Introduction
Pre-eclampsia (PE) is a leading cause of maternal and fetal/neonatal morbidity and
mortality worldwide. Clinical diagnosis and definition of PE is commonly based on
the measurement of non-specific signs and symptoms, principally hypertension and proteinuria1–3.
However, due to the recognition that measurement of proteinuria is prone to inaccuracies
and the fact that PE complications often occur before proteinuria becomes significant,
most recent guidelines also support the diagnosis of PE on the basis of hypertension
and signs of maternal organ dysfunction other than proteinuria3–5. Furthermore, the
clinical presentation and course of PE is variable, ranging from severe and rapidly
progressing early-onset PE, necessitating preterm delivery, to late-onset PE at term.
There may be associated intrauterine growth restriction (IUGR), further increasing
neonatal morbidity and mortality. These features suggest that the classical standards
for the diagnosis of PE are not sufficient to encompass the complexity of the syndrome.
Undoubtedly, proper management of pregnant women at high risk for PE necessitates
early and reliable detection and intensified monitoring, with referral to specialized
perinatal care centers, to reduce substantially maternal, fetal and neonatal morbidity6,7.
In the decade since Maynard et al.8 reported that excessive placental production of
soluble fms-like tyrosine kinase receptor-1 (sFlt-1), an antagonist of vascular endothelial
growth factor and placental growth factor (PlGF), contributes to the pathogenesis
of PE, extensive research has been published demonstrating the usefulness of angiogenic
markers in both diagnosis and the subsequent prediction and management of PE and placenta-related
disorders. Various reports have demonstrated that disturbances in angiogenic and antiangiogenic
factors are implicated in the pathogenesis of PE and have possible relevance in the
diagnosis and prognosis of the disease.
Increased serum levels of sFlt-1 and decreased levels of PlGF, thereby resulting in
an increased sFlt-1/PlGF ratio, can be detected in the second half of pregnancy in
women diagnosed to have not only PE but also IUGR or stillbirth, i.e. placenta-related
disorders. These alterations are more pronounced in early-onset rather than late-onset
disease and are associated with severity of the clinical disorder. Moreover, the disturbances
in angiogenic factors are reported to be detectable prior to the onset of clinical
symptoms (disease), thereby allowing discrimination of women with normal pregnancies
from those at high risk for developing pregnancy complications, primarily PE9–30.
Plasma concentrations of angiogenic/antiangiogenic factors are of prognostic value
in obstetric triage: similar to the progressively worsening clinical course observed
in women with early-onset PE, changes in the angiogenic profile leading to a more
antiangiogenic state can be found. Current definitions of PE are poor in predicting
PE-related adverse outcomes. A diagnosis of PE based on blood pressure and proteinuria
has a positive predictive value of approximately 30% for predicting PE-related adverse
outcomes31. Estimation of the sFlt-1/PlGF ratio allows identification of women at
high risk for imminent delivery and adverse maternal and neonatal outcome23,30,32–35.
Moreover, it has also been shown that the time-dependent slope of the sFlt-1/PlGF
ratio between repeated measurements is predictive for pregnancy outcome and the risk
of developing PE, and repeated measurements have been suggested36. However, the ‘optimal’
time interval for a follow-up test remains unclear. Finally, high values are closely
related to the need to deliver immediately22,23,37.
Additionally, in normal and complicated pregnancies, angiogenic factors are correlated
with Doppler ultrasound parameters, mainly uterine artery (UtA) indices38–42. Combining
the sFlt-1/PlGF ratio with UtA Doppler ultrasound, at the time of diagnosis of early-onset
PE, has prognostic value mainly for perinatal complications, being limited for the
prediction of maternal complications37,43. The additional measurement of the sFlt-1/PlGF
ratio has been shown to improve the sensitivity and specificity of Doppler measurement
in predicting PE44–48, supporting its implementation in screening algorithms.
Whereas studies on the predictive efficacy of the sFlt-1/PlGF ratio in the first trimester
have yielded contradictory results49, reports on the use of this marker as an aid
in prediction from the mid trimester onwards have led to its suggested use as a screening
tool, especially for identifying all women developing PE and requiring delivery within
the subsequent 4 weeks50–52.
