Monthly Archives: April 2017

Predicting Preeclampsia using sFlt-1:PlGF Ratio in Symptomatic Women

High blood pressurePreeclampsia 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.

Cell-free DNA screening tests in the general obstetrical population

DNAIt has been several years since cell-free DNA (cfDNA) tests for the detection of fetal aneuploidies became available. The first clinical studies of these tests were reported in women who, because of age or other reasons, were already at increased risk of having an affected pregnancy (i.e. “high risk” women). While these studies demonstrated the superior performance of cfDNA tests compared to traditional biochemical tests, their application to women at low risk was not encouraged because of lack of evidence regarding how well they would work in that population. A recent report on cfDNA screening tests in the general obstetrical population now provides much needed evidence.

Investigators at Brown University described several clinical utility aspects of cfDNA screening for common aneuploidies through the implementation of a statewide program called DNAFirst that offered cfDNA screening tests to the general pregnancy population in the state of Rhode Island. The clinical utility aspects that were investigated were a comparison of screening uptake rates before and after the DNAFirst program, an evaluation of a reflexive serum testing protocol for cfDNA tests that failed to produce a result, and explored women’s decision-making.

Over 11 months, 2,681 women agreed to undergo screening through 72 providers. Prior to undergoing testing, the women received information about cfDNA testing by primary obstetrical care providers. The median maternal age was 31 years and 79% of the women were younger than 35 years of age. There were 16 positive (i.e. abnormal for trisomy 21, 18, or 13) cfDNA results, 12 of which were confirmed as true positive and 4 of which were false-positive. 2,515 women had a negative screening result and all were true-negatives. 150 tests failed to produce a result (none of which were known to have trisomy). Collectively, these data produced a sensitivity of 100%, a positive predictive value of 75% and a false-positive rate of 0.15%. By comparison, the most effective biochemical screening test (the Integrated test) has a 90% detection rate, a 3% false-positive rate, and a positive predictive value of only 6%.

A small number of women who participated in the study (113) completed a survey asking them about their understanding of cfDNA testing. Women reported receiving information from their care provider in 9 minutes or less. While 85% understood that the test identified Down syndrome, 15% incorrectly thought it identified all genetic problems. 79% understood that a negative result did not rule out Down syndrome but 13% thought it did. These survey results suggest that most women do understand the basic concepts of cfDNA screening.

The study’s authors concluded that cfDNA screening tests perform very well in the general pregnancy population and that women understand the basic concepts of screening. Further, the tests were easily incorporated into routine practices. They encouraged clinical laboratories to offer cfDNA screening tests to improve access to better aneuploidy screening for the more than 2 million pregnant women in the United States who choose to undergo such testing each year.