Preeclampsia occurs in 5 to 8% of pregnancies and is a major contributor of premature deliveries and neonatal morbidity in the U.S. and worldwide. It is characterized by new onset hypertension and proteinuria after 20 weeks of gestation and delivery is currently the only treatment. Because the etiology of preeclampsia is poorly understood, our ability to distinguish between different hypertensive disorders of pregnancy remains limited. In addition, our ability to predict and prevent preeclampsia continues to be poor. We have previously blogged about the use of circulating angiogenic factors such as soluble fms-like tyrosine 1 (sFLT-1) and placental growth factor (PlGF) as early predictors of preeclampsia.
In January 2016 study (funded by Roche Diagnostics), Zeisler, et. al. examined the predictive value of the sFlt-1:PlGF ratio to predict the absence or presence of preeclampsia in women with suspected preeclampsia. The study included two groups of pregnant women with elevated blood pressure and suspected preeclampsia: a development cohort with 500 women (101 had preeclampsia or HELLP syndrome) and a validation cohort with 550 women (98 had preeclampsia).
Using the development cohort, the authors established an sFlt-1:PlGF ratio of 38 as a cutoff for predicting preeclampsia. Using the validation cohort, the authors used the sFlt-1:PlGF ratio of 38 to determine the ability to rule out preeclampsia within 1 week of presenting with symptoms and the ability to rule in preeclampsia within 4 weeks of presenting with symptoms. In the validation cohort, 15 women developed preeclampsia within 1 week (prevalence = 15/550= 2.7%) and the sFlt-1:PlGF ratio of 38 demonstrated a negative predictive value of 99.3% to rule out preeclampsia within one week of presenting with symptoms. In the validation cohort, 71 women developed preeclampsia within 4 weeks (prevalence = 71/550= 13%) and they reported a positive predictive value of 36.7% to predict preeclampsia within 4 weeks. The authors conclude that an sFlt-1:PlGF ratio of 38 or lower can be used to predict the short term absence of preeclampsia in women who are suspected of having preeclampsia.
I have depicted their data below in a familiar 2×2 format.
| Rule out preeclampsia within 1 week | ||||
| sFlt-1:PlGF ratio | Preeclampsia + | Preeclampsia – | Total | |
| >38 | 12 | 118 | 130 | + PV 9.2% |
| ≤38 | 3 | 417 | 420 | – PV 99.3% |
| Total | 15 | 535 | ||
| Sensitivity 80% | Specificity 78% | |||
| Rule in preeclampsia within 4 weeks | ||||
| sFlt-1:PlGF ratio | Preeclampsia + | Preeclampsia – | Total | |
| >38 | 47 | 82 | 129 | + PV 36.7% |
| ≤38 | 24 | 397 | 421 | – PV 94% |
| Total | 24 | 479 | ||
| Sensitivity 66% | Specificity 83% | |||
One can conclude that the sFlt-1:PlGF ratio has an excellent negative predictive value to rule out preeclampsia in both 1 week and 4 weeks (99.3 and 94% respectively), but the positive predictive value is poor for both (9.2 and 36.7% respectively). However, one needs to think critically about the data. In both populations, despite the fact that the women have symptoms of preeclampsia, the prevalence of preeclampsia is still low (2.7% within 1 week and 13% within 4 weeks). Therefore, a marker with high positive predictive value is needed.
If we take the data from the within 1 week population in the table above and instead of using the sFlt-1:PlGF ratio, we flip a coin such that we get a sensitivity of 50% and specificity of 50% the negative predictive value is still 97% (see table below). The sFlt-1:PlGF ratio improves the negative predictive value by 3% over the flip of a coin. Why is this? This is because the pretest probability of not developing preeclampsia within one week, in these symptomatic women, is already 97.3%. The sFlt-1:PlGF ratio adds little to the negative predictive value.
| Rule out preeclampsia within 1 week | ||||
| Coin Flip | Preeclampsia + | Preeclampsia – | Total | |
| + | 7.5 | 267.5 | 275 | + PV 2.7% |
| – | 7.5 | 267.5 | 275 | – PV 97% |
| Total | 15 | 535 | ||
| Sensitivity 50% | Specificity 50% | |||
In summary, it is clear that markers with a better positive predictive value are still needed to accurately predict women who are likely to develop preeclampsia even in a population of pregnant women with signs and symptoms.