Preeclampsia Research at the NICHD

NICHD Research aims to detect, treat, and prevent this potentially dangerous condition of pregnancy

Pregnant woman sitting on the couch in the living room and looking at her ultrasound scan of the fetus.

Preeclampsia is a syndrome that occurs during pregnancy and is marked by a sudden increase in the blood pressure of a pregnant woman after the 20th week of pregnancy. It can affect the mother's kidneys, liver, and brain. The condition can be fatal for the mother and/or the baby and can lead to long-term health problems.

According to the Centers for Disease Control and Prevention (CDC), 11.1% of pregnancy-related deaths in the United States for 2006 and 2007 (the latest data available) resulted from "hypertensive disorders of pregnancy," including preeclampsia. For 2009, CDC statistics also showed that "gestational hypertension," including preeclampsia, occurred in 41.2 live births out of 1,000, or more than 4% of all pregnancies.

Signs of preeclampsia can include high blood pressure, increased protein in the urine, and swelling in the face and hands. (A woman's feet and lower extremities may swell too, but this is common during pregnancy and may not signal a problem.) Statistics in the United States indicate that women with preeclampsia are usually asymptomatic, but may experience systemic symptoms, including headaches, seeing spots, and abdominal pain. The condition can also interfere with blood flow to the placenta, which connects a mother and the fetus, possibly restricting or impairing growth. Eclampsia is a more severe, but less common form of preeclampsia that can cause seizures and coma in the mother.

Currently, the only cure for gestational preeclampsia is to deliver the fetus. Health care providers may suggest other methods of prolonging the pregnancy to give the fetus more time to grow and mature. But they will constantly monitor the mother and fetus very closely for signs that the fetus needs to be delivered right away, even if it is before full term.

Understanding, detecting, preventing, and treating preeclampsia and related health issues are important goals for the NICHD. The Institute supports and conducts a number of research studies on preeclampsia, including (but not limited to):

  • Prepregnancy and pregnancy conditions that increase a woman's risk for preeclampsia
  • Disease process and health effects of preeclampsia in a mother and fetus
  • Molecular and cellular characteristics that define the severity and onset of preeclampsia
  • Useful markers for identifying women at risk for preeclampsia
  • Treatments that reduce a woman's chances of developing preeclampsia
  • Effective therapies for treating preeclampsia and eclampsia

The NICHD also supports networks and repositories that study preeclampsia. Several recent studies and ongoing research activities, some of which are described below, highlight the Institute's efforts to understand the causes, pathophysiology, and treatments for preeclampsia. Select a link to learn more:

Studies of the Risk Factors for Preeclampsia
Studies of Molecular Markers for Preeclampsia
Studies of the Maternal Effects of Preeclampsia
Other Supported Research on Preeclampsia

Studies of the Risk Factors for Preeclampsia

Supplementation with Vitamins C and E Does Not Reduce Preeclampsia Risk

A person's body constantly reacts with the oxygen that is inhaled. These reactions produce free radicals, which can interact with and damage other molecules in the body. The body can use antioxidants, such as vitamins C and E, to repair most of the damage caused by free radicals. Oxidative stress, an imbalance in the oxygen system that can disrupt the body's detoxification and repair abilities, is among the mechanisms that may contribute to the development of preeclampsia. Previous studies showed that free radicals might prevent the placenta from developing, interfering with the exchange of blood between mother and infant.

To further study the possible role of oxidative stress in preeclampsia, researchers funded through the NICHD Pregnancy and Perinatology (PP) Branch examined whether daily antioxidant supplementation with vitamins C and E reduced risks for serious adverse outcomes related to preeclampsia. The women (9 weeks to 16 weeks pregnant) took vitamins C and E (5,088 women) or a placebo (5,066 women) until delivery. The researchers studied several preeclampsia-related outcomes, including high blood pressure alone or high blood pressure in combination with other outcomes, including blood platelet counts, measures of liver or kidney damage, seizure, preterm birth (birth before 32 weeks of pregnancy), abnormally low infant birth weight, and perinatal death (fetal death after 20 weeks of pregnancy).

Vitamins C and E did not affect the risk of developing preeclampsia or the rates of adverse outcomes related to preeclampsia. The results indicated that vitamins C and E supplementation from 9 weeks to 16 weeks in pregnancy are not effective in reducing the risks or outcomes of preeclampsia. For details on this finding, visit PubMed ID: 20375405. Also see the NICHD news release: Vitamin C and E Supplements Do Not Reduce Risk for Blood Pressure Disorders of Pregnancy.

Placenta Abnormalities in Women with Early-Onset Preeclampsia

One of the ways to classify preeclampsia is based on when it occurs during the pregnancy, for instance early or late onset. However, the definitions of "early" and "late" vary. More precise definitions of early- and late-onset preeclampsia are important because early-onset preeclampsia is associated with a higher risk of maternal and fetal complications than is late-onset preeclampsia.

