®

Review
OPEN

Short Term Prediction of Preeclampsia

Dorota Sroka, Stefan Verlohren∗

Abstract
Preeclampsia (PE), a multisystem disorder in pregnancy, is a main cause of perinatal mortality and is associated with long-term
maternal complications. For a long time, PE was defined as the new onset hypertension and proteinuria after 20 weeks’ gestation. It
had been shown that this “gold standard definition” is not able to provide a sufficient prediction of PE-related fetal and/or maternal
complications. In 2018 the International Society for the Study of Hypertension in Pregnancy recommended a broader definition of the
disease. The new definition of the International Society for the Study of Hypertension in Pregnancy ruled out proteinuria as mandatory
for the diagnosis of PE. This new definition increases the number of patients diagnosed as preeclamptic by nearly 21%, which is not
accompanied by an increased severity of maternal outcomes. Including angiogenic biomarkers, however, has been shown to
increase detection of adverse outcomes.
The pathophysiology of PE is complex and not yet completely explained. Advances in prediction and diagnosis have been
achieved by discovery and clinical evaluation of biomarkers, especially of placental origin. A broad spectrum of biomarkers has been
tested, a few of them have been introduced into the clinical practice as of today. Especially angiogenic biomarkers that are rooted in
the pathophysiology of PE have been demonstrated to be important in the prediction and diagnosis of adverse outcomes. At a cut-off
value of the soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF)-ratio of 85, early-onset PE <34+0 weeks of
gestation can accurately be diagnosed with a sensitivity of 89% and a specificity of 97%. The Prediction of short-term outcome in
pregnant women with suspected preeclampsia (PROGNOSIS) study has shown that the high negative predictive value (99.3%) of the
sFlt-1/PlGF-ratio below 38 in patients with suspected PE rules out the onset of the disease within one week. PROGNOSIS Asia,
evaluating the sFlt-1/PlGF-ratio cut-off of 38 in an Asian population, confirmed the excellent accuracy in prediction.
Recently, the angiogenic biomarkers have been integrated in multi-marker prediction models. Digital approaches, integrating
algorithm-based decision support tools paired with home monitoring devices may be the next step in enhancing predictive accuracy
and thus bear the potential to reduce maternal and/or fetal morbidity and mortality and save costs for the payer in parallel. The
objective of this review is to provide an overview of current methods for predicting and diagnosing PE.
Keywords: Biomarkers; Prediction; Preeclampsia; sFlt-1/PlGF; Test performance

Preeclampsia (PE) – a frequent cause of adverse seven times lower in industrialized countries (0.4%) than in
outcomes in pregnancy developing countries (2.8%). In Europe maternal mortality
is mainly caused by hypertensive pregnancy disorders.2–7
PE is a disorder in pregnancy with multisystem involvement. Nonetheless, as a consequence of the variety of clinical
Currently, delivering the baby is the only causative manifestations, PE remains a diagnostic dilemma.
treatment, and for this reason PE remains a major cause PE is not a homogeneous unit. The heterogeneity of this
of maternal and fetal mortality and morbidity.1 In the report disorder involves multiple manifestations of maternal and
of the World Health Organization (WHO) of 2005, PE fetal outcomes. The clinical features of severe PE include
caused 12% of all maternal deaths. PE affects 2% to 8% of hypertension, hepatic dysfunction (eg, elevated trans-
pregnancies and causes over 70,000 maternal and 500,000 aminases, epigastric pain), acute renal failure, thrombocy-
perinatal deaths annual globally. Worldwide, the occur- topenia, pulmonary edema, cerebral edema (headache,
rence of PE varies significantly. According to an assessment visual blurring, vomiting). Fetal adverse outcomes are
of the World Health Organization, the incidence of PE is usually characterized by intrauterine growth restriction,
fetal distress, preterm labor, placental abruption, and
Department of Obstetrics, Charité – Universitätsmedizin Berlin, intrauterine fetal death. Furthermore, symptoms of the
Charitéplatz 1, 10117 Berlin, Germany. disease cannot be used in a risk assessment because the
∗
Corresponding author: Stefan Verlohren, Department of Obstetrics, symptoms of PE overlap to a great extent with those of
Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, normal pregnancy.8–10
Germany. E-mail: [email protected] The main factors leading to PE-related adverse outcomes
Copyright © 2021 The Chinese Medical Association, published by are (1) a lack of accuracy in the early diagnosis and (2) a lack
Wolters Kluwer Health, Inc. of causative treatment. The wide variability of clinical
This is an open access article distributed under the terms of the
Creative Commons Attribution-Non Commercial-No Derivatives License presentations and a nonlinear relationship of high blood
4.0 (CCBY-NC-ND), where it is permissible to download and share the pressure/proteinuria to adverse outcomes, are main con-
work provided it is properly cited. The work cannot be changed in any tributing factors.3 Next to its potentially life-threatening
way or used commercially without permission from the journal. effect on the immediate pregnancy outcome, PE leads to
Maternal-Fetal Medicine (2021) 3:2 long-term maternal complications including an increased
Received: 12 January 2021 risk of cardiovascular disease, such as hypertension,
http://dx.doi.org/10.1097/FM9.0000000000000097 coronary artery disease, and cerebrovascular accident.

