by Caryn Rogers

May is National Preeclampsia Awareness Month and the Preeclampsia Foundation has been holding Promise Walks all around the country to raise awareness of this disease and generate funds for research. Caryn Rogers, Senior Science Writer for the Preeclampsia Foundation has provided a research update and information about the etiology of the disease. The Preeclampsia Foundation is rich in resources for birth professionals and women, including an active forum for mothers dealing with this complication of pregnancy (or postpartum). Lamaze International is a proud web content sponsor of the Promise Walk.- Sharon Muza, Science & Sensibility Community Manager

The Preeclampsia Foundation would like to thank Lamaze International and Science & Sensibility for this opportunity to present a research overview during National Preeclampsia Awareness Month. Preeclampsia, which means "before the lightning" in Greek, is a leading cause of maternal and neonatal mortality and morbidity worldwide. The syndrome probably got the name from its tendency to strike suddenly, out of nowhere. One in ten women develops gestational hypertension during her first pregnancy, while about one in twenty develops preeclampsia. The latter condition has historically been poorly understood, but new research has led to a deeper understanding of preeclampsia. Some of the new research has been supported with Preeclampsia Foundation Vision Grants over the last ten years.

What is Preeclampsia

Preeclampsia is a multifactorial, heterogeneous pregnancy syndrome diagnosed after the appearance of both hypertension and proteinuria (protein in the urine) any time after mid-pregnancy. Its cause is still unknown. Though called the "disease of theories," research is closing in on triggers of the disorder, which will help to design specific treatments. Certain women have predisposing factors such as the presence of other diseases that make preeclampsia more likely. There may be specific genetic factors. While the disease's primary symptoms are hypertension and proteinuria, many other organ systems may be involved, especially the liver, brain, and platelets. Symptom presentation is unpredictable, with some cases appearing to fulminate within hours and other cases remaining mild for weeks. Finally, some preeclamptics progress to a convulsive phase - the disease known as eclampsia.

How is Preeclampsia diagnosed

Two blood pressure readings, taken at least six hours apart, of 140/90 mm Hg or greater, and the excretion of 300 mg or more of proteinuria in a 24-hour urine sample are the primary diagnostic requirements. Currently, many clinics are measuring the ratio of protein to creatinine in a single urine sample, using a value that predicts the total will be 300 mg or more in a day. In some instances, the disease is diagnosed without proteinuria when preeclampsia-specific signs and symptoms of other organ system involvement occur.

Signs and Symptoms of Preeclampsia

No Symptoms
Hypertension
Proteinuria
Edema (Swelling)
Sudden Weight Gain
Nausea or Vomiting
Abdominal (stomach area) and/or Shoulder Pain
Lower back pain
Headache
Changes in Vision
Hyperreflexia

Racing pulse, mental confusion, heightened sense of anxiety, shortness of breath or chest pain, sense of impending doom

adapted from Preeclampsia Foundation

What are the risk factors for Preeclampsia

Risk factors for preeclampsia include: first pregnancy, previous history of preeclampsia, multiple gestation, preexisting hypertension, diabetes, kidney disease, or organ transplant, obesity, age over 40 or under 18 years, maternal family history of preeclampsia. Polycystic Ovary Syndrome (PCOS); Antiphospholipid Antibody Syndrome (APS), lupus or other autoimmune disorders; and use of any Assisted Reproductive Therapy (ART).

Much of what is included in standard prenatal care was developed primarily to detect preeclampsia. This is why blood pressure and urine protein are checked at every visit and why visits come more closely together as the end of pregnancy approaches. The careful attention of care providers to these potentially invisible symptoms, and their communication of worrisome signs and symptoms to patients, has saved countless lives. Women who have been educated to know the signs and symptoms are able to practice the Preeclampsia Foundation's motto, "Know The Symptoms. Trust Yourself." 75% of those who knew the risks were able to take life-saving action when symptoms developed, versus 6% of those who did not know the signs and symptoms.

