Keywords preeclampsia - hypertension - placental growth factor - preterm preeclampsia - soluble
fms-like tyrosine kinase 1
Palavras-chave pré-eclâmpsia - hipertensão - fator de crescimento placentário - pré-eclâmpsia prematura
- tirosina quinase 1 tipo fms solúvel
Introduction
It is a great challenge to consider preeclampsia (PE) diagnosis and management in
settings of low and middle-income, where the burden of the disease still represents
a major public health concern, with high impact ([Fig. 1 ]) in maternal mortality and morbidity.[1 ]
[2 ] Even with considerable advances in research and healthcare, the management of PE
has changed little in the last decades, with outcomes relying on accurate diagnosis,
identification of severity and decision on the timing of delivery.[3 ] Globally, 42,000 women die each year from PE, and, for each death, other 50 to 100
women suffer from considerable morbidity.[2 ]
[4 ]
Fig. 1 Summary of the overall impact of hypertension in preeclampsia.
There are few excellent examples of success in reducing maternal mortality due to
hypertensive disorders, such as the United Kingdom (UK). Over the past 65 years, UK
presented an expressive drop in avoidable direct causes of maternal mortality, with
fewer than 1 in 10,000 deaths among pregnant and postpartum women currently.[5 ] During the last report, with data from 2012 to 2014, UK had only two maternal deaths
due to hypertensive disorders.[6 ] If we compare with the same period in Brazil, the reported number of maternal deaths
due to hypertension was a shocking 971 women.[7 ]
The investment in national guidelines and recommendations for clinical care, service
organization, and research priorities have been highlighted as responsible for such
results in the UK, with improved surveillance, diagnosis, and timely delivery. Special
focus on severe cases, including pulmonary edema, with fluid restriction protocols
and intracerebral hemorrhage, with adequate treatment of severe hypertension are examples
of targeted and effective recent interventions. Identifying conditions involved in
the decrease in maternal deaths from hypertensive disorders in the UK should help
other health systems to reduce their maternal death rates.[5 ]
[6 ]
[8 ]
Preeclampsia is certainly one of the most challenging situations during pregnancy.
It is not only influenced by innumerous conditions (genetic, immunological, environmental)
but it can also affect all organs, however in different ways, and we never know ahead
of time which patient will present with what symptoms and complications. For example,
a patient can be identified in a routine assessment with classic hypertension and
proteinuria, while others can open with seizures or severe placental compromise, with
fetal growth restriction or even placental abruption.[3 ] Knowing that, and with the growing understanding of the role the placenta plays,
especially in early onset PE (< 34 weeks gestation), in the last decades, studies
have advanced in showing that plasma concentrations of proangiogenic/ antiangiogenic
factors, released by the placenta (syncytiotrophoblast) can reflect the risks of disease
progression. Antiangiogenic, proteins such as soluble fms-like tyrosinekinase 1 (sFlt-1),
and proangiogenic placental growth factors (PlGF) directly and inversely correlate,
respectively, with disease onset.[9 ]
The updated UK national guideline, National Institute for Health and Care Excellence
(NICE), has included, for women with suspected PE, a recommendation that says: “triage
PlGF test and the Elecsys immunoassay sFlt-1/PlGF ratio, used with standard clinical
assessment and subsequent clinical follow-up, are recommended to help rule out PE
in women presenting with suspected PE between 20 weeks and 34 weeks plus 6 days of
gestation.”[10 ] Other international guidelines have also incorporated plasma concentrations of proangiogenic/antiangiogenic
factors in their recommendations.[11 ]
[12 ] Recently, these exams were authorized by the Brazilian National Agency for Supplementary
Health (ANS). However, in a setting with such a high impact of the condition, we believe
that the use of biomarkers must be supported by guidelines and that it must be in
accordance with national protocols on diagnosis and management of preeclampsia.[13 ] We present a suggestion for such implementation, considering key measurement cutoff
points that have been recently identified to have a high negative predictive value
for PE.
Relevant Definitions Considering PE
Relevant Definitions Considering PE
A major concern is the adequate diagnosis of the condition and severity. Definitions
of hypertension, proteinuria, end-organ damage, and severe disease are listed in the
boxes below ([Figs. 2 ] and [3 ]). Preeclampsia is considered when hypertension arises in previous normotensives
women, after 20 weeks gestation, with proteinuria. In the absence of proteinuria,
if there are signs of severity or end-organ damage, the diagnosis is also confirmed.[13 ]
Fig. 2 Definition of arterial hypertension and proteinuria.
Fig. 3 End-organ damage and severe disease.
When and How to Consider the Use of Angiogenic and/or Antiangiogenic Factors
[Figure 4 ] presents a suggested guideline/flowchart toward a suspected case of PE and situations
that could benefit from testing for proangiogenic and/or antiangiogenic factors. Considering
women with clinical suspicion of PE, we must be careful to carry out confirmatory
tests. However, in cases with severe features, emergency assistance must be imperative.
Patients who present with severe hypertension (systolic BP ≥ 160 and/or diastolic
BP ≥ 110 mm Hg), symptoms suggestive of imminent eclampsia (headache, scotomas and/or
epigastric pain), acute pulmonary edema, elevation of liver enzymes, thrombocytopenia,
among others, should receive immediate assistance and admission to a referral center.
Under no circumstances should the sFlt-1/PlGF test delay or guide approaches in these
cases.[10 ]
[13 ]
Fig. 4 Suggestion for using the sFlt-1/PlGF ratio in clinical practice.
