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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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Vitamin D and Microchimerisms:

Could the sun really have something to do with preeclampsia?
"Maternal vitamin D deficiency may be an independent risk factor for preeclampsia. Vitamin D supplementation in early pregnancy should be explored for preventing preeclampsia and promoting neonatal well-being," reads a paper published in the Journal of Clinical Endocrinology & Metabolism in 2007. Although some of us who had our babies in, say, Portland, Oregon, where the sun rarely shines, would love to claim Vitamin D deficiency, other preeclampsia survivors sweltered under the Arizona or California sun. If you think this might be a possible therapy to explore, talk to your health care professional and check out the discussions in our Community Forum on this topic.

Micro-what?
Researchers have found that women with preeclampsia, which causes high blood pressure in late pregnancy and can kill both mother and child, had five times the microchimerism of healthy women. Fetal cells, it turned out, are complex characters. A chimera is an organism with DNA from different sources, which of course is what fetal cells are, since their DNA derives from both mother and father. Read the article, The Yin-Yang Factor, published in Stanford Medicine Magazine, if you weren't already convinced that preeclampsia is a really complex disease.

Patent issued for preeclampsia diagnostic test
A press release from Miraculins announced that the United States Patent and Trademark Office has issued US Patent 7,754,495 entitled "Methods for Early Diagnosing of an Increased Risk of Preeclampsia." Previous issues of Expectations discussed this company's development of a diagnostic marker for preeclampsia.

 

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Last month, a team from the University of Alberta reported in the journal Hypertension on a method to determine that a woman is at high risk of developing preeclampsia. While this method may or may not be developed into a screening test in the future, it confirmed that changes in the metabolism and the vasculature of women who go on to develop preeclampsia can be detected at 15 weeks gestation.

Two Preeclampsia Foundation members were involved in media coverage on the topic and we are very grateful to them for bringing a human face to the stories about preeclampsia. Because of the press conference and media efforts of the University, a lot of lay press picked up the story and we are fortunate that the Foundation was mentioned in several of those stories. The research findings while seemingly exciting to a lay public are far from commercial realization and would need more validation for most governmental oversight bodies (e.g., FDA). Our message of "cautious optimism" is a responsible middle ground at this early juncture. Read more here.

Also, a new study into changes in maternal weight between pregnancies was published in the journal Obstetrics and Gynecology by a team from the University of St. Louis Medical Center. It confirmed that women who lose weight after a preeclamptic pregnancy have a lower risk of preeclampsia in later pregnancies than women who maintain their weight or who gain weight. Losing weight may change the uterine environment and help encourage normal placental development. A link to the abstract and discussion among forum participants may be found here.

The National Institutes of Health announced that research shows taking vitamin C and E supplements early in pregnancy does not reduce the risk for hypertensive disorders and other complications during pregnancy.

An Irish study to be published in an upcoming issue of Hypertension shows that metabolites found in women's blood early in pregnancy may be able to serve as accurate predictors of preeclampsia. This is a significant breakthrough, as biomarkers for preeclampsia have not previously been very precise. Further studies on the topic are planned.

 

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Several major disorders that occur during pregnancy result from failure of the placenta to implant correctly into the uterus or womb. During early pregnancy cells from the placenta, known as trophoblast cells, invade into the uterus and tap into the mother’s blood supply to sustain the growing baby. Failure of this process can lead to insufficient supply of blood to the placenta resulting in preeclampsia, as well as low birth weight babies, stillbirth or recurrent miscarriage.

The invading placental trophoblast cells intermingle with maternal immune cells in the uterine lining. Trophoblast express not only maternal but also paternal genes and these will be different or “foreign” to the mother. Maternal immune cells can recognize these “foreign” fetal molecules and are thought to regulate the implantation process, allowing sufficient but not excessive invasion of the placenta. In the preeclamptic pregnancy this interactive process goes wrong and there is inadequate modification of the blood vessels which can lead to “starvation” of the placenta and subsequently triggering of the preeclamptic syndrome later in gestation in the mother.

