Prediction of Preeclampsia Using the Soluble fms-Like Tyrosine Kinase 1 to Placental Growth Factor Ratio: A Prospective Cohort Study of Unselected Nulliparous Women

Abstract

We sought to assess the ratio of sFlt-1 (soluble fms-like tyrosine kinase 1) to PlGF (placental growth factor) in maternal serum as a screening test for preeclampsia in unselected nulliparous women with a singleton pregnancy. We studied 4099 women recruited to the POP study (Pregnancy Outcome Prediction) (Cambridge, United Kingdom). The sFlt-1:PlGF ratio was measured using the Roche Cobas e411 platform at ≈20, ≈28, and ≈36 weeks of gestational age (wkGA). Screen positive was defined as an sFlt-1:PlGF ratio >38, but higher thresholds were also studied. At 28 wkGA, an sFlt-1:PlGF ratio >38 had a positive predictive value (PPV) of 32% for preeclampsia and preterm birth, and the PPV was similar comparing women with low and high prior risk of disease. At 36 wkGA, an sFlt-1:PlGF ratio >38 had a PPV for severe preeclampsia of 20% in high-risk women and 6.4% in low-risk women. At 36 wkGA, an sFlt-1:PlGF ratio >110 had a PPV of 30% for severe preeclampsia, and the PPV was similar comparing low- and high-risk women. Overall, at 36 wkGA, 195 (5.2%) women either had an sFlt-1:PlGF ratio of >110 or an sFlt-1:PlGF ratio >38 plus maternal risk factors: 43% of these women developed preeclampsia, about half with severe features. Among low-risk women at 36 wkGA, an sFlt-1:PlGF ratio ≤38 had a negative predictive value for severe preeclampsia of 99.2%. The sFlt-1:PlGF ratio provided clinically useful prediction of the risk of the most important manifestations of preeclampsia in a cohort of unselected nulliparous women.

Keywords: clinical markers; cohort studies; immunoassay; pregnancy; risk factors.

Figure 1.

Receiver operating characteristic curve analysis of the relationship between (A) sFlt-1 (soluble fms-like tyrosine kinase 1) to PlGF (placental growth factor) ratio at 20 weeks of gestational age (wkGA) and (1) preeclampsia with delivery before 28 wkGA or (2) preeclampsia with delivery before 37 weeks where the onset of hypertension was before 28 wkGA (n=4), (B) sFlt-1:PlGF at 28 wkGA and preeclampsia leading to preterm birth (n=26), and (C) sFlt-1:PlGF at 36 wkGA and severe preeclampsia (n=106). The continuous sFlt-1:PlGF ratio is used, and the area under the receiver operating characteristic curve (AUROCC) with 95% confidence interval (CI) is given for each analysis.

Figure 2.

Cumulative incidence of the primary outcomes (Methods) by sFlt-1 (soluble fms-like tyrosine kinase 1) to PlGF (placental growth factor) ratio: (A) sFlt-1:PlGF at 28 wkGA and preeclampsia leading to preterm birth, (B) sFlt-1:PlGF at 36 wkGA and severe preeclampsia, stratified by maternal risk. High risk was defined on the basis of maternal risk factors or 20 wkGA uterine artery Doppler (see Methods for details), and (C) composite risk status at 36 wkGA. Screen positive was defined as (1) sFlt-1:PlGF ratio of >38 and maternal risk factors or (2) sFlt-1:PlGF ratio >110 irrespective of maternal risk factors. Screen negative was defined as all other women. Delivery without the given primary outcome was treated as a competing risk in all 3 analyses. Hence, the maximum value of the cumulative incidence is the same as the positive predictive value, and the curve illustrates the distribution of the timing of the deliveries with the outcome in question.