What is the clinical need for preeclampsia (PE) screening?
A: PE affects about 2% of pregnancies globally and is a major cause of maternal and perinatal mortality and morbidity. This condition has two major subtypes: early-onset (or preterm) PE, which develops before 34 weeks of gestation, and late-onset PE, which occurs at or after the 34-week mark. Currently, the standard diagnostic indicator for both PE types is the presence of hypertension and proteinuria, but these clinical criteria alone may not adequately predict adverse outcomes.
While early-onset PE is the less prevalent subtype, it is associated with an even greater risk of adverse outcomes than late-onset PE. Developing an effective method for early identification of pregnancies at high risk for preterm PE is therefore one of the major challenges of modern obstetrics.
Currently, what are the most promising biomarkers for PE screening and diagnosis?
While the exact cause of PE is unknown, impaired placentation—i.e. a placenta that doesn’t function properly—is thought to be the condition’s underlying mechanism. This theory is supported by the finding that women with PE have abnormal blood flow in their uterine arteries and reduced maternal serum levels of placental products. In light of this, it is not surprising that placental growth factor (PlGF) is the most discriminating biomarker for PE—and for early-onset PE in particular—that researchers have found to date. PlGF levels are significantly lower in pregnant women who go on to develop PE, and researchers have used PlGF combined with other factors to achieve a 93% detection rate for the risk of developing PE in the first trimester, with a false-positive ratio of 5%. The other factors included maternal history, prior and family history of PE, maternal blood pressure, uterine artery pulsatility index, and pregnancy-associated plasma protein A (PAPP-A).
The antiangiogenic factor soluble fms-like tyrosine kinase 1 (sFlt-1) and the sFlt-1:PlGF ratio have also shown promise in clinical research as biomarkers for predicting and diagnosing PE in the second and third trimester.
What are the advantages of using the sFlt-1:PlGF ratio to detect PE?
Starting in mid-pregnancy, healthcare providers can confirm a diagnosis of PE by measuring the levels of sFlt-1 and PlGF in maternal serum. Because women with PE have a significantly higher sFlt-1:PlGF ratio than women with other hypertensive disorders, this ratio enables providers to distinguish between patients who will develop PE and those with chronic or gestational hypertension. The sFlt-1:PlGF ratio has superior diagnostic power compared to either of these biomarkers alone, and several studies show that this ratio is highly predictive for ruling out PE, with a negative predictive value close to 99%. The sFlt-1:PlGF ratio combined with Doppler ultrasound measurements also has increased sensitivity and specificity for PE compared with a Doppler ultrasound by itself.
However, the ratio’s positive predictive value is < 37%, which is quite low. An ideal biomarker for preeclampsia should have a high positive predictive value in addition to a high negative predictive value. Further research is therefore needed in this area.
So what should labs use to detect preeclampsia?
First-trimester maternal serum levels of PlGF and PAPP-A along with other maternal factors form a suitable panel for predicting the development of PE. For women in their second and third trimesters, labs should then measure maternal serum concentrations of sFlt-1 and PlGF to differentiate healthy women from women with PE. A high sFlt-1:PlGF ratio and a rapid elevation in the sFlt-1:PlGF ratio are associated with significantly increased risk for an immediate delivery.
Overall, the earlier labs identify a woman at high risk for PE, the better the chances are of improving her pregnancy’s outcome. Once a high-risk patient is identified, she can undergo intensive maternal and fetal monitoring, which in turn could lead to earlier diagnosis of PE while also preventing serious complications through timely pharmacological interventions.
Saswati Das, MBBS, MD, is a specialist in the Department of Biochemistry at Ram Manohar Lohia Hospital, Ministry of Health and Family Welfare India in Delhi. +Email: [email protected]