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There is also an increased possibility of developing diabetes to 360 (8.2%).16 Tochio et al. have recently evaluated the
mellitus, ocular complications, and renal failure.4 impact of the new ISSHP criteria in Japan. They showed an
increase in the number of diagnoses of PE as 14.6% of
patients who were earlier diagnosed with GH. In that
The evolving definition of PE
study the proportion of adverse outcomes between the two
The evolution of its definition is closely rooted in the groups was insignificant.17 These publications consistently
technical development of tools to detect certain clinical show that the rate of patients being diagnosed with PE is
features of the syndrome. The definition published in 2002 increased by application of the new criteria of ISSHP and
by the American College of Obstetricians and Gynecol- ACOG.
ogists (ACOG) had the greatest influence on scientific Recently, Lai et al.18 investigated the impact of the new
literature for a long time. According to this definition, PE definitions of PE at term (37+0 weeks of gestation) on
was characterized as “the new-onset of hypertension identification of maternal and fetal adverse events. Firstly,
(>140/90 mmHg) and proteinuria (>300 mg/24 hours and in accordance with the studies cited above, they have
or a protein-to-creatinine ratio of 30 mg/mmol) after shown that application of the broader definition proposed
20 weeks’ gestation”.11 Most scientific papers that by ACOG and ISSHP increased the number of diagnosed
evaluated new tools for predicting or diagnosing and cases. In a cohort of 15,248 pregnancies the traditional
even treating the disease have tested these against this definition identified 1.8% as having PE and ACOG 2.1%.
“gold standard”. Also clinically, “hypertension plus They now investigated several variations of the new ISSHP
proteinuria” was the best and most common practice to definition. When only maternal factors of the definition
detect PE and its adverse outcomes.12 However, it soon were taken into account (ISSHP-M), a total of 2.6% of
had been shown that measurement of blood pressure and women were labeled as preeclamptic. When fetal factors
assessment of proteinuria have a low positive predictive such as fetal death or fetal growth restriction were also taken
value (PPV) for predicting adverse outcomes. “Hyperten- into account (ISSHP-MF), a total of 2.8% were diagnosed.
