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Several years ago, Dr. Jun “Jim” Zhang, a senior investigator at the National Institute of Child Health and Human Development approached the Preeclampsia Foundation about working together on an epidemiological research study. Here was the study’s rationale:

“Preeclampsia is a syndrome of hypertension accompanied by proteinuria. It is a major pregnancy complication, associated with premature delivery, fetal growth restriction, abruptio placentae, and fetal death, as well as maternal morbidity and mortality. Although preeclampsia has been recognized for centuries, the etiology of this disorder remains unknown. Familial clustering of preeclampsia has long been identified, leading to the concept of a genetic basis for this syndrome. We propose a familial genetic study of preeclampsia. As such a study is often difficult to do, we plan to conduct a pilot study to test the feasibility, logistics and examine frequency of genetic polymorphism of certain genes in the target population.”

A total of 60 women who had preeclampsia during their first pregnancy were identified through the Preeclampsia Foundation. Women who had chronic hypertension or diabetes prior to the first pregnancy were excluded. We also tried to enroll their family members in the study. All subjects were asked to complete a self-administered questionnaire and collect mouth wash samples, in order to collect the buccal cells from which DNA was extracted. Women who reported having hypertension during pregnancy were also asked to sign a medical record release form, and a copy of their medical record was obtained to confirm the diagnosis of preeclampsia.

Forty-six women returned the questionnaires and samples, resulting in a 77% participation rate – a very high response for research studies. The actual enrollment rates for the biological mother, father, mother-in-law, and father-in-law ranged between 61% and 26%; and the actual enrollment rates for full sisters, brothers-in-law, full brothers and sisters-in-law ranged between 23% and 36%.

“Thus,” concluded the abstract, “conducting a familial genetic epidemiologic study with self-administering questionnaires, mouthwash and buccal swabs is feasible. However, strategies for increasing participation rates among family members are warranted.”

We concluded the collection process in early 2006, and the resulting abstract was submitted to the International Society for Studies on Hypertension in Pregnancy and the Society for Pediatric and Perinatal Epidemiology annual meetings. Our Study Managers, Anne Garrett and Carrie Barrion, presented the poster at the latter meeting.

 

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On November 20-22, 2007, a meeting was held in Vancouver, British Columbia to discuss The Preeclampsia Integrated Estimate of Risk Study (PIERS) which was lead by Dr. Peter von Dadelszen. Besides being the lead investigator for the study, Dr. von Dadelszen is also a member of the Preeclampsia Foundation’s prestigious Medical Advisory Board, President of the North American Society for the Study of Hypertension in Pregnancy (NASSHP), and the President of ERIPED (Equipede Recherché Interdisciplinaire sur la Pre-Eclamspie et ses Determinants), Canada’s preeclampsia research alliance.

The goal of the 41-month PIERS study was to create a rigorous standard care protocol for the diagnosis and intervention of preeclampsia and the purpose of the meeting was to move to the next level of the PIERS study. After prospective gathering of data for seven years, and publishing the findings, the next step was to strategize about what had been learned and figure out how to get hospital administrators to adopt the findings as the standard protocol for care.

Representing the Preeclampsia Foundation in non-scientific roles during the two-day PIERS meeting were Executive Director J. Thomas Viall and Fiona Morrow, Forum Administrator and preeclampsia survivor. Morrow was involved in the PIERS study and presented the human component behind the graphs and charts by sharing her story and answering questions. Viall could tell by the eagerness of the interaction that she really got the audience’s attention and described her speech as “emotive and clear.” He said their entire presentation, “…was very powerful. Many of the scientists and medical professionals had tears in their eyes.” They were “just stricken.” Viall credits von Dadelszen with presenting and keeping the human component “front and center” to keep the researchers focused on the importance of the study. “There are moms losing babies, and husbands losing wives,” said Mr. Viall.

The researchers looked at past practice and records of how 400 women were evaluated for, and diagnosed with preeclampsia, as well as the recommendations that were made for intervention. The researchers compiled a snapshot of how, in these 400 cases, monitoring was done; what diagnostic protocols were used, and what interventions were taken. They matched those data to the outcomes of each of the women and found that five percent of the women had negative outcomes (loss of life, stroke, seizures, organ failure, etc). The next step was to develop a standard protocol for all possible cases of preeclampsia, because one cannot predict the outcomes.