This short review of the literature highlights that measurement of the sFlt-1/PlGF
ratio has the potential to become an additional tool in the management of PE, particularly
as automated tests that allow rapid and easy measurement of these markers are now
widely available. Nevertheless, although these markers were incorporated recently
into the German guidelines53, no formal recommendation regarding how to use sFlt-1,
PlGF or the sFlt-1/PlGF ratio has been established in any official protocol.
The purpose of this paper is to answer questions that are frequently asked around
the use of the sFlt-1/PlGF ratio in the diagnosis and prediction of PE and regarding
the implications for clinical practice, in particular, ‘When?’ and ‘In which women?’
should the sFlt-1/PlGF ratio be measured and, ‘What should be done with the results?’,
and to provide guidance to educate physicians on the use of the sFlt-1/PlGF ratio
in clinical practice. To achieve this, international experts in the use of angiogenic
markers have strived to develop a consensus statement on the clinical use of the sFlt-1/PlGF
ratio and the consequential management in pregnant women with suspected PE or at a
high risk of developing PE.
Consensus statement
This consensus statement aims to apply a ‘risk for developing PE algorithm’ to two
different patient populations:
women with signs and symptoms of PE and
asymptomatic women at high risk of developing PE.
At the outset, it should be emphasized that: 1) the sFlt-1/PlGF ratio has not been
evaluated as a screening test and 2) the sFlt-1/PlGF ratio does not replace other
techniques to monitor high-risk patients. Furthermore, decisions regarding delivery
are not based solely on the sFlt-1/PlGF ratio, but are always made in the context
of other established techniques and clinical signs and symptoms. Finally, most of
the studies on the sFlt-1/PlGF ratio have been performed using the Elecsys® assay
and the cut-off levels described in this guidance have been validated so far only
for this assay18,54.
Gestational age-specific sFlt-1/PlGF ratio cut-offs of > 85 (20 + 0 to 33 + 6 weeks)
and > 110 (34 + 0 weeks to delivery) have been shown to be highly suggestive of PE55.
The same study identified a cut-off of 33 for exclusion of PE (sensitivity, 95%; specificity,
94%). However, no insight was gained regarding the likelihood of these women developing
PE over the course of their pregnancy. In the PROGNOSIS study56,57, a single sFlt-1/PlGF
ratio cut-off (<38) was validated to rule out reliably PE within 1 week (negative
predictive value >96%) and rule in PE (≥38) within 4 weeks (positive predictive value
>25%). The cut-offs for the sFlt-1/PlGF ratio used in this Opinion are based on these
studies, adjusted for both early and late gestational age (Table 1).
Table 1
Soluble fms-like tyrosine kinase receptor-1 (sFlt-1)/placental growth factor (PlGF),
ratio cut-offs for prediction and diagnosis of pre-eclampsia (PE) in singleton pregnancy
Utility of sFlt-1/PlGF ratio
Cut-off
Reference
Early onset (< 34 weeks)
Late onset (≥ 34 weeks)
Suspicion of PE
38
38
Zeisler et al.57
Diagnosis of PE
85
110
Verlohren et al.55
Use of the sFlt-1/PlGF ratio in women with signs and symptoms of pre-eclampsia
This population includes both women with suspicion of PE (Table 2) and women with
PE already confirmed. The criteria contributing to suspicion of PE (adopted from the
inclusion criteria in the PROGNOSIS and PreOS study56) are very ‘open’, covering any
suspicion of PE, and are in line with usual clinical experience.
Criteria contributing to suspicion of clinical diagnosis of pre-eclampsia (PE)
Clinical signs and symptoms
De-novo elevated blood pressure*
Aggravation of pre-existing hypertension
De-novo protein in urine†
Aggravation of pre-existing proteinuria
One or more other reason(s) for clinical suspicion of PE:
PE-related symptoms
Epigastric pain
Excessive edema /severe swelling (face, hands, feet)
Headache
Visual disturbances
Sudden weight gain (>1 kg/week in third trimester)
PE-related findings
Low platelets
Elevated liver enzymes
(Suspected) intrauterine growth restriction
Abnormal uterine artery Doppler (mean PI > 95th centile in second trimester and/or
bilateral notching)
†
Standard definition of hypertension (≥140 mmHg systolic and/or ≥ 90 mmHg diastolic)
need not apply.