Pathophysiology

Placentas from preeclamptic pregnancies are characteristically shallowly implanted. During differentiation, the blastocyst will divide into an internal set of cells (the embryoblast), and an outer layer that will become the placenta (the trophoblast). When the blastocyst embeds into the decidua, the trophoblast remodels the uterine spiral arteries that supply blood to the endometrium. This remodeling activity persists into the second trimester of pregnancy. In normal pregnancies, this remodeling produces arteries that deliver appropriate blood flow to the placenta; in preeclamptic pregnancies the remodeling process is flawed.

Trophoblastic cells enter the spiral arteries and induce apoptosis, which is the initiation of cell death in the endothelial cells lining the walls of the arteries. Once the cells have died, the trophoblastic cells convert into an endothelial form and adhere to the walls of the vessels. These cells ignore maternal signaling to contract the vessel, which is why, in a normal pregnancy, these arteries are relaxed at all times, bathing the placenta in oxygen and nutrients. In preeclamptic placentas, the remodeling does not extend as far as normal, impeding appropriate nutrition and oxygenation.

One theory is that shallowly implanted placentas may not be able to transfer the total of oxygen and nutrients the fetus requires to develop ideally. The flow of blood through the spiral arteries is affected by their smaller size. Several genetic mechanisms that can cause shallow implantation have been identified with more likely to be discovered as investigation into trophoblastic cells continues. (Colucci, 2011; van Dijk, 2010)

Once fetal growth accelerates in the later trimesters of pregnancy, the fetal demand for more oxygen than the placenta is capable of ferrying eventually leads to placental hypoxia. Hypoxia triggers the placental release of a protein called soluble fms-like tyrosine kinase (sFlt-1.) SFlt-1 binds to vascular endothelial growth factor (VEGF) and a placentally derived factor that mimics it, placental growth factor (PlGF), rendering both unavailable to the receptors they usually target. SFlt-1 levels are measurably elevated in pregnant women who go on to develop preeclampsia. (Levine 2006; Maynard 2003)

In the vasculature, VEGF shepherds repair molecules along the walls of the blood vessels, plugging the holes that appear with normal wear and tear. When free VEGF is bound by sFlt-1, it cannot do this repair work. Because the rate at which the repair slows depends on the amount of sFlt-1 that the placenta is producing and also on the amount of VEGF a woman's body naturally produces, the symptoms that follow this damage vary widely. The effect of reduced levels of free VEGF and PlGF is that the vasculature is unable to achieve normal vasodilation and resists signals to contract or dilate appropriately.

Another circulating antiangiogenic factor is soluble endoglin, or sEng, which binds to and disrupts the normal functioning of TGF-beta, a protein that controls proliferation, cell differentiation and other functions in most cells.  Thus sEng, too, has also been identified as a culprit in preeclampsia. Although its mechanisms are not as clearly understood as those of sFlt-1, it's been empirically confirmed that women who develop preeclampsia at term have increasing serum levels of sEng beginning as early as gestational week 25. There are also suggestions that women are more likely to develop the dangerous variant of preeclampsia known as HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) if their levels of sEng are highly elevated relative to their sFlt-1 levels, and that they are more likely to develop severe preeclampsia when sFlt-1 levels are high relative to sEng. (Baumwell, 2007)

Depending on individual underlying susceptibilities and the ratios of antiangiogenic factors, a pregnant woman can develop the following symptoms at any rate and in any order, combination, and degree of severity, starting after midgestation and continuing for up to six weeks postpartum: hypertension, proteinuria, sudden weight gain and swelling, nausea, vomiting, upper right quadrant abdominal pain, shoulder pain that feels like a pinched nerve along the bra strap (referred from the liver), lower back pain, headache, visual disturbances, hyperreflexia, racing pulse, mental confusion, heightened sense of anxiety, shortness of breath or chest pain, sense of impending doom, abruption, IUGR, fetal distress, thrombocytopenia, either very low or conversely a large increase in urine output, seizure, pulmonary edema, liver rupture, abruption, and death.

