The Pregnancy Lab

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 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

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."