Biomarker Ratio Could Predict Development of Severe Preeclampsia

A study published in NEJM Evidence found that the ratio between serum soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) was able to predict the risk of pregnant women developing preeclampsia with severe features (sPE) between 23 and 35 weeks of gestation.

Preeclampsia is a hypertensive disorder that affects approximately 5% of pregnant women and is one of the leading causes of maternal and neonatal morbidity and mortality in the United States. The multicenter study aimed to identify and validate an sFlt-1:PlGF ratio to stratify the risk of developing sPE in women with hypertension and hospitalized in late pregnancy.

The primary outcome of the study was development of sPE within 2 weeks of enrollment in the study. Women from 18 US tertiary care and community hospitals were recruited from urban and suburban settings. Pregnant women who were older than 18 years, between 23 weeks and 34 weeks and 6 days’ gestation, and had a hypertensive disorder of pregnancy were eligible for the study. Women with multiple gestations and receiving intravenous heparin were excluded.

Women provided a blood sample and were followed up for 2 weeks or until delivery. sFlt-1 and PlGF levels were both measured in a blinded fashion.

Sever hypertension, thrombocytopenia, impaired liver function, severe persistent right upper quadrant or epigastric pain, progressive renal insufficiency, pulmonary edema, new-onset cerebral or visual disturbances, and headache unresponsive to medication were all features that constituted sPE in women with preeclampsia.

There were 1014 women enrolled in the study who had a singleton pregnancy and a hypertensive disorder of pregnancy. The mean gestational age was 30 weeks (range, 23-35 weeks) and the mean age of the women was 31 years (range, 18-50 years). Just over a third of the women were Black and 47% had chronic hypertension. The highest systolic blood pressure was 162 (21) mmHg and diastolic was 96 (13) mmHg. There was a median urine protein to creatinen ratio of 0.31 (IQR, 0.16-1.04).

The incidence of sPE within 2 weeks was 31.3% in the 220 women in the deriviation cohort. The median sFlt-1:PlGF ratio differed in the women who developed sPE within 2 weeks (200; IQR, 53-458) compared with those who did not (6; IQR, 3-26). An sFlt-1:PlGF ratio greater than or equal to 40 had a prognostic performance estimate of 81% sensitivity (95% CI, 70-90) and 81% specificity (95% CI, 74-87). The positive predictive value was 66% (95% CI, 55-76) and the negative predictive value was 90% (95% CI, 84-95) for the primary outcome.

The incidence of sPE within 2 weeks was 33.5% in the 556 women in the validation cohort. The median sFlt-1:PlGF ratio was elevated in women who developed sPE in all clinical sites, with the sFlt-1:PlGF ratio about 40 times higher compared with those who did not develop sPE (291 [IQR, 121-777] vs 7 [IQR, 3-40]). An sFlt-1:PlGF ratio greater than or equal to 40 had a prognostic performance of 94% sensitivity (95% CI, 89-96) and 75% specificity (95% CI,70-79). There was a positive predictive value of 65% (95% CI, 59-71) and a negative predictive value of 96% (95% CI, 93-98). When restricting the analysis to women with chronic hypertension and patients who identified as Black, the results were similar.

The sFlt-1:PlGF ratio was 10 times higher in women who developed adverse maternal outcomes compared with patients who did not (279 [IQR, 53-774] vs 22 [IQR, 4-171]). Composite adverse maternal outcomes were more common in women with a ratio greater than or equal to 40 compared with women with a ratio less than 40 (16.1% vs 2.8%; risk ratio, 5.8; 95% CI, 2.8-12.2).

sFlt-1:PlGF ratio was 30 times higher in women with adverse fetal and neonatal outcomes compared with those without (182 [IQR, 36-548] vs 6 [IQR, 3-24]). Compositve adverse fetal and neonatal outcomes were also more common in the women with an sFlt-1:PlGF ratio greater than or equal to 40 compared with those with a ratio of less than 40 {79.8% vs 26.0%; risk ratio, 3.1; 95% CI, 2.5-3.8).

Women were also more likely to deliver within 2 weeks if they had an sFlt-1:PlGF ratio greater than or equal to 40 (HR, 3.1; 95% CI, 2.3-4.2).

The researchers concluded that serum sFlt-1:PlGF ratio of 40 was able to predict the development of sPE, adverse outcomes, and delivery within 2 weeks of testing pregantn women with hypertension who were hospitalized between 23 and 35 weeks of gestation.

Reference

Thadhani R, Lemoine E, Rana S, et al. Circulating angiogenic factor levels in hypertensive disorders of pregnancy. NEJM Evid. Published online November 9, 2022. doi:10.1056/EVIDoa2200161