Considering women with clinical suspicion of PE, without severe features, it is important
to perform tests toward the proper diagnosis. After PE confirmation by the known recommended
tests, the patient should be referred to a referral center for adequate follow-up
(depending on gestational age and findings). The sFlt-1/PlGF ratio does not replace
the usual tests for the diagnosis of PE and, at this time, should not be performed
for diagnostic confirmation.
Women with clinical suspicion of PE, who present negative tests for the diagnosis
of PE (absence of proteinuria or target organ damage) between 20 and 36 6/7 weeks,
should undergo the sFlt-1/PlGF test. In these cases, the sFlt-1/PlGF ratio can help
in more adequate follow-up and care planning.[10 ]
The sFlt-1/PLGF ratio at a threshold of 38 can reassure about the absence of PE at
that giving time, as well as indicate a low possibility of onset in the following
week, with a negative predictive value (NPV) of 99.3% (97.9–99.9).[14 ] It can also help in the clinical reasoning regarding the non-appearance of PE in
2 weeks [NPV 97.9% (96.0–99.0)], 3 weeks [NPV 95 0.7% (93.3–97.5)], and up to 4 weeks
[NPV 94.3% (91.7–96.3)].[15 ] Nevertheless, even with low values of the sFlt-1/PLGF ratio, given a new clinical
suspicion of PE, due to suggestive signs and/or symptoms, the team should proceed
with PE investigation through routine exams.
Values above 38, but below 85 up to 34 weeks or below 110 after 34 weeks indicate
a higher risk of PE. However, due to the low positive predictive value (PPV) in this
situation [PPV 36.7% (28.4–45.7)], the diagnosis of PE cannot be ascertained exclusively
by the ratio.[14 ] These patients need close surveillance for maternal and fetal assessment and new
PE investigation depending on clinical findings. Medical visits should be frequent,
with adequate counseling on possible suggestive signs and symptoms of severe features.
These higher ratio values, although not confirmatory of PE, may reflect, in clinical
practice, conditions associated with increased risks of adverse outcomes. The management
of such cases will depend on the local institutional protocol, but greater maternal
and fetal surveillance in this group of patients is necessary. In individual cases
and in accordance with local protocols, such patients may be hospitalized for closer
follow-up. Again, when there is a clinical suspicion of PE or severe features, the
usual tests for its diagnosis should always be performed.
Cost-effectiveness of Biomarker Testing
Cost-effectiveness of Biomarker Testing
Considering cost-effectiveness, some studies, conducted in different countries have
shown that the use of sFlt-1/PlGF tests compared with non-use to manage patients with
suspected PE, could be cost-saving, by avoiding unnecessary procedures and hospitalization.
Analysis of the economic impact in the UK indicated that hospitalizations of women
with suspected preeclampsia were reduced by 56%, resulting in savings of £344 per
patient.[16 ]
[17 ]
[18 ]
[19 ] The cost-saving per patient was also found in other countries, such as Italy, Germany,
Switzerland (ranging between € 346 and €670) (17–19), US ($1,215),[20 ] and Japan (16,373 JPY).[21 ] In Brazil, comparing public and private health care, the calculated savings was
R$185.06 and R$635.84 per patient, respectively.[22 ]
In another study, a probability model was assessed to verify the PlGF testing cost-effectiveness.
The use of PlGF testing for suspected preterm PE had a 59.9% probability of representing
a cost-saving compared with the current practice, with a total cost-saving of £149
per woman when including the cost of the test. Given the estimated number of births
in England and the incidence of pregnant women that have suspected PE before 37 weeks,
PlGF testing could result in a potential cost-saving of £2,891,196 each year across
the English NHS. The majority of cost-savings associated with PlGF testing are through
a reduction observed in maternal outpatient appointments among women testing with
a PlGF > 100 pg/ml.[23 ]
[24 ]
Although the cost-analysis to rule out PE seems to reduce expenses, more evidence
is needed when considering such intervention in clinical practice and especially in
low and middle-income settings.
The sFlt-1/PLGF ratio is an ally in the diagnosis of PE, mainly to rule out suspected
cases among patients with clinical suspicion of PE between 20 and 36 6/7 weeks;
The test should not be performed alone, in the first half of pregnancy, for the early
prediction of PE;
In suspected cases of PE, the sFlt-1/PlGF ratio can be requested; however, it should
NOT replace the routine exams for the diagnosis of PE, which should be mandatory;
The sFlt-1/PlGF ratio should NOT be performed after a confirmed PE diagnosis. This
use finds support in research settings but not in clinical practice;
The sFlt-1/PlGF ratio should NOT be performed routinely in patients with no clinical
suspicion of PE, as a screening for the disease;
In women with suspected PE, a sFlt-1/PlGF ratio < 38 can rule out the diagnosis of
PE for 1 week (VPN = 99.3) and up to 4 weeks (VPN= 94.3);
In women with suspected PE, a sFlt-1/PlGF ratio > 38 does not confirm the diagnosis
of PE; however, it can assist clinical management;
In cases of severe hypertension (BP ≥ 160 and/or PAd ≥ 110 mm Hg) and/or symptoms
(imminent eclampsia), hospitalization is imperative, regardless of the result of the
sFlt/PlGF ratio;
The sFlt/PlGF ratio should NOT be requested every week (re-test) in cases that do
not present again a clinical suspicion of PE;
The sFlt-1/PlGF ratio should NOT be used to define timing of delivery.
Conclusion
The use of biomarkers in obstetric clinical practice is a reality in many countries
and can help support clinical decisions on the management of cases, enabling more
accurate differential diagnoses and, mostly, excluding the diagnosis of PE, thus avoiding
unnecessary interventions, especially hospitalizations and elective prematurity (10).
However, to ensure adequate use of biomarkers, it is key to follow a protocol that
considers clinical findings and interpretation of results.
