Pre-eclampsia: sFlt-1/PlGF ratio

Definition of PE

The definition of PE is based on the de novo association beyond 20 weeks of amenorrhoea (WA), hypertension (HTN) and proteinuria: systolic blood pressure (SBP) ≥ 140 mm Hg and/or diastolic blood pressure (DBP) ≥ 90 mm Hg over two measurements at 4 hr intervals and proteinuria ≥ 0.3 g/24 hr (or urinary protein/creatinine ratio ≥30 mg/mmol) (Magee SOGC 2014). However, 20% of PE cases do not present with proteinuria. The latest recommendations therefore also recognise the diagnosis of PE in the case of hypertension associated with signs of disorders in maternal organs, including in the absence of significant proteinuria. PE is said to be early when it occurs before 34 WA. There are also postpartum forms of PE (up to 6 weeks postpartum).

In 1 case in 10, PE takes a severe form and its development may be very rapid after onset of the first symptoms. PE is said to be severe in the presence of at least one of the following maternal criteria: Severe HTN (PAS ≥ 160 mm Hg and/or PAD ≥ 110 mm Hg), renal impairment (oliguria <500 mL/24 h or creatinine> 135 μmol/L or proteinuria> 5 g/d), acute pulmonary oedema or severe epigastric pains or HELLP syndrome (Haemolysis Elevated Liver Enzymes Low Platelets), eclampsia or persistent neurological disorders, thrombocytopenia (platelets <100 x10⁹/L), retroplacental haematoma, foetal retention (intrauterine growth restriction or severe IUGR, abnormal foetal heart rhythm) (Formal expert recommendations SFAR/CNGOF/SFMP/SFNN 2009, ACOG or American College of Obstetricians and Gynecologists 2013).

The associated maternal and foetal morbidity/mortality rates are high

In France, PE is responsible for a third of premature births (induced premature birth to save the life of the mother or foetus), a quarter of perinatal deaths and is a major cause of IUGR. It is the second most frequent cause of maternal deaths of obstetric origin after postpartum haemorrhage. In addition, PE causes long-term complications: women who have had PE have a significantly increased risk of cardiovascular morbidity and mortality and/or of metabolic syndrome.

There are multiple risk factors

Genetic (personal or family history of PE), immunological (PE is four to five times more common in nulliparous than in multiparous women, primipaternity, short sperm exposure, etc.), physiological (patient older than 40 years, sub-Saharan Africa and West Indies origin, BMI > 35 kg/m²), pre-existing pathologies (pre-existing hypertension, anti-phospholipid syndrome, systemic lupus erythematosus, insulin-dependent diabetes, etc.), factors related to pregnancy (multiple pregnancy, etc.).

Incidence varies widely between countries, ranging from 3% to 7% of pregnancies in nulliparous and 1% to 3% in multiparous women; in France, the incidence is estimated at 1% to 3% in nulliparous women and 0.5% to 1.5% in multiparous women (Goffinet 2010).

PE is the result of abnormal placentation

In patients with PE; the trophoblastic invasion is incomplete and the remodelling of the spiral arteries is defective. This results in insufficient blood flow for the foetus, with placental hypoxia with retardation of foetal-placental development, and the release of syncytial apoptotic debris, which is the cause of maternal endothelial disease. PE therefore develops during placentation, between 8 and 16 weeks, but the symptoms do not appear until the second trimester (Tsatsaris 2010) (Fig. 1).

Fig. 1: Pathophysiology of pre-eclampsia (Tsatsaris 2010)

The relevant biological markers for the first trimester of pregnancy are different to those for the second and third trimesters

The screening of PE in the first trimester of pregnancy was described in the ‘Shedding light on …’ of February 2015 (Biomnis & Vous Issue 75). Summing up, the advantage of early screening in the first trimester of pregnancy is to identify patients at risk of developing PE who could benefit from preventive measures including prophylactic aspirin before 16 WA. The ASPRE study (Rolnik 2017) has indeed demonstrated the benefit of implementing low-dose aspirin treatment in the prevention of early PE in patients at risk (150 mg/d, treatment to begin between 11 and 14 WA) and to be continued to 36 WA): 15 PEs before 34 WA in the placebo group (n = 822) versus 3 PEs before 34 WA in the aspirin group (n = 798). In a meta-analysis, Roberge (2018) showed that aspirin started before 16 WA and at a dose ≥ 100 mg reduces the risk of early PE. This screening takes into account maternal risk factors, biophysical variables (mean arterial pressure and ultrasound examinations of the uterine arteries) and biological assays (PAPP-A and PlGF) to calculate early and late PE risk.