Women with early-onset preeclampsia often have lesions in their placenta. These abnormalities, which include blood vessel malformation, can negatively impact fetal health and growth. The placenta, which is attached to the fetus by the umbilical cord, functions as an exchange site between maternal blood and fetal blood. Oxygen and nutrients in the mother's blood are transferred to the fetus, and waste is transferred from the fetus to the mother, through the placenta. The exchange of oxygen, nutrients, and waste requires a large number of blood vessels to extend from the mother into her placenta. In women with preeclampsia, for unknown reasons, some vessels do not form normally during pregnancy, so the placenta does not receive an adequate supply of the mother's blood—this is called "underperfusion" of the placenta.

To better define early- and late-onset preeclampsia, researchers funded by the PP Branch examined lesions characteristic of deficient blood flow in the placenta in women with preeclampsia. The researchers compared tissue samples from 910 women with preeclampsia to those from 7,397 women who did not have a high blood pressure disorder during pregnancy. All of the women delivered their infants after at least the 20th week of pregnancy. The researchers examined tissue samples collected at birth from the placenta, fetal membranes, and umbilical cord for the characteristic lesions.

The number of lesions associated with deficient blood flow in the placenta was higher in women with preeclampsia. Also, delivering the baby earlier in the pregnancy was associated with increased risk for lesions, such that, the earlier the delivery, the higher the risk. Women with early-onset preeclampsia also had more lesions than did women with late-onset preeclampsia. For details on this finding, visit PubMed ID: 21848483.

Insulin Resistance During the Third Trimester Increases Preeclampsia Risk

Insulin is a hormone secreted by pancreatic beta cells that is important for regulating metabolism and energy. During digestion, the stomach and intestines break down carbohydrates in food into a sugar called glucose. Glucose is the body's main source of energy. After digestion, glucose moves into the blood, which is why it is called blood sugar. The body needs insulin to move the glucose out of the blood and into cells. Sometimes the body does not use insulin the way that it should and sometimes the pancreas does not secrete sufficient insulin, meaning that excessive glucose stays in the blood, eventually causing high blood sugar levels.

This inability to efficiently use insulin is called insulin resistance and it plays a key role in the development of type 2 diabetes and high blood pressure. Women with conditions associated with insulin resistance, such as gestational diabetes and obesity, have a higher risk of developing preeclampsia, but it is not known whether insulin resistance itself is related to the development of preeclampsia in pregnant women.

In a randomized study, researchers in the PP Branch-funded Maternal-Fetal Medicine Units (MFMU) Network studied whether insulin resistance during pregnancy was associated with the later development of preeclampsia. Fasting blood samples were collected from the women when they entered the study (at 9 weeks to 16 weeks of pregnancy), at a time during the "midtrimester" (between 22 weeks and 26 weeks of pregnancy), and at admission for delivery.

This study included 1,187 women who had submitted a fasting blood sample. Of these women, 85 developed preeclampsia. In addition, 510 women had increased blood pressure or protein in their urine, two signs of preeclampsia, although they did not have preeclampsia. Midtrimester (between 22 and 26 weeks of pregnancy) insulin resistance was higher among the women who developed preeclampsia compared with the women who did not. The results of the study indicated that midtrimester maternal insulin resistance is associated with the subsequent development of preeclampsia. For details on this finding, visit PubMed ID: 21458622.

Prepregnancy Obesity and Immune Responses Increase Preeclampsia Risk

Changes in a woman's body during pregnancy can cause widespread inflammation. Being overweight or obese before pregnancy can further complicate this inflammation. During immune responses, the body produces immune-related proteins that can be beneficial because they promote healing. But if these proteins cause too much inflammation, they can be harmful.

Previous studies have shown that obesity induces immune responses, called complement activation, that are known to increase a woman's risk for preeclampsia. To examine the relationship between prepregnancy obesity and immune responses and their effects on preeclampsia risk, researchers supported by several NIH Institutes including those in the NICHD's Division of Epidemiology, Statistics, and Prevention Research (DESPR), conducted a prospective study of 1,013 pregnant women. In the study, the researchers examined the women's blood levels of complement activation proteins in relation to preeclampsia risk and prepregnancy obesity.

The researchers found that women who were obese before pregnancy and who had increased immune responses during pregnancy were more likely to develop preeclampsia. The findings suggested that prepregnancy obesity and immune responses during pregnancy increase preeclampsia risk. For details on this finding, visit PubMed ID: 22542119.

Theobromine, a Compound Found in Chocolate, Does Not Reduce Preeclampsia Risk

Chocolate is a rich source of flavinoids, compounds that improve heart health and lower blood pressure. Previous studies have shown that chocolate consumption during pregnancy reduces preeclampsia risk. For example, in one of these studies, women who consumed chocolate during their first and third trimesters were less likely to develop preeclampsia than were women who did not have the chocolate. In the same study, women with higher serum umbilical cord levels of theobromine, the major alkaloid in chocolate, were also less likely to develop preeclampsia than were women who did not have chocolate.

Theobromine is also richly concentrated in food sources other than chocolate, including coffee and some over-the-counter medications, such as stimulants, analgesics, and diuretics. Because theobromine is consumed by many women in the form of food and medications, researchers are interested in confirming whether it reduces preeclampsia risk.