†
Standard definition of proteinuria need not apply. PI, pulsatility index.
According to the described cut-off values of the sFlt-1/PlGF ratio, three ‘subgroups’
of women have to be considered:
sFlt-1/PlGF ratio < 38: these women will most likely not develop PE for at least 1 week;
sFlt-1/PlGF ratio > 85 (early-onset PE) or > 110 (late-onset PE): these women are
very likely to have PE or another form of placental insufficiency;
sFlt-1/PlGF ratio 38–85 (early-onset PE) or 38–110 (late-onset PE): these women do
not have a definite diagnosis of PE but are highly likely to develop PE within 4 weeks.
sFlt-1/PlGF ratio < 38
Women with an sFlt-1/PlGF ratio < 38 do not have PE at the time of the test and in
all likelihood will not develop PE for at least 1 week; it is thereby of great value
for reassuring the clinician and the patient. This cut-off is irrespective of gestational
week and predictive performance is not improved by gestational-age-adapted cut-offs.
More than 80% of patients will be in this patient group; therefore, clinicians are
able to exclude the majority of patients and focus on those who need more attention
and care. How to manage this group can be left to the clinician's discretion. No further
determinations are needed unless a new suspicion arises.
Statement 1: sFlt-1/PlGF < 38
sFlt-1/PlGF ratio < 38 rules out PE, irrespective of gestational age, for at least
1 week. Further management is according to the clinician's discretion.
sFlt-1/PlGF ratio >85 (early-onset PE) or >110 (late-onset PE)
Women with an elevated sFlt-1/PlGF ratio > 85 (early-onset PE) or > 110 (late-onset
PE) are highly likely to have PE or some form of placenta-related disorder and should
be managed according to local practice/guidelines. A severely elevated sFlt-1/PlGF
ratio (>655 in early-onset PE; > 201 in late-onset PE) is associated closely with
the need to deliver within 48 hours22,23,37 and should prompt extra surveillance in
an appropriate clinical setting. In early-onset PE, antenatal corticosteroids to accelerate
fetal lung maturation should be considered strongly.
Statement 2: sFlt-1/PlGF ratio > 85 (early-onset PE) or > 110 (late-onset PE)
Diagnosis of PE or placenta-related disorder is highly likely. Management according
to local guidelines.
Severely elevated sFlt-1/PlGF ratios (> 655 at <34 + 0 weeks; > 201 at ≥ 34 + 0 weeks)
are associated closely with the need to deliver within 48 h. Close surveillance and
(if < 34 weeks) prompt initiation of antenatal corticoids to accelerate fetal lung
maturation are mandatory.
A repeat measurement of the sFlt-1/PlGF ratio may help to distinguish whether a patient
is at moderate, high or very high risk of developing a complication, such as PE, depending
on the dynamics of the increased sFlt-1/PlGF ratio. In women with relatively stable
test results, the physician can be confident that the woman will not deteriorate rapidly.
In these cases a follow-up sFlt-1/PlGF test in 2 weeks may be considered. However,
it is still not possible to determine how these women will progress after this point
and the trend indicating pathology is unknown.
Statement 3: sFlt-1/PlGF ratio > 85 (early-onset PE) or > 110 (late-onset PE), repeat
measurement
Re-measure after 2–4 days to determine trend and follow up according to clinician's
discretion depending on severity.
The test frequency can be adapted to the clinical situation and trend in sFlt-1/PlGF
ratio dynamics.
sFlt-1/PlGF ratio 38–85 (early-onset PE) or 38–110 (late-onset PE)
Women with an sFlt-1/PlGF ratio of 38–85 (early-onset PE) or 38–110 (late-onset PE)
do not have PE at the time of the test. Although the majority will not develop PE,
these women may be at risk for developing PE within 4 weeks and should be monitored
more closely, although the time interval for a follow-up test remains unclear. In
one study in pregnant women in early gestation (< 34 weeks), 100% of women in this
intermediate zone had a preterm birth, even in the absence of PE58. Therefore, these
women should be considered as high risk and more intensive follow-up is required,
depending on gestational age.