sion and proteinuria” to predict adverse outcomes Lastly, when angiogenic factors were included additionally
associated with PE has a PPV of approximately 20%.13 (ISSHP-MF + AI), the resulting proportion of preeclamptic
The ACOG guidelines were the first to recommend a pregnancies was 3.3%. However, with respect to the
broader definition of PE. In 2018 also International Society predictive accuracy of the variations of the definition,
for the Study of Hypertension in Pregnancy (ISSHP) the ISSHP-MF + AI best predicted adverse events. As
adopted this definition. According to ISSHP proteinuria compared to the traditional, ACOG, ISSHP-M and ISSHP-
is no more obligatory to diagnose PE. Nevertheless, MF definitions, ISSHP-MF + AI identified severe hyperten-
proteinuria is present in about 75% of cases. The ISSHP sion in 66.9% (vs. 40.6%, 46.1%, 56.2%, and 59.2%
defined PE as new onset of hypertension (blood pressure respectively). A composite of maternal adverse events was
≥140 mmHg systolic or ≥90 mmHg diastolic) after identified in 100% by all definitions but the traditional
20 weeks of pregnancy in association with proteinuria (72.2%) and a composite of maternal and fetal morbidity
and/or signs of maternal organ involvement, such as acute and mortality was identified best by ISSHP-MF + AI with
renal failure (creatinine ≥90 mmol/L; 1 mg/dL), liver 71.1% as compared to 62.2% by ISSHP-MF, 59.8% by
dysfunction (elevated liver enzymes, eg, alanine amino- ISSHP-M, 49.4% by ACOG and 46.9% by the traditional
transferase (ALT) or aspartate aminotransferase (AST) definition. This work generates important evidence in
>40 IU/L, right upper quadrant or epigastric abdominal support of the broader forms of the definition of PE. But
pain), neurological signs, or hematological complications most importantly it highlights the essential role of the
such as hemolysis, low platelet count (<150  109/L), angiogenic biomarkers for predicting adverse events and
disseminated intravascular coagulation, or placental insuf- thus their inclusion in the definition of the disease.12,15–18
ficiency including fetal growth restriction, abnormal
umbilical artery Doppler wave form analysis, intrauterine
Pathogenesis of PE
fetal demise. If a woman has high blood pressure during
pregnancy and her previous blood pressure is unclear, she Although the root cause of PE has not yet been identified,
should be treated during gestation as if she had gestational significant knowledge about the underlying etiology has
hypertension (GH) or PE. Accurate examinations should be been gained over the past two decades. According to the
performed to establish whether it is caused by chronic current state of knowledge, PE is primarily a placental
hypertension. In some cases, PE for the first time can develop disorder, with contributing factors from other organ
or be identified as intrapartum or early postpartum.14 systems such as the immune system or the maternal
In 2020, Khan et al. have demonstrated that the ISSHP’s cardiovascular system.12 According to this unifying
new definition increased the number of patients being hypothesis, disturbed trophoblast invasion and resulting
diagnosed with PE by nearly 21% (from 2.8% to 3.4%) failure remodeling of spiral artery leads to reduced
and when the new ACOG definition was applied, the placental perfusion. In PE, the endovascular as well as
number increased by 7% (from 2.8% to 3.0%). However, interstitial invasion of the trophoblast is shallow and does
outcomes in the cases diagnosed by application of the new not extend into the myometrium, which in turn leads to the
definition were milder than those cases of PE, which were failure of remodeling of spiral arteries.19
classified by the earlier ISSHP recommendations.15 Bouter Many influencing factors such as immunological,
et al. in 2020 have evaluated the impact of the new ISSHP genetic, and environmental factors have been identified
criteria on a group of pregnant women (n = 4395) in the to partake in this process that is disturbed in women
Netherlands. This study also showed a significant increase later developing adverse PE-associated outcomes.20 In
in the number of diagnoses of PE from 272 patients (6.2%) failing trophoblast invasion, immune maladaptation

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plays an important role. Decreased expression of the associated with an increased prevalence of multiple
transplant antigens HLA-G and HLA-E, which protect gestation and with a higher median maternal age in their
the trophoblast from maternal natural killer cells, lead to first pregnancy.31–35
lytic effects on the trophoblasts and rejection of the When screening for PE, it is important to do so in the first