Approximately 300 women participated in this phase of the initiative. When the standard protocol of care, which was very stringent, was used for these women, it produced a significant decrease in negative outcomes; which dropped from five percent to approximately seven-tenths of one percent. Viall pointed out, that unfortunately, there was no shift in neonatal outcomes with the standard care protocol. Viall thought this study might present a major opportunity for the Preeclampsia Foundation, in that the Foundation could seek grants to do similar studies in the U.S., based on the PIERS findings. The goal would be to change diagnostic and intervention protocols in the States, though Viall acknowledged that differences in the Canadian and U.S. health care systems might present certain challenges. At a minimum, he said, “the Preeclampsia Foundation could be a clarion voice for the patient by promoting its view of best practices.” We must continue to be the honest broker with no agenda other than minimizing negative outcomes…that will help to save lives.”

Acknowledging that preeclampsia is an even bigger problem in the developing world, the meeting also focused on the development of condensed recommendations for diagnosis and intervention in less developed countries. ”I had the opportunity to meet and speak to the Coordinator of Maternal and Perinatal Health activities within the Reproductive Health Division of the World Health Organization. He was quite impressed with our work and I do believe we will stay in touch and consider ways in which we can collaborate in the future,” said Viall. While delving into the underdeveloped world is “not necessarily a front line mission-issue for the Preeclampsia Foundation, the Board of Directors has begun to look at ways we might begin developing materials and guidelines to have an impact beyond North America,” said Viall.

 

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Say “matrix” and visions of a kick-boxing, black-clad Keanu Reeves may come to mind. No, this is not a movie review.

Every day, a small army of Harvard Medical School researchers reports to The Life Sci­ences Building in Boston’s Longwood Medi­cal Area. It’s new, ultra high-tech. It towers over its neighboring hospitals and research facilities and, with its clean lines, giant glass panels and sweeping marble stairway, would be a set designer’s dream for another sequel to “The Matrix”. The men and women who spend so much of their lives in this futuristic workplace are pulmonologists, oncologists, nephrologists, neurologists; they are natives of France, Norway, Sweden, Finland, India, China, Japan, Turkey, and the U.S. They study and work under the leadership of Dr. Raghu Kalluri, Chief of the Division of Matrix Biology at Beth Israel Deaconess Medical Center.

Composed of proteins and found through­out the body, the matrix serves as a platform for cells. Kalluri says just ten years ago, scien­tists believed that a cell contained all the in­formation it needed to function. Researchers have since discovered that the extracellular matrix actually tells the cells how to behave. After countless division, cells become liver cells, kidney cells, brain cells.all kinds of cells. Kalluri says the matrix supporting kidney cells, for example, tells those cells to “behave like a kidney”. Transfer them to a matrix in the brain and they’re no longer act­ing like kidney cells, but rather assuming the function of brain cells. Kalluri says as many as 50 different human diseases can be traced to defects in proteins outside the cell, which would explain in part, why the matrix has become a field of study in itself. And matrix biology has served as a powerful attraction for these graduate students and medical professionals from a range of disciplines.

New Jersey native, Scott Potenta, whose research paper had just been accepted the day we spoke, says he’s always been inter­ested in matrix proteins and their effect on cell behavior. He is studying the way blood vessels react in diseases such as cancer. Valerie LeBleu, a native of France and the first Har­vard graduate student to work at the Matrix Biology Lab, is trying to find alternatives to dialysis for treatment of Alport Syndrome, a genetic kidney disease that affects 1 in 5,000 people. LeBleu and Potenta say they appreci­ate the richness of the laboratory, which is obvious in the diversity of the workforce and the wide representation of specialties, all of which foster the sharing of knowledge and experience. Formal discussions at stations in the main laboratory, as well as informal con­versation over coffee in the break room can and do give way to new ideas, and more than a few “aha!” moments. Both of these young researchers and their colleagues made it clear to this reporter, it’s a privilege to work in this cutting-edge environment.

Their days are spent comparing graphs on a split computer screen or peering into micro­scopes deciphering cells on a slide, manipu­lating organic solutions, each with their own requirements for survival: simple refrigera­tion or having to be gingerly lowered into giant cylinders, filled with dry ice.