The multi-organ nature of the syndrome means that a woman can feel fine, have hypertension and proteinuria that becomes apparent after testing, and then be admitted to the hospital with failing kidneys, liver and other organs. Or she can have a headache and begin seizing with comparatively low blood pressure and only mild proteinuria. The various presentations of preeclampsia make it challenging to consistently diagnose and manage appropriately.

The blood pressure increase indicates vascular damage that compromises the mother's health and damages the spiral arteries which connect the placenta to the woman's body. Women with preeclampsia also have a dysregulated metabolic response to pregnancy. (von Versen-Hoeynck, 2007) Gestational diabetes is a risk factor for preeclampsia, and women with PE are more likely to have elevated cholesterol readings and alterations in many serum biomarkers. Placental debris from an enhanced inflammatory immune response is thought to sweep into the maternal bloodstream and trigger these metabolic responses. (Redman, 2012) Researchers are newly aware of this signaling mechanism and further research is in progress.

Treatment and Prevention

As of May 2013, the only definitive treatment for preeclampsia is delivery of the placenta. These pregnancies, whether or not they are initially low-risk, are medically complicated and are generally managed by OB-GYNS, sometimes in consult with maternal-fetal medicine specialists. Timing of delivery is one of the only tools available to manage and balance the competing interests of worsening maternal disease, a failing placenta, and a potentially premature baby. Patients are managed with close monitoring, anti-hypertensives as necessary, and sometimes steroid shots to accelerate fetal lung maturation, depending on gestational age. In severe cases, this monitoring occurs while the woman is hospitalized in a tertiary care center. Magnesium sulfate may be given to reduce the risk of seizure. In severe disease, delivery sometimes must take place regardless of gestational age to best protect both lives (even a very preterm baby can be better out than in when the placenta is failing and the mother's liver is threatened) and is seriously considered in cases of severe preeclampsia for any worsening of symptoms after 34 weeks.

The HYPITAT trial has led to a new ACOG recommendation, to be released later this year, that any gestational hypertension (readings above 140/90 mm Hg) be induced at 37 weeks gestation. (Koopmans, 2009) The data show equally good outcomes for the neonate in either arm of the trial, and substantially reduced maternal risk of severe hypertension.

Calcium supplementation to prevent preeclampsia has been evaluated in large randomized controlled trials (RCTs) and found to have no benefit except perhaps in populations with very low dietary intake. Antioxidant supplementation - specifically vitamins C and E, also evaluated in large RCTs, has shown no benefit. Supplemental baby aspirin showed no benefit or harm in two large RCTs, but meta-analysis showed a potential benefit to an as-yet-unidentified high-risk population when begun in the first trimester. The older therapies of dietary salt restriction, diuretics, and bed rest have not been shown to have benefits and may cause harm so are not recommended.

Risk of Cardiovascular Disease

In addition to being at higher risk of preeclampsia in any subsequent pregnancies, women with a history of preeclampsia are at roughly double the risk of developing heart disease or stroke over the five to fifteen years following delivery. Many women develop chronic hypertension postpartum. There are risk factors common to both preeclampsia and heart disease, and there is also evidence that preeclampsia can cause damage to the heart.

Lifestyle changes are known to lower risk of heart disease, so women with a history are recommended to stop smoking (or never start), eat a heart-healthy diet, get regular exercise, and maintain a normal BMI. Because preeclampsia unmasks a higher risk, proactively consulting her physician and preferentially a general internist or cardiologist to discuss heart health postpartum can also help to monitor for the chance that heart disease will develop.

Lowering the Risk

Although there are no known therapies at this point, there are ways to reduce the risk of preeclampsia to mother and baby. Pre-conception or inter-conception care is gaining increasing value as women can be assessed and counseled to begin a pregnancy in the best possible health. Regular prenatal care, with close monitoring of symptoms, will detect the onset of hypertension in many women. For those whose disease progresses rapidly between appointments, knowledge of the signs and symptoms of the condition is the best protection. To this end, the Preeclampsia Foundation provides evidence-based patient education materials to care providers and encourages women to contact their care providers to report any headache, nausea, elevation in hypertension, changes in swelling or urine output, visual disturbances (like sparkles and flashing lights,) and pain in the upper right of the abdomen or along the bra strap. Being informed and closely monitored saves lives.

