 consecutive pregnant women with PE and 320 women with uncomplicated pregnancy (Citation100). Despite most of the CBC parameters (i.e., mean white blood cell, neutrophil, platelet, and MPV) did not differ between groups, the neutrophil to lymphocyte ratio (NLR) was found to be significantly increased in the PE group. A NLR cut-off value of 4.01 was associated with an AUC of 0.57, 0.79 sensitivity, and 0.39 specificity.

Despite the activation of coagulation occurs at early stages in the pathogenesis of PE (Citation101,Citation102), coagulation and fibrinolytic system proteins have been investigated only in the second or third trimester of pregnancy (Citation103–105) and none prospective study has been performed to investigate the predictive role coagulation and fibrinolytic biomarkers. Enhanced thrombin– antithrombin complex (TAT) formation and thrombin generation have been observed in women affected by hypertensive disorders of pregnancy (Citation106–108). An increase of plasma fibrinogen levels was observed in early pregnancy compared with pre-pregnancy, but no significant difference in fibrinogen and other coagulation markers were found between women with PE and physiological pregnancies in a cross-sectional study carried out by Hale et al. (Citation109). In a further study, Han et al retrospectively analyzed the changes of blood coagulation parameters and platelet indices in 79 normal and 95 PE pregnancies (Citation110). Among the various parameters tested in early pregnancy (i.e., activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen, thrombin time (TT), platelet count, platelet distribution width (PDW) and MPV) the diagnostic performance (i.e., AUC) ranged from 0.49 to 0.74, with the best performance displayed by TT (AUC, 0.74).

Circulating nucleic acids and microRNAs

Among the novel approaches for predicting PE, two innovative and non-invasive approaches may be regarded as valuable perspectives. The former entails the measurement of circulating nucleic acids, both as cell-free DNA (cfDNA) and cell-free fetal DNA (cffDNA), whereas the latter is based on the evaluation of epigenetic biomarkers, essentially represented by microRNAs (miRs) expression (Citation111–115).

Total cell free DNA in maternal plasma or serum is the sum of cfDNA (of maternal origin) and cffDNA (of fetal origin). Although cffDNA only represents 2–6% of circulating DNA in maternal blood during physiological pregnancy (Citation116), an increased amount of cffDNA is commonplace in the blood of women with PE, probably reflecting underlying placental abnormalities or hypoperfusion, and finally resulting in increased apoptosis and necrosis of placental cells (Citation114,Citation115). Impaired fetal DNA clearance from maternal plasma has been suggested as another potential cause of increased cffDNA concentration in PE (Citation117).

The presence of cffDNA in maternal peripheral blood was discovered in 1997 by Lo et al. (Citation118), leading the way to the publication of a study aimed to evaluate cffDNA concentration in the plasma of pregnant preeclamptic women (mean gestational age, 32 weeks) two years later (Citation119). The role of cffDNA for predicting PE was then confirmed by ensuing studies in women in the second trimester of pregnancy (Citation120,Citation121).

In 2014, Martin et al. (Citation111) performed a systematic literature review including 13 studies which investigated cffDNA levels as a putative marker of PE, and concluded cffDNA measurement is indeed a promising approach for predicting PE, especially for early-onset PE. More recently, Vlková et al carried out a systematic literature review including 22 studies which measured fetal DNA in preeclamptic pregnancies (Citation122). Unfortunately, a meta-analysis was unfeasible due to the large heterogeneity of the studies, which was mostly attributable to sampling time (ranging from 9 to 41 GWs) and to the techniques used for measuring cffDNA. Notably, the more common techniques for cffDNA quantification are based on the amplification of Y-chromosome-specific gene sequences, especially by the measurement of SRY target or DYS14 sequence, with the latter technique being more sensitive than the former (Citation123). The major drawback of these methods is that they can only be used when the fetus is male. To overcome this problem, Lo et al. (Citation124) developed an innovative test based on the evaluation of mapsin (SERPINB5) methylation status, which was finally found to be useful for discriminating fetal and maternal DNA in maternal plasma.