In the next row of lab stations, is Dr Keizo Kanasaki, a Japanese native and research fel­low in medicine. Kanasaki collaborated with Kalluri on a paper reported in the May 11, 2008 online “Nature”. They theorize that preeclampsia is actually linked to an absence of 2-ME, and that administering that pro­tein to women with the disease would be a viable treatment. Because this is a women’s disease, you might think that Kanasaki is an obstetrician. He is a nephrologist; he studies the kidney. Which brings us back to the common ground for all of these dedicated researchers…the matrix. Discoveries within that mass of protein, the scaffolding for cells throughout the human body, could yield the keys to unlocking the mystery of pre-eclampsia and, hopefully, lead to prevention.

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Posted on in Research

Currently there's no way to know for certain whether preeclampsia will develop during any given pregnancy. This leaves pregnant women and their care providers with little choice but to wait for symptoms to appear... dangerous symptoms that mean the disease has progressed to the point where mother and baby are critically ill and will need intensive monitoring and carefully timed delivery to protect their health and lives. The only screening method to date is to measure those symptoms when they appear.

Early detection wouldn't be a treatment. But what if a screening test could let us know, weeks or even months in advance, that we'd probably be getting ill? Knowing might change the way we seek care - possibly choosing specialist care providers with the education and experience to manage medically complicated pregnancies. Women in parts of the world (like Wyoming in the winter) where such care is in short supply might be moved to bigger cities where NICUs and maternal-fetal medicine (MFM) specialists are more accessible. Neonatal specialists could be brought into the consulting team, and steroid shots to accelerate fetal lung development could be planned. All of these interventions together have the potential to lower the rates of fetal and maternal death and severe complications dramatically. (By the way, you may agree or disagree with this assessment; either way, we'd really like to hear your perspective in this important survey we recently launched.)

 

Since many experts consider such a test preferable to our current screening methods, recent research has tried to find a workable test with high levels of both specificity and sensitivity. An ideal test would be one that picked up *all* cases of preeclampsia - it would be sensitive - and *only* cases of preeclampsia, with no false positives - it would be specific. In practice this is all but impossible to achieve, but it's quite possible to find tests with very high levels of sensitivity and specificity, with one measure performing slightly better than the other.

 

So for researchers this creates a choice between creating tests that would produce false positives, and tests that would miss some cases. The worst-case scenario of a false positive is likely to be unnecessary close monitoring; it would not be an indication for immediate delivery. It would provide a reason to follow the pregnancy more closely for symptoms that do indicate that the acute phase of the illness has developed. Since the worst-case scenario of a false negative is a missed case of preeclampsia leading to death of mother and/or baby, public health researchers would prefer to develop tests that will overdetect cases of preeclampsia, but with a low rate of false positives.

 

At a meeting of the American Society of Nephrology (ASN) in November, Dr. Vesna Garovic (Mayo Clinic) reported on a study into the use of urinary podocytes as a screening test for preeclampsia, a test that may turn out to have both high sensitivity and specificity for preeclampsia. Podocytes are cells which line the blood vessels in the kidneys and act as filters which keep protein in the bloodstream. Their loss allows protein to spill into the urine, one of the primary signs of preeclampsia.

 

Garovic's research team used a population of 267 women and collected their urine between 25-28 weeks gestation. The samples were examined for podocytes. The 15 women who went on to develop preeclampsia all had podocytes in their urine at that gestational age. The 15 women who developed gestational hypertension did not. The control group of women who had normal pregnancies also did not.

 

Previous research from the same group has indicated that podocytes are present in the urine when preeclampsia symptoms first appear. When they shed into the urine, they cause disruptions in the filtration barrier in the kidney, resulting in proteinuria. The "classic lesion" of preeclampsia - glomerular endotheliosis - may include the loss of these podocytes from the glomeruli in the kidneys.

 

To confirm that this test works well, it will need to be repeated in multiple centers serving broader populations of pregnant women, and to make it available for general use, it will need to be turned into a commercially available testing product. That said, these are very hopeful results - unlike the soluble factors researchers are also pursuing, podocytes appear to only be elevated in women who go on to develop preeclampsia. The soluble factors are elevated in all pregnant women, and just unusually elevated in preeclamptics, which makes it very difficult to develop a screening test with high sensitivity and specificity.

