Category Archives: Preeclampsia

Preeclampsia

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.

Can a personalized approach improve IVF success rates?


Test Tube Baby

This post was written by Robert D. Nerenz, PhD, an assistant professor of pathology and laboratory medicine at the University of Kentucky, in Lexington.

In the United States, an estimated one in seven couples experience infertility and for many of these couples, in vitro fertilization (IVF) represents their best chance of achieving pregnancy. However, IVF cycles constitute a significant expense (approximately $12,500 per cycle), disrupt patients’ daily lives and only result in a healthy, live birth 30% of the time! Furthermore, the majority of IVF cycles performed in the United States involve the transfer of multiple embryos. This is of particular concern because multiple embryo transfer carries a finite risk of a multiple gestation pregnancy. Bringing multiple infants to term is associated with an increased risk of poor fetal and maternal outcomes including decreased birth weight, increased rate of fetal death, preeclampsia, gestational diabetes and preterm labor. Clearly, there is a significant need to improve IVF success rates while also minimizing the likelihood of multiple gestation pregnancies.

One strategy that may accomplish both of these goals is to perform “single embryo transfer” by implanting one embryo that has a high likelihood of producing pregnancy and, ultimately, a live birth. This is the focus of an upcoming symposium at the AACC meeting to be held July 29th at 10:30 am in Atlanta, Georgia. Fertility clinics around the world currently attempt to do this by observing embryos under a microscope and choosing the best embryo on the basis of its physical appearance. Unfortunately, this approach does not provide any information about the embryo’s genetic status. This is an important limitation because aneuploidy (the gain or loss of a chromosome) is the most common cause of pregnancy loss. It is also estimated to occur in ≥10% of clinical pregnancies and becomes more frequent with increasing maternal age.

To ensure that aneuploid embryos are not selected for transfer, several research groups have developed methods collectively known as comprehensive chromosome screening (CCS). CCS involves culturing embryos for 5-6 days, removing a few cells from the trophectoderm (the outer cell layer that develops into the placenta), isolating the DNA from those cells and assessing the copy number of each chromosome using techniques such as quantitative PCR, comparative genomic hybridization, or single nucleotide polymorphism arrays. Following determination of the embryos’ genetic status, only embryos with the normal number of chromosomes are chosen for transfer. In multiple prospective, randomized controlled trials described here and here, CCS has been shown to increase the pregnancy rate and decrease the frequency of multiple gestation pregnancies. As a result, CCS is beginning to make the transition from the research setting to use with patients.

The ability to transfer only euploid embryos represents the most promising application of novel technologies to IVF but ongoing research is focused on other ways to improve the IVF success rate. Many different groups are analyzing the culture medium that embryos are grown in prior to implantation. It is hoped that this will provide information about the embryos’ metabolic health and might help identify which embryos are most likely to result in pregnancy and live birth. Other groups are evaluating endometrial gene expression profiles to assess endometrial receptivity and ultimately determine the best time to perform embryo transfer. While both of these approaches have technical limitations and are not quite ready for primetime, they have the potential to greatly improve our current standard of care and may be ready for clinical use in the near future.

Are there any good markers to predict preeclampsia?


David has written about preeclampsia in the past, but I thought I'd talk about some specific studies that have been published on that topic.

Recall that preeclampsia is when a pregnant woman develops high blood pressure and protein in the High blood pressure urine after the 20th week of pregnancy and it is usually associated with edema (swelling). Although preeclampsia occurs in only 5 to 8% of pregnancies, it is a major contributor of premature deliveries and neonatal morbidity in the United States. Because the etiology of preeclampsia is not well understood, the ability to predict and prevent preeclampsia continues to be poor.

Numerous biochemical markers have been studied for their ability to predict the onset of preeclampsia. Why do we seek a marker to predict preeclampsia when there is not a good treatment? It is hoped that if we could identify who was likely to develop preeclampsia then we could study interventions in that group which may ultimately lead to a way to prevent it. Unfortunately, no good markers have been identified as of yet.