placenta.21 Trophoblast invasion and angiogenesis are trimester in order to allow for interventions such as
regulated by the natural killer cells, which are present in aspirin- prophylaxis, which has to be started early in order
the human decidua. Gamliel et al. have described a special to be effective.36–43 Prophylaxis with aspirin reduces the
subset of human decidual natural killer cells, which risk of early-onset PE by about 75% in pregnancies with
“remember” pregnancy and better support subsequent compliance of ≥90%.44 However, it is not realistic to
pregnancies. This serves as a potential explanation of target aspirin to all mostly healthy pregnant women for
reduced risk for PE in multipara that had uneventful first low compliance and therefore it is necessary to find a
pregnancies.22 cohort of pregnant women at a sufficiently high risk of PE,
In line with the two-stage model of PE, generalized where prophylaxis is fully justified. However, as the Fetal
endothelial dysfunction, potentially affecting all organ Medicine Foundation, London, UK, has elegantly shown
systems results from the “initial lesion”, the failed in many publications, the risk factors on its own have a
trophoblast invasion. Clinically, placental dysfunction low accuracy for such early screening. Nevertheless, up to
either leads to a predominantly “fetal phenotype”, that is, now many guidelines such as the British National Institute
the occurrence of intrauterine growth restriction, or to a for Clinical Excellence still recommend a screening for PE
predominantly “maternal phenotype” with high blood by maternal risk factors as prediction test for PE.45 This
pressure and organ complications. Mixed forms, especially achieves a detection rate of only 37% in preterm PE and
in the case of an early-onset PE, are the most common 28.9% in term PE.46,47 In the Fetal Medicine Foundation
clinical forms.19,23 (FMF) approach, the additional examination of biochemi-
For a long time, the “connecting link” between that initial cal and biophysical factors including measuring the mean
lesion, originating in the first and early second trimester and arterial blood pressure, the uterine artery Doppler analysis
the generalized effects, per definition taking place in the late as well as measuring biomarkers such as the placental
second and third trimester, was not known. Karumanchi et protein A (PAPP-A) and the above mentioned PlGF is able
al.24 have identified an imbalance of angiogenic and anti- to detect up to 75% of women destined to develop PE
angiogenic factors as a key event. They first observed an necessitating delivery <37 weeks of gestation at a false-
altered expression of placental factors such as soluble fms- positive rate (FPR)of 10%.48
like tyrosine kinase-1 (sFlt-1) and placental growth factor
(PlGF) in patients with PE. PlGF is an angiogenic factor that Angiogenic and anti-angiogenic factors in short
is mainly released from trophoblast cells and interacts with term prediction of PE
vascular endothelial growth factor (VEGF)-receptors
(synonym: fms-like tyrosine kinase 1, Flt-1) on the cell As mentioned above, a major breakthrough in better
surface of endothelial and other cells as well as its soluble identifying women destined to develop adverse outcomes
splice variant sflt-1.25 In the dysfunctional placenta, the of PE was the discovery of the angiogenic and anti-
expression of the antiangiogenic sFlt-1 is increased and angiogenic biomarkers. Soon, a host of studies identified
expression of PlGF is decreased.24,26,27 The increased the clinical use of implementing the biomarkers in the
bioavailability of sFlt-1 leads to inhibition of VEGF and predictive and diagnostic work-up in patients with clinical
PlGF and resulting endothelial dysfunction.28,29 This has suspicion of PE in second and third trimester.12,49–58
been proven in many pre-clinical studies: by increasing It has been proven that the sFlt-1/PlGF-ratio is superior
expression of sFlt-1 levels in rat models, it was possible to to the predictive performance of PlGF alone, with area
induce a preeclamptic phenotype.30 Moreover, endothelial under the curve (AUC) of 0.941 and 0.917, respectively.59
cell culture studies have shown that endothelial dysfunction Early case-control studies have identified a sFlt-1/PlGF-
after removal of the sFlt-1 is reversed.24 Overexpression of ratio cut-off value for the use as a diagnostic tool in PE.
sFlt-1 is an relevant element in the pathogenesis of PE that With a cut-off value of the sFlt-1/PlGF-ratio of 85, early-
links placental dysfunction with impaired maternal vascular onset PE <34+0 weeks of gestation can be diagnosed with
function.26 a sensitivity of 89% and a specificity of 97%. The cut-off
value of 85 is not exceeded on average in patients
with other hypertensive diseases during pregnancy.