 

Interestingly, it's likely that the podocytes are damaged because of the increased level of sFlt-1, which binds VEGF, which impairs repair of the podocytes and increases the rate at which they die off. It seems likely, given this new research, that it will be easier to detect the damage to the podocytes themselves than it will be to detect an increase of the soluble factors above the point where damage is likely.

 

If it's possible to develop a test similar to a standard pregnancy test, this might be a very effective method which wouldn't require laboratory work, and would make screening much easier and more rapid. Pregnant women who will likely go on to develop preeclampsia could be moved to the care teams that manage complications before they are critically ill, allowing both them and their babies to receive appropriate medical care that would probably reduce poor outcomes substantially.

 

 

A special thanks to Dr. Vesna Garovic at Mayo Clinic, for her expertise and technical input.

 

 

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On May 24, 2012, the U.S. Senate passed the Food and Drug Safety and Innovation Act, which reauthorizes funding for activities related to the drug and device approval process at the U.S. Food and Drug Administration (FDA). The legislation also includes requirements and provisions for faster review of new and innovative therapies in order to allow patients to be able to access these therapies more quickly. The next step is for the U.S. House of Representatives to pass the bill, and then a final bill will go to the President for signature.

During debate on the Senate bill, Senator Mark Warner (D-VA) spoke on the necessity of finding ways to strengthen and improve the FDA’s review process of new and innovative diagnostic tests, including biomarkers. While biomarkers are not specifically addressed by the legislation, during his remarks, Senator Warner specifically cited preeclampsia as an example of why the country needs to move biomarkers forward and develop a better process for the FDA to work with industry. The following is a copy of the Senator’s remarks as recorded in the Congressional Record:

“Preeclampsia is a disorder that affects hundreds of thousands of pregnant women every year, which undiagnosed, can put a woman at risk for death and the fetus at risk of still-birth.

Doctors currently use a mix of imprecise signs and symptoms to diagnose it but often times such signs and symptoms are wrong. However, researchers have found a biomarker—a particular biological process or sign—that can accurately identify women with preeclampsia that are at risk for pregnancy complications.

Unfortunately, tests for novel biomarkers are taking five or more years to get approved by the FDA, delaying patients from receiving the benefits of more accurate diagnoses and treatments.

I was pleased that a recent commitment letter between the FDA and industry specifically mentions the FDA’s commitment to work together with industry to create a transitional IVD, or “T IVD” process for the development of tests for novel biomarkers.

I look forward to seeing how this T IVD process develops in discussions between FDA and industry and am interested in progress towards its implementation, which supports advances in the sciences and promotes access to these emerging diagnostics.

If reducing healthcare costs is a national priority, we need to act today. I encourage my colleagues to pass S. 3187 and allow the FDA to work more closely with the medical industry to safely bring new technologies to the marketplace.”

The Preeclampsia Foundation is engaging with industry and the federal government to ensure biomarkers for preeclampsia can be carefully considered and the barriers to movement can be understood and addressed. The Foundation is pleased to have Congressional attention focused on this issue.

 

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Every two years, the International Society for the Study of Hypertension in Pregnancy (ISSHP) World Congress brings together the top researchers and clinicians in the field of hypertension in pregnancy to share innovations and encourage collaborations in research and clinical practice. As in year's past, the Preeclampsia Foundation participated in the 2012 meeting held July 9-12 in Geneva, Switzerland.

Like the current Olympics which inspire us to "Citius, Altius, Fortius" (Latin for "faster, higher, stronger"), the World Congress inspires participants to demonstrate new found knowledge and skills, and to push each other forward. In the enthusiasm of science-swapping and networking at a meeting like ISSHP, sometimes the larger purpose of our endeavors - saving lives and improving health outcomes of mothers and babies worldwide - may be forgotten by those racing from one intriguing lecture to the next.

That's where the Preeclampsia Foundation comes in. It is a testament to the extraordinary outreach of our mission that not only are we widely recognized as a key patient resource by individual health care providers, but are sought out by industry leaders as THE voice to provide a reminder of the patient perspective amongst the plethora of science and research. Our impact can be summarized in that one word: "voice." By joining our members' collective experiences along with the experience of wonderful new friends from European patient advocacy groups, we have become a powerful entity for change. A voice that is not only heard, but valued.