In 2004 the World Health Organization did a systematic review of 7,191 potentially relevant scientific papers on this topic. Eighty-seven articles were ultimately included in the analysis and the WHO concluded that “As of 2004, there is no clinically useful screening test to predict the development of preeclampsia.”

However, also in 2004, Levine et al published a paper indicating that the circulating angiogenic factors called soluble fms-like tyrosine 1 (sFLT-1) and placental growth factor (PlGF) could be potential markers for the early prediction of preeclampsia. These proteins play a role in angiogenesis and are hypothesized to be required for normal embryonic vascularization. This caused a lot of excitement and led to many promising studies that examined the clinical utility of measuring Sflt-1 and PlGF to predict the onset of preeclampsia.

Unfortunately, these markers have not turned out to be all we had hoped they would be. In 2007 Widmer et al published the results from a systematic review of studies of sFlt-1 and PlGF. Ten of 184 available studies analyzing sFlt-1 and 14 of 319 studies analyzing PlGF were included in their review. The authors said that the evidence supports the possibility that sFlt-1 and PlGF are associated with the pathophysiology of preeclampsia or its phenotypes. In addition, third trimester changes in the blood concentrations of the markers were associated with preeclampsia, especially when the disease was severe. However, they concluded that “… the evidence is neither strong enough nor sufficient to recommend placental growth factor and sFlt-1 to screen women at risk to develop preeclampsia…" and "Prospective studies employing rigorous laboratory and study design criteria are needed to determine the clinical usefulness of these tests."

Apparently, there is a study called the "WHO Global Program to Conquer Preeclampsia" which was scheduled to start mid 2006; in this investigation approximately 10,000 women will be screened serially to evaluate these biomarkers for preeclampsia. So far, no data has been published on the results of this study…so stay tuned!

Predicting preeclampsia


Blood pressure Preeclampsia is a hot topic!  Lots of research is going on in an effort to identify biomarkers that can be used to predict preeclampsia in pregnant women.  Why all the fuss?  Well, simply put, preeclampsia is rather dangerous.  A quick review of the facts:

  • Preeclampsia is the development of hypertension (high blood pressure) and proteinuria (protein excreted in the urine) that occur in a woman after the 20th week (late 2nd trimester) of pregnancy.
  • Complications of preeclampsia include:
    • Its progression to eclampsia, which is the onset of seizures in the mother.  This occurs in about 1% of women with preeclampsia and is potentially life-threatening.
    • HELLP syndrome (Hemolysis, Elevated Liver enzymes, and Low Platelets). This occurs in 10-20% of women with preeclampsia and is potentially life-threatening.
    • Bleeding problems
    • Placental abruption (the separation of the placenta from the uterus before the baby is born)
    • Rupture of the liver
    • Stroke
    • Death (albeit rarely)
  • Preeclampsia can't be prevented and the only effective treatment is delivery of the placenta (and, obviously, the baby)

So, if preeclampsia can't be prevented and the only effective treatment is delivery, then what good is predicting it?  That's a good question!  One reason to identify robust prediction tests is that they would permit more effective research into ways of prevent it from occurring in the first place.

Most of the research in preeclampsia prediction tests is focused on chemicals that can be measured in the mother's blood, and that list of chemicals is very, very long.  The darling of all biomarkers studied to recently are the so-called "angiogenic" markers.  These are molecules that are involved in the growth and development of blood vessels.  Because preeclampsia is believed to be caused by abnormal placentation (and the placenta is full of blood vessels), angiogenic markers are logical candidates for predictive tests.

I believe that the jury is still out when it comes to the actual use of angiogenic or other biomarkers for predicting preeclampsia.  Some diagnostic companies have jumped on the bandwagon to bring these tests to clinical laboratories but I think this is a case of "watch and wait."