The important molecules displayed by the trophoblast that are recognized by maternal immune cells are members of the HLA (Human Leucocyte Antigen) family known as HLA-C. The maternal receptors that recognize and interact with HLA-C are the KIR family (Killer Immunoglobulin-like Receptors). These two gene families (HLA and KIR) are very variable or polymorphic meaning that each mother will inherit a particular set of KIR genes and the fetus an HLA-C gene from both mother and father. This means maternal KIR will bind to fetal HLA-C can vary from one pregnancy to another. The interaction should lead to successful implantation but sometimes the combination of these genes from mother and baby results in inadequate invasion and leads to complications in the pregnancy.

Last month, in the Journal of Clinical Investigation, a team from the University of Cambridge reported new findings on the genetics underlying preeclampsia and other placental diseases. Women with a particular set of KIR genes – the KIR-AA genotype – who were carrying a fetus with a HLA-C2 gene were at higher risk of developing preeclampsia than those carrying other KIR/HLA-C gene combinations. This was especially so if the fetus had inherited the HLA-C2 gene from the father.

These genetic findings do not translate directly into therapeutic interventions in preeclampsia although it may be useful eventually in choosing a compatible sperm donor in IVF. The results tell us more about why placental implantation goes wrong sometimes. They might explain the old idea of the “dangerous male”, where pregnancy with particular men often results in preeclampsia. The report does emphasize the common underlying processes that would explain why a history of miscarriage or infertility is associated with a heightened risk of preeclampsia in subsequent pregnancies. Furthermore this risk cannot be affected by lifestyle, which helps those of us who “did everything right” to explain what went wrong.

Also this month, a team from the University of British Columbia, Vancouver, followed up on the connection between blood levels of vitamin D and preeclampsia in the British Journal of Obstetrics and Gynecology. It makes sense to think that the levels of vitamin D in the maternal bloodstream might have something to do with the later development of preeclampsia, because the vitamin is already known to affect some immune responses and because early small observational studies have shown an increased level of preeclampsia in the group of women with low vitamin D levels.

To check this, researchers measured serum levels of vitamin D in a population of women at high risk for preeclampsia, and then recorded their pregnancy outcomes. While the majority of the women had low levels (over three-quarters of the test population had lower levels than normal, and half were technically deficient), there was no connection between the severity of their pregnancy outcomes and the level of deficiency. In other words, some women with normal vitamin D levels still had severe preeclampsia, and some women who were deficient according to current guidelines did not go on to develop preeclampsia at all. This finding suggests that supplementing vitamin D may not have an effect on preeclampsia, although it is still interesting that women who develop the condition also tend to have low levels. There may be some connection between "having the sorts of genes or environment that lead you to develop low levels of vitamin D" and "having the sorts of genes or environment that lead you to develop preeclampsia."

 

A special thanks to Dr. Ashley Moffett, University of Cambridge, and Dr. Timothy Green, University of British Columbia for their expertise and technical input.

 

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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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Is there a nutritional connection to preeclampsia? That idea seems plausible at first, as when the blood samples of women have been analyzed, some researchers have found altered levels of various vitamins and minerals. Furthermore, preeclamptic women have altered patterns of weight gain during pregnancy; and obese women are more likely to develop preeclampsia.

 

Such considerations may lead one to speculate that certain diets may prevent or reverse the disease, in which case the appropriate diet becomes a therapeutic intervention. However the best research to date suggests this just isn't so.

 

Reviews of all the trials we could locate show that the major and well-designed trials mainly show no benefit. The very large trials show either no benefit to the generalized population (i.e. Calcium supplementation), or even potential harm (i.e. Vitamins C and E). Likewise, attempts to alter rate of maternal weight gain during pregnancy towards normal levels does not alter preeclampsia rates either.


In some instances, preeclampsia itself might be causing the alterations in nutritional status. The placenta, because it is shallowly implanted, needs to use other strategies to improve its ability to ferry nutrients to the fetus, strategies that include altering the maternal metabolism. In addition, obese women may be more likely to carry genes that both make them more likely to develop obesity in a modern environment and to develop preeclampsia in pregnancy.