Predictive test for pre-eclampsia in the second and third trimesters

This test is for patients between 20 and 37 WA, at risk of pre-eclampsia with at least one warning sign. It is intended as an aid to the clinician in deciding whether to treat patients at home or to admit them to hospital. This test can also be used to refer the patient to the appropriate care system as soon as the first symptoms appear and to anticipate the foeto-maternal complications. In addition, and always in conjunction with the patient medical record, this test can provide an aid to the diagnosis of PE and in the decision to extract the foetus and its placenta, by Caesarean section or by inducing labour.

This test is based on the trophoblast production of angiogenic factors, in particular PlGF (Placental Growth Factor) and antiangiogenic factors such as sFlt-1 (fms-like tyrosine kinase 1, soluble fraction of the type 1 VEGF receptors). In a ‘normal’ pregnancy the placenta produces elevated levels of PlGF which, by binding to its Flt-1 membrane receptor, causes vasodilation. In PE, the ischaemic placenta releases sFlt-1 which captures circulating forms of PlGF; as a result the latter is not available to bind to its membrane receptor and vasoconstriction persists.

The imbalance of serum concentrations of sFlt-1 and PlGF is detectable several weeks before the clinical occurrence of PE: approx. 5 weeks before the occurrence of PE, the concentration of sFlt-1 increases significantly while the concentration of PlGF decreases significantly. The PROGNOSIS study (multicentre, prospective and non-interventional, double-blind) evaluated the sFlt-1/PlGF ratio for the short-term prediction of PE in pregnant women at risk. An sFlt-1/PlGF ratio ≤ 38 (threshold applies for the Roche technique, the threshold depends on the respective technique used) makes it possible to refer patients to outpatient care with a negative predictive value (NPV) of 99.3% in Week 1 (sensitivity 80.0% and specificity 78.3%); more than 80% of patients will belong to this low-risk group. An sFlt-1/PlGF ratio ≥ 38 flags the need for more intensive management and hospitalisation of patients at high risk with a positive predictive value (PPV) of 36.7% at Week 4 of developing a PE (Stepan 2015, Zeisler 2016).

With regard to PE diagnosis, Stepan (2015) proposed the sFlt-1/PlGF ratio thresholds of > 85 (before 34 WA) and the > 110 (after 34 WA) for PE diagnosis, with direct consequences on the care of patients.

Practical information

• Sample: serum at 2-8°C.
• Screening in the first trimester:
  Eurofins Biomnis code: PECLA.
  Sample should be collected between 11 WA and 13 WA + 6 days (in parallel to screening for foetal trisomy 21).
• Predictive or diagnostic test:
  Eurofins Biomnis code: TPREE.
  Samples to be collected from 20 WA. Information to be provided: date of pregnancy.

References

Magee LA, Pels A, Helewa M, Rey E, von Dadelszen P. Canadian Hypertensive Disorders of Pregnancy Working Group. SOGC Clinical practice guideline: Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary. J Obstet Gynaecol Can 2014;36:416-41.

Société Française d’Anesthésie et de Réanimation, Collège National des Gynécologues Obstétriciens Français, Société Française de Néonatalogie, Société Française de Médecine Périnatale. Recommandations formalisées d’experts communes SFAR/CNGOF/SFMP/SFNN : Prise en charge multidisciplinaire des formes graves de prééclampsie, 27 janvier 2009. Available on http://www.cngof.asso.fr/

ACOG available on http://www.acog.org/Resouces and publications/Task force and work group reports/Hypertension in pregnancy

Goffinet F. Epidemiology. Ann Fr Anesth Reanim 2010;29:e7-e12.

Tsatsaris V, Fournier T, Winer N. Pathophysiology of preeclampsia. Ann Fr Anesth Reanm 2010;29:e13-e18.

Rolnik DL, Wright D, Poon LC et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017;377:613-22.

Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis. Am J Obstet Gynecol 2018; 218:287-93.

Stepan H, Herraiz I, Schlembach D et al. Implementation of the sFlt-1/PlGF ratio for prediction and diagnosis of pre-eclampsia in singleton pregnancy: implications for clinical practice. Ultrasound Obstet Gynecol 2015;45:241-6.

Zeisler H, Llurba E, Chantraine F et al. Predictive value of the sFlt-1:PIGF ratio in women with suspected preeclampsia. N Engl J Med 2016;374:13-22.