The Foundation's efforts to improve health care practices and catalyze research were also felt at ISSHP. Two investigators presented research findings developed through our collaboration in the Brain Study- and for many of our readers - it was your participation in this study that provided such meaningful data. In one oral presentation, findings suggested an association between history of preeclampsia and post-traumatic stress disorder. In the other, findings suggested an increase in neurocognitive disorders among women with history of preeclampsia. Both studies are being developed for publication and will be promoted via this newsletter when they're published. Both studies were exceedingly well received, with other researchers encouraging us to conduct further studies on long-term patient impact to improve clinical care.

We also presented two research travel grants, which helped promising young investigators attend this important meeting, interact with seasoned researchers, and become committed members of the hypertension in pregnancy community.

Every day, our website and social media platforms receive thousands of visitors from more than 200 countries around the world, so it was particularly wonderful to meet global health care providers who interact with those patients and who themselves use our website regularly. Unfortunately, we are sometimes the only source for additional patient support and education. So though no one received any laurel wreaths or gold medals during the Foundation's international journey, the patients are the real victors through the furthering of global preeclampsia research.

 

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Five weeks ago, the Preeclampsia Foundation led a historic gathering of nine companies, as well as some of the leading clinicians and researchers in the field of preeclampsia. We also had leaders and front line obstetricians from outside the "inner circle" to ensure we weren't doing too much naval gazing.

This Biomarker Consortium was evidence of several of our core values: we wanted to be influential, catalytic and bold. As the patient advocacy organization caring passionately about improving pregnancy outcomes, we were uniquely positioned to invite and get positive responses from every company who has or is investing in biomarkers as a more advanced technology to diagnose preeclampsia or screen pregnant women for future disease.

I was energized by the ideas and commitment in the room, by the spirit of collaboration and the recognition that together we can do much to advance the momentum and attention on preeclampsia. A report is being developed now, but even better, participants are continuing to generate numerous ideas about how to grow the consortium and develop themes and projects we can rally around.

Warm wishes,

Eleni Z. Tsigas
Executive Director

 
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That was my goal with the once-in-a-lifetime opportunity I was given to present one of three President's Program lectures at the American College of Obstetricians & Gynecologists' Annual Clinical Meeting.

"Patient Perspectives on Preeclampsia" - or as I joked, "lessons from this side of the stirrups" - was well-received by the standing-room-only crowd in the main auditorium of the San Diego Convention Center. More importantly, the many comments I received after the lecture satisfied me that I achieved my objective - to reach their hearts with compelling, real-life stories illustrating the impact preeclampsia has on mothers, fathers, and babies; and to reach their minds by inspiring clinical practice behaviors that include educating each and every expectant mother with non-alarmist, but sound information about the signs and symptoms of preeclampsia, as well as addressing the psychological and long-term physical impact of the disease. (Presentation available for purchase)

If you have ever shared your experience with us, know that you, and the stories of 10,000+ other women, were with me in spirit on May 7. The ACM News wrote about my presentation and the other two preeclampsia lectures (delivered engagingly by renown preeclampsia researcher Dr. James Roberts and clinician Dr. John Barton).

The awareness and education theme was echoed in a Foundation news announcement at the San Diego Promise Walk. With co-authors Dr. Doug Woelkers and Ms. Jennifer Carney, we announced our official list of the Top 10 Pregnancy Guidebooks. This report was created using five criteria designed to ascertain how well the books treated the topic of preeclampsia in a way that would be useful to the one in 12 pregnant women whose pregnancies become complicated by it. Several of the top guidebook authors have already contacted us, thankful that their diligence has been recognized, even while women's real-life feedback has reinforced our findings that the bestsellers aren't always the best books.

And although I'm no Twitter expert, it was fun to join College staff and two Ob/Gyn physicians on a Twitter Chat on preeclampsia that resulted in tens of thousands impressions, and to shoot a quick interview that was aired onsite for the 5,000+ people in attendance.

By all accounts, the entire experience left us all exhausted, but exhilarated. We frequently tout the importance of a patient-provider relationship and it was abundantly evident that the country's leading Ob/Gyn organization shares this goal. We are very grateful.

 

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