Solving the Mystery of Preeclampsia

As a storyteller myself, there are few things I love more than a good story, even more so if it is a good medical mystery. I recently attended a day long continuing education seminar on pregnancy complications presented by Jamie Otremba CNM. I found both her style and content very appealing, but my best and juiciest learning came during the segment on preeclampsia (the segments on domestic violence and late pretermers were very good also). Ms. Otremba gave me my money's worth when she wove an intriguing tale about a bright young nephrologist whom about a ten years ago noticed something very familiar looking about the kidney lesions he noted in the pregnant women with preeclampsia that he treated. His investigations led him to discover the pathogenesis of preeclampsia. Ms. Otremba regaled us with the story of his adversity as he tried to get attention for his very important discovery- outside of his specialty area. So intriguing was the tale of Ananth Karumanchi that I decided to do a little detective work of my own. I started with the article in New Yorker magazine that Ms. Otremba mentioned.
A physician and staff writer by the name of Jerome Groopman published an article in 2006 in New Yorker magazine finally giving Ananth Karumanchi broad exposure to his work. Theories about preeclampsia abounded, but the true cause continued to allude the scientific community. For those who are unfamiliar, preeclampsia is a disease of pregnancy that manifests as high blood pressure (greater than 140/90) and proteinuria (protein in the urine). Edema (swelling) and neurological changes such as visual disturbances and hyperreflexia (brisk reflexes) can also occur. If left unabated, preeclampsia can lead to seizures (a condition called eclampsia) and liver damage caused by HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets). The only known cure is removal of the placenta (delivery of the infant), at which point, the symptoms quickly reverse, and the woman gets better (if no permanent organ damage has been done to the liver or kidneys). If preeclampsia manifests late in pregnancy (as it most often does), a preterm infant is delivered. If it manifests in early pregnancy, the fetus may have to be sacrificed for the mother's wellbeing.
It was known that the placenta was the crux of the problem, but how? Groopman details how Karumanchi's careful research isolated two anti-angiogenic proteins (they prevent blood vessel growth) made by the placenta. These proteins, serum fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (s-Eng) are made by the placenta to control placental growth, and counteract the effects of pro-angiogenic proteins, vascular endothelial growth factor (VEGF) and placental growth factor (PIGF). In preeclampsia the sFlt1 and s-Eng overwhelm the maternal blood stream and cause blood vessel damage throughout leading to widespread vascular permeability and increased vascular resistance. The sFlt1 ultimately causes the hypertension (high blood pressure) and the s-Eng is responsible for the decreased platelets and liver damage seen in the more severe forms of the disease. The amount of these substances increase over time which explains why this is mostly a disease of late pregnancy. It appears to come out of the blue, but in fact the placenta was damaged from the beginning.
Following conception when the fertilized ovum (egg) is a blastocyst (about 100 cells) and starting to imbed itself in the uterine wall (the decidua) small fingerlike protrusions called trophoblasts (precursors of the placenta) grow into the decidua and reorganize uterine spiral arteries in order to set up a good blood supply for the developing fetus. In preeclampsia, this invasive network of trophoblasts and spiral arteries is incomplete, and sets in motion the abnormal release of anti-angiogenic factors leading to ongoing placental insufficiency for the fetus, and vascular insufficiency for the mother, both of which manifest increasing damage as the pregnancy progresses.
Karumanchi after several attempts, was able to publish his findings (increased levels of sFlt1 and s-Eng in the blood stream of women with the disease) in scientific journals and now heads a prestigious lab at Beth Israel Deaconess Medical Center in Boston, complete with government funding. Dr. Karumanchi and his team are now hard at work on what seemed impossible 20 years ago, a treatment for preeclampsia. His research also has implications for cancer treatment interestingly enough, since tumors, like fetuses are dependent on diverting and establishing rich vascular networks.
Preeclampsia and eclampsia continue to plague African-American women at higher rates along with diabetic women and women with preexisting hypertension, obesity, or previous preeclampsia. Those older than 35 and younger than 18 (of all races) are also at a higher risk. No one is sure why, but theories abound. There is still much about this disease that is a mystery.
Last week, my friend Dotty's daughter-in-law delivered a baby boy at 36 weeks due to induction for preeclampsia. She was not in any of the high risk categories. I assured my friend that for preeclampsia, induction is often indicated. Dotty remarked on the small placenta, and the feeding difficulties that are typical for late preterm gestation (more on that in a later post). I am delighted to see inroads being made. They are looking not only at methods of treatment, but early diagnostic tools as well (though the discovery was made 10 years ago and there are still no medications or biologic markers on the market, but I understand that these things take time). I suppose we are all still waiting for the happy ending to this story.

Narrative Report of Research Activities in the Karumanchi Laboratory

Role of angiogenesis in the pathogenesis of preeclampsia (PE) (currently the major focus of the laboratory): Our laboratory has identified sFlt-1, an antagonist of circulating vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), from preeclamptic placentas and has confirmed that it is released into the blood stream in vast excess in patients with preeclampsia. Exogenous administration of sFlt-1 into pregnant rats reproduces the phenotype of preeclampsia, namely proteinuria, hypertension and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt-1 contributes to the pathogenesis of preeclampsia. We have also demonstrated that circulating sFlt-1 and PlGF levels can be used for the clinical diagnosis and the prediction of preeclampsia. Work is in progress to understand the regulation of sFlt-1 production by the cytotrophoblasts of the placenta. We are also testing the effects of antagonizing excess sFlt-1 with growth factors and small molecule compounds in our animal model of preeclampsia with the goal of finding novel treatment options for this disease. Additionally, we are currently characterizing other gene products that are elevated in preeclampsia and which may be synergistic to sFlt-1 in the pathogenesis of preeclampsia and may serve as biomarkers for the early diagnosis of preeclampsia. This project is part of our interest in studying the contribution of endothelium in the pathogenesis of proteinuria and other vascular diseases.

Groopman, J. (2006). The preeclampsia puzzle: making sense of a mysterious pregnancy disorder. The New Yorker.

Karumanchi, S.A., et el. (2008). A longitudinal study of angiogenic and anti-angiogenic factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small )for gestational age neonate. The Journal of Maternal-Fetal and Neonatal Medicine. 21(1). 9-23.

Levine, R.J., Qian, C., Maynard, S.E., Yu, K.F., Epstein, F.H., Karumanchi, S.A. (2006). Serum sFlt1 concentration during preeclampsia and mid trimester blood pressure in healthy nulliparous women. American Journal of Obstetrics and Gynecology. 194(4). 1034-41.

Silasi, M., Cohen, B., Karumanchi, S.A., Rana, S. (2010). Abnormal placentation, angiogenic factors, and the pathogenesis of preeclampsia. Obstetrics and Gynecology Clinics of North America. 37(2): 239-53.

Staff, A.C., Braekke, K., Johnsen G.M., Karumanchi, S.A. (2007). Circulating concentrations of soluble endoglin in fetal and maternal serum and in amniotic fluid in preeclampsia. American Journal of Obstetrics and Gynecology. 197(2). 176-8.