Statement 4: sFlt-1/PlGF ratio 38–85 (early-onset PE) or 38–110 (late-onset PE)
The sFlt-1/PlGF ratio provides information about the patient before the onset of overt
signs and symptoms. An sFlt-1/PlGF ratio of 38–85 or 38–110 provides extra information
as to which women are at moderate risk or at high risk of developing PE within 4 weeks.
Current PE or a placenta-related disorder can be ruled out, but women are at (high)
risk (especially in the early-onset group).
Early onset: Consider a follow-up sFlt-1/PlGF test in 1–2 weeks, according to the
individual clinical situation. Results are to be treated accordingly.
Late onset: An intermediate result of the sFlt-1/PlGF ratio is suggestive of impending
placental dysfunction. Consider lowering the threshold for induction of delivery.
In women with confirmed PE, measurement of the sFlt-1/PlGF ratio does not provide
additional diagnostic information, but it can be useful for prognostic purposes, in
a similar way to that described in Statements 2 and 3.
Statement 5:
The sFlt-1/PlGF ratio has been proven as an aid in diagnosis for PE.
In a woman with PE already confirmed (high blood pressure and proteinuria) the sFlt-1/PlGF
ratio may be useful to determine the severity of the disorder.
Use of the sFlt-1/PlGF ratio in asymptomatic women at high risk of pre-eclampsia
This group includes:
women with established criteria associated with an increased risk of developing PE;
women who are identified to be at risk as a result of a UtA Doppler examination;
women with any perceived increased risk of PE.
Women at higher risk of PE based on established criteria obviously need to be followed
up more carefully and UtA Doppler may be considered. An estimation of the sFlt-1/PlGF
ratio should be performed in those asymptomatic women considered to be high risk based
on history or abnormal UtA Doppler. The optimal time for starting measurement of the
sFlt-1/PlGF ratio in these high-risk patients is 24–26 weeks, given that at this time
point the differences in the values of the sFlt-1/PlGF ratio between women with normal
outcome and those destined to develop early PE are usually already significant. Those
women with a normal sFlt-1/PlGF test result can be reassured that PE can be ruled
out for at least 1 week but not for the whole pregnancy, and therefore serial measurements
should be considered. Currently, there are no recommendations regarding time interval
for a follow-up test. Conversely, women with abnormal sFlt-1/PlGF ratios should be
considered as having suspected PE and should be managed accordingly.
Using the sFlt-1/PlGF ratio for clinical management: general considerations
Maternal complications cannot be avoided completely but women at high risk can be
hospitalized.
No data exist on the usefulness of the sFlt-1/PlGF ratio to avoid maternal complications.
No data exist to show that maternal outcome is better now than it was before use of
the sFlt-1/PlGF ratio.
No randomized controlled trials have been performed to test the usefulness of the
sFlt-1/PlGF ratio regarding maternal or fetal outcomes.
The test should be used in the population in which it is most reasonable, i.e. in
the high-risk population. The economics and resource utilization need to be considered
too.
Conclusions
The diagnostic and predictive value of the sFlt1/PlGF ratio in patients at risk of
placenta-related disorders, i.e. PE, HELLP syndrome, IUGR and stillbirth, has been
shown in the recent literature and estimation of the sFlt-1/PlGF ratio has become
an additional tool in the management of these disorders, primarily PE. Repeat measurements
of the sFlt-1/PlGF ratio are suggested to improve individual risk assessment in these
patients, but this has to be proven by further studies.
To date, the use of sFlt-1, PlGF or the sFlt-1/PlGF ratio has not been incorporated
into official guidelines. In this statement, we have aimed to give good clinical practice
guidance for implementation of this method into the management algorithm of pregnant
women. Use of the sFlt-1/PlGF ratio may help to optimize care by improving management
of women with suspected PE.
Disclosures
Apart from reimbursement of travel expenses to expert meetings, A.G., D.W., E.K.,
F.C. and I.H. declare no conflicts of interest. A.R., D.S., E.L., H.S., M.V. and S.B.
have also received grant support from Roche Diagnostics for involvement in the PROGNOSIS
study (2010−1013) and/or the PreOS study. D.S., H.S. and S.V. have received lecture
fees from Roche Diagnostics. O.L. has acted as a consultant for Roche Diagnostics.
S.V. has received research support from Roche and acted as an advisor for Roche and
has received speaker fees from ThermoFisher.