Screening and early detection of PE Neither GH nor patients with chronic hypertension
Traditionally, the determination of risk factors is used showed any significant increases in the quotient in the
for “screening” for PE. Over time, a heterogeneous serum of the patients.54 After 34 weeks of gestation, the
set of such risk conditions has been identified. These optimal cut-off to diagnose PE is an sFlt-1/PlGF-ratio of
include being nulliparous, having PE during previous 110.52 Cut-off values may vary depending on the type
pregnancy (in the case of pregnancy with the same of the platform used. It has been proven that measurements
partner), being <20 years old or >40 years old, having of sFlt-1/PlGF-ratio between Elecsys® and Kryptor plat-
African American ancestry and body mass index above 35. forms are comparable with a cut-off value of >38 and
The chances of developing the disease also increases >85. Nonetheless, it had been shown that when using
preexisting medical disorder such as chronic hypertension, Kryptor, the lower PlGF and higher sFlt-1/PlGF values
diabetes mellitus, chronic renal disease, and antiphospho- were noted.60
lipid syndrome. Use of assisted reproductive technologies Prospective studies have validated the cut-off of 85 for
increases the incidence of PE due to the fact that it is short term prediction in patients with suspected PE. In a

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study of 616 patients with clinical suspicion of PE, Rana Asia study investigated the ability of the sFlt-1/PlGF-ratio
et al. reported that the sFlt1/PlGF-ratio cut point of 85 for prediction of adverse events in patients with suspicion
identified PE-related adverse events with a sensitivity of of the PE. This prospective, multicenter study enrolled 764
72.9% and a specificity of 94.0%. With an AUC of 0.92, women at 20+0 to 36+6 weeks of pregnancy. Inclusion and
adding the sFlt-1/PlGF-ratio improves adverse outcome exclusion criteria were in accordance with the PROGNO-
prediction.61 They next showed that women with high SIS study. The high NPV of the sFlt-1/PlGF-ratio at the cut-
blood pressure, proteinuria, and a sFlt-1/PlGF-ratio <85 off of 38 was confirmed: in patients with signs and
(=non-angiogenic PE) did not develop adverse outcomes (0 symptoms of the disease and a sFlt-1/PlGF-ratio <38, PE
of 46), whereas 27 of 51 women with high blood pressure, within 1 week is ruled out with an NPV of 98.6%. The
proteinuria, and a sFlt-1/PlGF-ratio ≥85 (=angiogenic PE) positive PPV of a sFlt-1/PlGF-ratio >38 to rule in the
developed adverse outcomes.61 disease within 4 weeks was 30.3% (95% CI: 23.0%–
The PROGNOSIS study (Prediction of short-term 38.5%). In this study the PPV of a sFlt-1/PlGF-ratio at the
outcome in pregnant women with suspected preeclampsia cut-off of 38 for the predicting PE and/or PE-related
study) determined a sFlt-1/PlGF-ratio cut-off for the short- complications was 65.5% (95% CI: 56.3%–74%). This
term prediction of PE in women presenting at high risk for work highlights the important role of the angiogenic
the disease. PROGNOSIS was a large prospective biomarkers for predicting adverse outcomes.62 The above-
multicenter study, published in The New England Journal mentioned cut-offs have been furthermore evaluated for
of Medicine in January 2016. The negative predictive value twin pregnancies.63–65
(NPV) of the sFlt-1/PlGF-ratio cut-off of 38 to rule out PE Recently, our group has shown that integrating maternal
for 1 week in patients with clinical suspicion was 99.3% and fetal data into a multimarker regression model
(95% CI: 97.9%–99.9%). The PPV of a sFlt-1/ PlGF-ratio increased predictive accuracy in prediction of adverse
38 to rule in the condition within 4 weeks in women at maternal or fetal outcome over the use of the biomarkers
high risk was 36.7% (95% CI: 28.4%–45.7%). The PPV alone. Our retrospective real-world study enrolled 1117
of a sFlt-1/PlGF-ratio >38 for predicting PE and/or PE- pregnant women with suspected PE after 20+0 weeks of
related maternal and/or fetal/neonatal complications was pregnancy. The AUC for PE-related maternal and/or fetal
65.5% (95% CI: 56.3%–74%). Furthermore, additional adverse outcome by the full model, including ultrasound
analyses showed that a sFlt-1/PlGF-ratio <38, the NPV data such as pulsatility index of the umbilical artery,
remains high for up to 4 weeks. These results have clinical data such as blood pressure and proteinuria, lab
impressively proven the ability to rule out the disease in data such as sFlt-1 and PlGF but also symptoms and risk
patients at risk (Fig. 1).56 factors (0.89) was higher than that of sFlt-1/PlGF-ratio
The results of the PROGNOSIS study have been alone (0.86). This multimarker model the onset of adverse
confirmed in an Asian population. The PROGNOSIS maternal or fetal outcome can be predicted with a

Figure 1. Use of the sFlt-1/PlGF-ratio in clinical practice. A sFlt-1/PlGF-ratio of 38 or lower can rule out PE with a NPV 99.3% for 1 week,56 NPV 97.9% for
2 weeks and NPV 94.3% for 4 weeks.55 In clinical practice, we suggest a follow-up in four weeks. Women with suspected preeclampsia with a sFlt-1/
PlGF-ratio between 38 and 85 are at high risk of developing preeclampsia (PPV 36.7%) and/or preeclampsia-related adverse outcome (PPV 65.5%) within
the next 4 weeks.55 A follow-up visit should be performed in one week or earlier, dependent on other clinical findings.50 In women with suspected
preeclampsia <34 weeks of gestation with a sFlt-1/PlGF-ratio ≥85, sensitivity and specificity for the occurrence of preeclampsia-related adverse events
were 88% and 99.5%, respectively. In women after 34+0 weeks of pregnancy and sFlt-1/PlGF-ratio ≥110, sensitivity and specificity were 58.2% and
95.5%, respectively.52 Women with sFlt-1/PlF-ratios >85/110 should be followed up individually or be hospitalized.50 a/o: And/or; AEs: Adverse events;
NPV: Negative predictive value; PE: Preeclampsia; PPV: Positive predictive value; sFlt-1/PlGF: Soluble fms-like tyrosine kinase-1/placental growth factor.