References and Recommended Reading

Baumwell, S., & Karumanchi, S. A. (2007). Pre-eclampsia: clinical manifestations and molecular mechanisms. Nephron Clinical Practice, 106(2), c72-c81.

Colucci, F., Boulenouar, S., Kieckbusch, J., & Moffett, A. (2011). How does variability of immune system genes affect placentation?. Placenta, 32(8), 539-545.

Garovic, V. D., Bailey, K. R., Boerwinkle, E., Hunt, S. C., Weder, A. B., Curb, D., ... & Turner, S. T. (2010). Hypertension in pregnancy as a risk factor for cardiovascular disease later in life. Journal of hypertension, 28(4), 826.

Koopmans CM, Bijlenga D, Groen H, Vijgen SM, Aarnoudse JG, Bekedam DJ, van den Berg PP, de Boer K, Burggraaff JM, Bloemenkamp KW, Drogtrop AP, Franx A, de Groot CJ, Huisjes AJ, Kwee A, van Loon AJ, Lub A, Papatsonis DN, van der Post JA, Roumen FJ, Scheepers HC, Willekes C, Mol BW, van Pampus MG; HYPITAT study group. (2009) Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks' gestation (HYPITAT): a multicentre, open-label randomised controlled trial. Lancet. 374(9694):979-88

Levine, R. J., Lam, C., Qian, C., Yu, K. F., Maynard, S. E., Sachs, B. P., ... & Karumanchi, S. A. (2006). Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. New England Journal of Medicine, 355(10), 992-1005.

Maynard, S. E., Min, J. Y., Merchan, J., Lim, K. H., Li, J., Mondal, S., ... & Karumanchi, S. A. (2003).Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. Journal of Clinical Investigation, 111(5), 649-658.

Powers RW, Jeyabalan A, Clifton RG, Van Dorsten P, Hauth JC, et al. (2010) Soluble fms-Like Tyrosine Kinase 1 (sFlt1), Endoglin and Placental Growth Factor (PlGF) in Preeclampsia among High Risk Pregnancies. PLoS ONE 5(10): e13263. doi:10.1371/journal.pone.0013263

Redman, C. W. G., Tannetta, D. S., Dragovic, R. A., Gardiner, C., Southcombe, J. H., Collett, G. P., & Sargent, I. L. (2012). Review: Does size matter? Placental debris and the pathophysiology of pre-eclampsia. Placenta,33, S48-S54.

Turner, J. A. (2010). Diagnosis and management of pre-eclampsia: an update.International journal of women's health, 2, 327.

van Dijk, M., & Oudejans, C. (2010). Stox1: key player in trophoblast dysfunction underlying early onset preeclampsia with growth retardation.Journal of pregnancy, 2011.

von Versen-Hoeynck, F. M., & Powers, R. W. (2007). Maternal-fetal metabolism in normal pregnancy and preeclampsia. Front Biosci, 12, 2457-2470.

Warning, J. C., McCracken, S. A., & Morris, J. M. (2011). A balancing act: mechanisms by which the fetus avoids rejection by the maternal immune system. Reproduction, 141(6), 715-724.

World Health Organization. (2011). WHO recommendations for prevention and treatment of pre-eclampsia and eclampsia. Geneve: WHO.

About Caryn Rogers

A native of Tempe, Arizona, Ms. Rogers is a graduate of Arizona State University. A freelance science writer and editor for medical nonprofits, she has been the senior science writer for the Preeclampsia Foundation since 2006. She lives with her family in Mt. Lebanon, PA, where she also plays the violin. Ms. Rogers can be contacted through the Preeclampsia Foundation or via email

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