The example of Vitamin D shows how one such supplementation research line has developed and been disproved. Sure, vitamin D levels are lower in early-onset preeclamptic women, but this happens once the symptoms of the disease have already appeared. And if we check women at the end of the first trimester, the women who will go on to develop preeclampsia cannot be picked out of the rest of the population. Some reviewers wonder if the researchers analyzed the correct form or metabolyte of Vitamin D when deciding if the woman is "deficient." Supplementing vitamin D doesn't seem to do much beyond raising vitamin D levels in blood work

 

That said, there is an important role for nutrition in pregnancy and it behooves everyone to check with a qualified health care provider to assess the appropriateness of their diet as soon as they learn they are pregnant.

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Margaret Meade once said, "Never doubt what a small committed group of citizens can do to change the world. Indeed, it is the only thing that has."

At the Preeclampsia Foundation, we like to say, "Never doubt what a large cohort of preeclampsia survivors can do to catalyze research. Indeed, it is the only thing that will."

Welcome to our Special Research Edition of Expectations.

I've heard thousands of stories with poor outcomes that started with "If only I had known" or "If only I had known and pushed harder to be taken seriously." What women wanted to know were the signs and symptoms of preeclampsia. With that information, they would have immediately responded to that unrelenting headache or the searing pain running up over the shoulder. They would have known to push back, if their complaints weren't taken seriously, with a request to be have their blood pressure checked, be seen by an expert, or have blood drawn for analysis.

After so many stories, we initiated research to quantify what we already knew anecdotally regarding the need for patient education. Our own 2008 "Lack of Preeclampsia Awareness Study" and studies performed by Dr. Whitney You and published in 2011 in the American Journal of the Obstetrics & Gynecology, confirmed our suspicion that not enough women are informed about preeclampsia, and even if they are informed, comprehension is poor.

Thus began an active part of our mission: patient education. Those outcomes are now being realized as the professional organization that board certifies the majority of our nation's obstetricians will be formally recommending patient education as a regular part of prenatal and postpartum care. Our Illustrated Preeclampsia Symptoms Tear Pad has been included in a California state-wide collaborative, CMQCC, that is intended to reduce maternal deaths.

Improving patient education tools and methods is just one way that women affected by preeclampsia -- our "cohort" -- identified a problem and then worked to change it. (Our work in patient education is definitely not done, but enormous progress has been realized.)

But can preeclampsia survivors advance medical research? Can we push scientists more quickly to a prevention, a cure, or an intervention (other than delivering the baby)?

Before the summer is out, we will be launching The Preeclampsia Registry, a living data source of patients and family members, to accelerate research.

There is plenty of precedent that citizen scientists, armed with their own "stories" and DNA, have successfully isolated genes responsible for their disease, or identified useful therapies. We, too, can catalyze research, equip researchers with novel hypotheses and a cohort -- a cohort not just willing, but impatient to see progress and to use their own cases as the enabling data.

What's ahead for The Preeclampsia Registry?

Approximately 100 "beta users" have already enrolled in the registry to help us test the technology. We have already secured approval from our Institutional Review Board. Before the summer is over, the registry will be open for public enrollment, including international registrants. Participants will include those directly affected and their female relatives who will enter self-reported information, upload medical records, and, in Phase 2 (planned for next year), biological samples such as DNA.

Researchers will be able to do studies over long periods of time, across geographical boundaries, and within various demographic groups.

How can you participate?

1. Check back often at www.PreeclampsiaRegistry.org for the upcoming announcement about the Registry's public launch.

2. Participate in our soon to be announced Patient Advisory Council, a diverse group of affected individuals who will influence research questions.

3. Give a gift to the Preeclampsia Foundation and, if you wish, earmark it for The Preeclampsia Registry.

I'm looking forward to joining Registry participants as we add our collective experiences to the scientific body of knowledge that will make a difference for future mothers and their babies!

Warmest regards,

Eleni Tsigas
Executive Director

 

 

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The Preeclampsia Registry

    The Preeclampsia Registry is a "Living Database" bringing together those affected, their family members, and researchers to advance knowledge and discover preventions and treatments for preeclampsia, HELLP syndrome, and related hypertensive disorders of pregnancy.

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