Rolnik et al. (Citation125) studied 20 women with early PE needing delivery at <34 weeks, 20 women with late PE needing delivery after 34 GWs and 200 normotensive pregnant women, who had cfDNA at both 11–13 and 20–24 GWs. In women with early PE a significantly increased total cfDNA (2104 genome equivalents (GE) versus 1590 GE/mL) along with decreased fetal fraction (6.8% versus 8.7%) were found compared to normotensive women. More recently, Kim et al. (Citation126) performed a case-control study including 17 gestational hypertension cases, 34 women with PE, and 84 controls. A panel of different markers was used, showing that the best model for PE prediction was that including first-trimester cffDNA biomarkers (i.e., DSCR3 and HYP2) combined with PAPP-A (AUC, 0.83; 95% CI 0.69–0.93).

MiRs are short non-coding molecules (between 19 and 24 nucleotides) which act by regulation of post-transcriptional gene expression. Since circulating miRs are very stable and can be easily measured in extracellular fluids (e.g., plasma or serum), they have been proposed as non-invasive biomarkers for diagnosis and monitoring of several human diseases over the past few years (Citation127). Some studies using human placentas demonstrated that several miRs are differentially expressed in PE compared with physiological pregnancies, and that target genes of these miRs are implicated in apoptosis, immune response and lipid metabolism (Citation128). Between the various miRs which were found to be up- or down-regulated in serum or plasma of PE patients (Citation113–115), miR-210 has attracted more interest due to the fact that its expression is up-regulated in placental tissue (Citation129,Citation130) and in the sera of PE patients, with levels increasing in parallel with the severity of PE (Citation131). Notably, miR-210 was found to be over-expressed in first-trimester extravillous trophoblast, thus leading to reduced trophoblast invasion and uteroplacental hypoperfusion (Citation132).

Li et al measured the serum expression of several miRs (miR-152, miR-182, miR-183, miR-210, miR-1, miR-328, miR-363, miR-377, miR-500, and miR-584) in 32 pregnancies with PE and 32 healthy pregnancies (Citation133). These miRs were selected according to the previous evidence showing that they were up- and down-regulated in placentas (Citation128,Citation134–137). Interestingly, in the study of Li et al. the expression levels of serum miR-152, miR-183, and miR-210 were found to be enhanced in pregnancies complicated with PE, but only starting from the second trimester. Other miRs, especially miR-516-5p, miR-517*, miR-518b, miR-520a*, miR-520h, miR-525, and miR-526a were identified as predictive biomarkers of PE when measured at 12–16 GWs by Kotlabova et al. (Citation138). Ura et al. studied 24 pregnant women who successively developed PE and 24 healthy pregnant controls, observing that miR-1233 was the most over-expressed biomarker in PE patients at 12–14 GWs (Citation114). At variance with these results, Luque et al. measured the serum expression levels of as many as 754 miRNAs in maternal samples at 11-14 GWs, but failed to find significant differences between PE cases (n = 31) and healthy controls (n = 44) (Citation139). In another study Akehurst et al. assessed miRs expression in plasma along with in placenta samples obtained at 16 and 28 GWs in 18 women who developed PE and 18 matched women with normotensive pregnancies (Citation140). The results of this study showed that only miR-206 was differently expressed in both placental tissues and serum samples between cases and controls, but only after the 28 GW. The only miRNA that was found to be differentially expressed at 16 GW was miR-23a∗, which was decreased in women who developed PE. Despite the often limited sample size, the evidence emerged from miRs studies thus opens intriguing perspective for the use of these biomarkers in early prediction of PE (). However, further investigations are needed to define which among the various potential useful miRs may be characterized by the best diagnostic performance.

Table 3. Circulating miRs expression for prediction of PE at early stage of gestation (<20th GW).

Conclusions

Some angiogenic and anti-angiogenic biomarkers, especially the sFlt1:PlGF ratio were found to have a borderline clinical significance for early diagnosis of PE, but doubts remain as to whether their measurement before the 20th GW would retain sufficient diagnostic performance for routine implementation in clinical practice. As regards other biomarkers which were assessed in PE, promising preliminary data were often contradicted by results of ensuing investigations. Their clinical usefulness is also seriously lessened by some analytical issues (i.e., manual and cumbersome techniques, long turnaround time, low throughput instrumentation, lack of standardization) which make their measurement challenging or ultimately unfeasible in most clinical laboratories. Overall, differential miRs expression seems a promising approach for early prediction of PE, although additional research and well-designed prospective studies are needed for validating reliable diagnostic tests for early diagnosis of PE.

Disclosure statement

The authors report no conflicts of interest.

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