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sensitivity of 80.0%, and a specificity of 87.3%. The PPV in Germany from 44.6% to 24.0%. This leads to a
was 75.0% and NPV was 90.2%.66 predicted cost reduction of €361 per a pregnant women.
The above-mentioned work concentrated on the The sFlt-1/PlGF-ratio assessment presumably reduce
identification of the disease in patients at high risk. Next overtreatment in women in whom the subsequent outcome
to that, screening for PE is also feasible at later stages of will be normal and detect those at high risk to ascertain
pregnancy to allow for the identification of the condition in adequate management.4
an unselected screening-population in order to guide
surveillance intervals. The FMF group has shown that in
Outlook: current research – potential future
the screening for PE necessitating delivery within and after
4 weeks from measurement at 31–34 weeks of pregnan- biomarkers
cy, a model which included maternal risk factors and Metabolomics – a new direction in research on PE
multiples of the median values of biomarkers was equally
effective to values of the sFlt-1/PlGF-ratio for prediction of There remains a need to further improve prediction of PE.
Metabolomics is one of the current methods used to identify
delivery <4 weeks. However, for >4 weeks the Bayesian
metabolites, molecules that represent the phenotypic
approach used by FMF was more effective.67,68 For 35–
37 weeks, the AUC for PE at 2 weeks after measurement signature of the studied disorder and the gene expression
line. The clarification of the metabolic profile of PE might
by the Bayesian model (0.975) was higher than that of
potentially enable both the prediction and better under-
PlGF alone (0.900) or sFlt-1/PlGF-ratio (0.932).69 Other
standing of pathogenesis in terms of cellular and molecular
models included maternal factors, uterine artery pulsatility
mechanisms and it might improve the understanding of this
index (UtA-PI), mean arterial pressure, PlGF and sFlt-1,
complex disease in all its aspects: prevention, detection, and
were developed to estimate the risk of PE in the second and
therapeutic management.47,74
third trimesters of pregnancy. In the model presented by
Sovio et al. at the University of Cambridge and University
Gallo et al. the detection rate by screening at 19–24 weeks
of Bristol have recently investigated the impact of maternal
of pregnancy was 99% at <32 weeks gestation, 85% at
serum metabolomics of prediction of pregnancy outcome.
<37 weeks gestation, and 46% at ≥37 weeks gestation,
at a FPR of 10%.70 Application of a multi-marker Samples were collected at 12, 20, 28, and 36 weeks of
pregnancy in patients with early- and late-onset of PE and
prediction model at 30–34 weeks of gestation demon-
from a control group. Both 4-hydroxyglutamate and C-
strated the detection rate of 98% for preterm PE and 56%
glycosyltryptophan were predictive at 36 weeks’ gestation
for term PE with 10% FPR.71 Screening for PE at 35–
of late-onset PE. 4-Hydroxyglutamate was also able to
37 weeks of pregnancy predicted about 85% (95% CI:
predict early-onset PE at 12 (0.67), 20 (0.73), and 28 (0.73)
70–91) of PE cases, at a FPR of 10%.72 For easier PE risk
weeks’ gestation. In this study, the predictive performance
assessment, the FMF has developed a calculator, which is
of 4-hydroxyglutamate at 12 weeks of gestation was better
available on the website: https://fetalmedicine.org/re
than PAPP-A (0.56) and PlGF (0.59). 4-Hydroxyglutamate
search/assess/preeclampsia.
