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Preeclampsia sFlt-1/PlGF Ratio, Serum

The preeclampsia sFlt-1/PLGF Ratio is used in the risk assessment of patients with clinical signs and symptoms consistent with developing preeclampsia with severe features.

The sFlt-1/PlGF ratio test can be used from 20 weeks to 36 + 6 weeks as a tool for short-term prediction and aid for diagnosis in high-risk women or among women with a clinical suspicion of preeclampsia. The ratio test can also be used in women after 37 weeks, in all cases where preeclampsia is suspected, or as a follow-up to evaluate uteroplacental dysfunction.

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Preeclampsia is a major complication of pregnancy that is associated with significant morbidity and mortality for both the mother and baby and affects 2–7% of all pregnancies. Worldwide it is responsible for 500,000 fetal/neonatal deaths and 70,000 maternal deaths every year.

The International Society has defined preeclampsia for the Study of Hypertension in Pregnancy (ISSHP) as gestational hypertension accompanied by at least one of the following new-onset conditions at or after 20 weeks gestation: proteinuria, maternal organ dysfunction (acute kidney injury, liver involvement, neurological complications, hematological complications), or uteroplacental dysfunction.

After 20 weeks gestation, women are assessed for their risk of preeclampsia by measuring blood pressure (BP) and proteinuria at routine clinical visits and by evaluating non-specific clinical features. BP and proteinuria are measured throughout pregnancy, especially in the second and third trimesters, to assess women for preeclampsia. It is estimated that about 30% of all pregnancies will, at some point, undergo evaluation for preeclampsia. Reasons for suspicion of preeclampsia include preeclampsia-related symptoms (e.g., excessive edema/severe swelling of the face, hands, or feet, headache, visual disturbances, sudden weight gain, and epigastric pain) and preeclampsia-related findings (e.g., low platelets, elevated liver transaminases, fetal growth restriction (FGR), and abnormal resistance to blood flow in the uterine arteries detected by Doppler sonography). Many of the clinical features of preeclampsia are non-specific, thus making the diagnosis both challenging and time-consuming, especially in patients who have overlying signs and symptoms from other diseases such as chronic hypertension, chronic kidney disease, and systemic lupus erythematosus (SLE).

Although the etiology of preeclampsia is still being debated, the discovery of circulating angiogenic factors in the pathogenesis of the disease has been a significant advance in the field for both diagnosis and prognosis. Circulating angiogenic factors have received considerable attention, particularly the anti-angiogenic factor, soluble fms-like tyrosine kinase 1 (sFlt-1), and the pro-angiogenic factor, placental growth factor (PlGF). These molecules can be measured in plasma and serum and are usually reported as a ratio. These molecules are made mainly in the placenta and are non-invasive markers of placental health. They have been shown to specifically relate to the onset and severity of preeclampsia and eclampsia. As such, among women with suspected preeclampsia, the sFlt1/PlGF ratio has a very high negative predictive value in ruling out the development of preeclampsia within 7 days, adverse maternal outcomes within 14 days, or delivery with preeclampsia within 14 days. The use of angiogenic markers to guide care may reduce the time to diagnosis of preeclampsia and identify women at increased risk of peripartum severe maternal morbidity, including postnatal hypertension. Prediction of adverse outcomes may be improved by combining angiogenic markers with other clinical, routine laboratory, and ultrasonographic data.

The ratio is also associated with adverse outcomes in women at high risk for development of preeclampsia, including those with anti-phospholipid syndrome, diabetes or multifetal gestation, a previous history of hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome, early indications of abnormal development of the placenta (as determined by uterine artery Doppler, and FGR). The sFlt-1/PlGF ratio can be used for differential diagnosis amongst these women.

Maternal and fetal adverse outcomes

Extreme ratio test values are instrumental in predicting short-term adverse maternal outcomes in women with preeclampsia. The higher the ratio, the higher the risk of maternal complications requiring hospital intervention, such as acute lung edema, HELLP syndrome, placental abruption, renal failure, refractory hypertension, or eclampsia.

A high ratio is associated with adverse neonatal outcomes such as intrauterine fetal death (IUFD) and fetal growth restriction (FGR) associated with preeclampsia and risk of neonatal intensive care unit admissions and preterm delivery. The ratio can help predict fetal outcomes related to the prematurity of the baby and growth-related outcomes. The higher the ratio, the higher the risk of complications for both mother and baby.

Twin pregnancies

Women with twin pregnancies are twice as likely to develop preeclampsia compared with singleton pregnancies. In twin pregnancies, the ratio test has been shown to provide prognostic and diagnostic information, and although biomarker levels differ between singleton and twin pregnancies, reference ranges have recently been established. These data show that the ratio ranges are similar in women with twin and singleton pregnancies until 29 weeks’ gestation but are higher in twin pregnancies after 29 weeks. This suggests that the use of the ratio test beyond 30–32 weeks is less discriminatory for preeclampsia in twin pregnancies than when used in singletons, and results should be interpreted with caution.

The role of ratio is not yet established, and more data are required on its use in multiple pregnancies.

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