has a potential as a PE predictor in the first trimester of
pregnancy.75
Health-economic of using the sFlt-1/PlGF-ratio in Kenny et al. have also evaluated the impact of maternal
the short term prediction of PE serum metabolomics of prediction of PE. In their case-
In Europe over 90% of PE associated maternal mortality control samples were collected from the 97 women with PE
are potentially preventable. The guidelines of the German and 335 controls. Both dilinoleoyl-glycerol (DLG) and
Society for Gynecology and Obstetrics recommend that heptadecanoyl-2-hydroxy-sn-glycero-3-phosphocholine,
patients diagnosed with severe hypertension or manifest used to complement PlGF test, successfully increased the
PE need to be hospitalized and mild GH should be treated predictive performance of test. PlGF alone was able to
in Ambulatory Care. Though, because of the diagnostic predict early-onset PE with sensitivity of 48%. Models
uncertainty patients with a suspicion of PE, which is not combining DLG with PlGF and DLG, heptadecanoyl-2-
confirmed may be unnecessarily.4 hydroxy-sn-glycero-3-phosphocholine, and PlGF in-
The economic effect of the sFlt-1/PlGF-ratio was creased predictive value for PE and achieved the sensitivity
measured in the UK based on PROGNOSIS results, and of 74% and 78% respectively.76
by the National Institute for Health and Care Excellence. Bahado-Singh et al. in a study of 98 women, 35 with
Introduction of the sFlt-1/PlGF-ratio test into clinical late-onset PE and 63 controls, investigated the impact of
practice reduced costs by £344 per patient compared with metabolomic and proteomic systems of prediction of term
scenario, when sFlt-1/PlGF-ratio was not assessed. PE. First and third trimester serial metabolite were able to
Diagnostic improvement and reduction of unnecessary predict late-onset PE with AUC of 0.817 which corre-
hospitalization were main factors, which generated sponds to a sensitivity of 0.816 and specificity of 0.710.
savings.73 Nonetheless, such ratings cannot be directly Serial integrated protein biomarkers from first and third
extrapolated from one health system to another and trimester had a high predictive value for late-onset PE with
should be assessed predicated on each country’s individual AUC of 0.987 which corresponds to a sensitivity of 0.1 and
system. In Germany, the payer system uses diagnosis- specificity of 0.984.77
related groups to allocate a remuneration for the therapy
of a particular disease. The application of the sFlt-1/PlGF- Cell-free fetal DNA (cffDNA) as a predictive factor
ratio assessment with a cut-off value of 38, in the model The risk of PE can also be influenced by fetal factors in the
adjusted to the German diagnosis-related groups payment maternal blood, including genotype and cffDNA. A whole
system, could decrease the number of hospitalized patients genome association study, involving 310,238 controls and

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4380 patients who developed PE, detected, that a genetic Rolnik et al. have also investigated cfDNA as a PE marker.
variant in the fetal DNA near Flt-1 can be associated with In their case–control study cfDNA levels were measured in
an increased risk of PE. Increased level of cell-free fetal 240 blood samples, 20 from women with early-onset PE, 20
DNA is another potential marker that the research is from women with late-onset PE, and 200 control samples.
focusing on. It can be detected also before a clinical The study showed that the values of total cfDNA in women
manifestation of a disease.78 Kim et al.79 have also with early-onset PE were significantly increased. However,
investigated the impact of levels of cffDNA and total cell- the results between groups did not differ significantly when
free DNA (cfDNA) as a PE marker. In their case-control the values were converted to multiples of the median.82
study 135 pregnancies were examined, including 17 cases
of pregnancy-induced hypertension, 34 PE cases, and 84
N-terminal pro-B-type natriuretic peptide (NT-
control cases. The study showed that the values of HYP2
as a cfDNA marker, and DSCR3 and RASSF1A as a proBNP) – a cardiovascular marker to predict PE
cffDNA marker were significantly higher in PE and GH in The involvement if the cardiovascular system in the
the first and the second trimester of pregnancy. The model etiology of PE is often discussed.83–85 Next to its potential
combining values of DSCR3, HYP2, and PAPP-A had a etiologic role, PE includes many disruptions to the normal
detection rate of 67% for PE and 58% for GH with a adaptation of the female organism to pregnancy including
constant 10% FPR.79 increased peripheral vascular resistance, high blood
Kwak et al. have also investigated the impact of the pressure, and vasoconstriction. The heart responds to this
elevation of cfDNA levels as a PE marker. In their nested stress with a production of cardiovascular markers, which
case–control study methylated HYP2 (m-HYP2) levels have been investigated as a prediction tool for PE. The NT-
were measured in 204 blood samples, 68 from women proBNP is one of the markers released in response to
with GH and 136 control samples. The study showed that myocardial hypoxia from myocardial myocytes. Sabriá
the values of m-HYP2 in women with PE were significantly et al.86 in 2018 have investigated a new prediction model,
increased in the third trimester of pregnancy. However, which was based on a combination of NT-proBNP, sFlt-1/
values of m-HYP2 in the second trimester of pregnancy in PlGF-ratio, and gestational age. This model of prediction
patients who subsequently developed PE did not differ examined pregnancies with a suspicion of PE between 24
from those in controls.80 and 36+6 weeks of gestation. The study showed that the
Amaral et al. in a study of 277 women, 91 with PE, 88 prediction of parturition caused by PE in the model
with GH, and 98 controls, reported higher total cfDNA including NT-proBNP was significantly improved com-
levels in GH and PE than in healthy pregnancies (both pared to the sFlt-1/PlGF-ratio alone. Verlohren et al.51 in
P < 0.0001). In addition, elevated levels of cfDNA were their study also investigated the role of NT-proBNP in
correlated with more severe cases of GH and adverse prediction of PE, however, in their study additional
clinical outcomes. Furthermore, with a cut-off value of assessment of cardiovascular markers only increased the
total cfDNA of 160 ng/mL PE can be diagnosed with a detection of GH, but the detection of PE was not
sensitivity of 82.4% and a specificity of 84.7%. Neverthe- significantly improved. Therefore, more prospective
less, total cfDNA did not differentiate between GH and PE studies on a larger cohort are needed to determine which
(AUC: 0.576, P = 0.0789).81 biomarkers are most helpful to predict PE.53,86,87

Table 1
Overview of relevant studies investigating the diagnostic and predictive performance of tests for preeclampsia.
Biomarker/model Number of patients Onset of PE Sensitivity Specificity AUC
46
Maternal characteristics and previous history 8366 Early-onset PE 37% 95% 0.794
Late-onset PE 28.9% 95% 0.796
UtA-PI, maternal risk factors88 32,157 Early-onset PE 77.8% 95% 0.922
Late-onset PE 42.8% 95% 0.798
sFlt-1/PlGF-ratio cutoff of 3856 1050 80.0% 78.3% 0.861
sFlt-1/PlGF-ratio cut off 38 at 31–34 weeks’ gestation89 8063 80.0% 98.1%
sFlt-1/PlGF-ratio cut off 38 at 36 weeks’ gestation90 4099 54.7% 86.2% 0.81
sFlt-1/PlGF-ratio cutoff of 8561 616 72.9% 94.0% 0.85
Maternal factors and MoM values of sFlt-1 and PlGF67 8063 0.987
Maternal risk factors, MAP, sFlt-1/PlGF-ratio, UtA-PI 8079 (19–24 weeks’ gestation)70 Early-onset PE 99% 90% 0.998
Late-onset PE 46% 90% 0.801
8268 (30–34 weeks’ gestation)71 Early-onset PE 98% 90% 0.992
Late-onset PE 56% 90% 0.808
3920 (35–37 weeks’ gestation)72 Late-onset PE 84% 90% 0.938
66
sFlt-1/PlGF-ratio, Doppler investigations, MAP, proteinuria 1117 80.0% 87.3% 0.887
sFlt-1/PlGF-ratio, NT-proBNP, the gestational week86 134 73.6% 85.9% 0.845
4-hydroxyglutamate75 519 Early-onset PE 55.2% 90% 0.733
DSCR3, HYP2, and PAPP-A79 135 67% 90% 0.832
AUC: Area under the curve; MAP: Mean arterial pressure; MoM: Multiples of the median; NT-proBNP: N-terminal pro-B-type natriuretic peptide; PAPP-A: Pregnancy-associated plasma protein A; PE:
Preeclampsia; sFlt-1/PlGF: Soluble fms-like tyrosine kinase-1/placental growth factor; UtA-PI: Uterine artery pulsatility index.

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Conclusions Germany. BMC Health Serv Res 2018;18(1):603. doi:10.1186/

s12913-018-3406-1.
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Funding preeclampsia at term on identification of adverse maternal and perinatal
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