In one study, NICHD's DESPR researchers examined 2,105 women from the Collaborative Perinatal Project, which was conducted from 1959 to 1974. About 3% of the women in the study developed preeclampsia. Researchers examined the blood levels of theobromine and the risk for preeclampsia. There was no evidence of an association between theobromine levels and increased or decreased preeclampsia risk. The results suggest that theobromine is not the compound in chocolate that lowers preeclampsia risk. For details on this finding, visit PubMed ID: 19535985.

Studies of Molecular Markers for Preeclampsia

Molecular Imbalance Precedes Preeclampsia

Recent studies have examined proteins that may be important in the development of preeclampsia or that could be used as markers to detect preeclampsia. In one of these studies, DESPR researchers examined tumor necrosis factor (TNF)-alpha in the blood of women with risk factors for preeclampsia. This protein causes inflammation when it interacts with its receptors. In the study, risk factors for preeclampsia included prepregnancy diabetes, high blood pressure, and preeclampsia during a previous pregnancy. The researchers collected blood samples from all of the women at 13 to 26 weeks of pregnancy and again at 24 to 28 weeks of pregnancy. Approximately 20% of the women developed preeclampsia. The researchers found that, even before the appearance of symptoms, TNF-alpha receptor 2 (TNF-R2) was increased in women who developed preeclampsia. For details on this finding, visit PubMed ID: 19306961.

In another study, researchers in the PP Branch-supported MFMU Network, examined several circulatory system-related proteins for their role in preeclampsia. The proteins included soluble fms-like tyrosine kinase (sFlt1), soluble endoglin (sEng), and low placental growth factor (PlGF). In earlier studies, blood concentrations of these three proteins varied in low-risk women who developed preeclampsia, as seen by increases in sFlt1 and sEng and decreases in PlGF. In the MFMU Network study, researchers examined the blood levels of these three proteins in women at high risk for developing preeclampsia. High-risk women included those with diabetes before pregnancy, high blood pressure, or preeclampsia during a previous pregnancy. High-risk women also had increases in sFlt1 and sEng and decreases in PlGF. For details on this finding, visit PubMed ID: 20948996.

Some of the causes and/or effects of preeclampsia are thought to be due to deficient blood flow in the placenta. In another PP Branch-supported study, researchers examined blood concentrations of sENG, PlGF, soluble vascular endothelial growth factor receptor-1 (sVEGFR‑1), and sVEGFR-2 in women with late-onset preeclampsia. These four proteins are involved in circulatory system health. For purposes of the study, the researchers considered "late-onset preeclampsia" as preeclampsia that developed at 34 weeks of pregnancy or later. Blood samples from 64 control women with normal pregnancies and 66 women with late-onset preeclampsia were analyzed.

Women who developed late-onset preeclampsia were more likely to have deficient blood flow in the placenta and also lower blood levels of PlGF compared to women who did not develop preeclampsia. The women who developed preeclampsia were further grouped according to whether or not they had evidence of deficient blood flow. The women with late-onset preeclampsia and evidence of deficient blood flow had lower blood levels of PlGF and changes in sVEGFR-1 and sENG levels, compared to preeclamptic women without evidence of deficient blood flow. This study provides evidence that the balance of circulatory system proteins is altered in preeclampsia and that the balance is even more altered when there is deficient blood flow in the placenta. For details on this finding, visit PubMed ID: 21867402.

Overall these studies identified changes in the molecular balance of proteins in women who develop preeclampsia. These changes may be involved in the development of preeclampsia and researchers are continuing to examine their importance.

Glycogen Phosphorylase, a Marker of Some Heart Illnesses, Is Also a Marker for Preeclampsia

Preeclampsia causes cardiac problems. One of the markers of certain heart problems is the protein glycogen phosphorylase isoenzyme BB (GPBB). Measurement of higher blood levels of GPBB can indicate that an individual has a particular type of heart problem, such as myocardial infarction, which occurs when the body does not pump enough oxygen to the heart muscle, leading to heart damage. Maternal cardiac problems seen during pregnancy include myocardial infarction and heart failure. Both conditions are seen more often in women who develop preeclampsia than in those who do not.

While higher blood levels of GPBB indicate certain heart conditions, the association between GPBB and preeclampsia risk was previously unknown. To examine the role of GPBB in preeclampsia risk, researchers funded by the PP Branch evaluated changes in GPBB levels in the blood of 396 pregnant women. Women who developed "preterm preeclampsia" (preeclampsia prior to 20 weeks of pregnancy) had increased GPBB in their blood compared to women who did not develop preeclampsia. Women with "term preeclampsia" (preeclampsia after 20 weeks of pregnancy) did not have increased GPBB. The findings indicated that GPBB is increased in women with preterm preeclampsia, suggesting that it could serve as a marker for this condition. For details on this finding, visit PubMed ID: 22215716.

C-Reactive Protein (CRP), a Marker of Inflammation, Does Not Predict Recurrent Preeclampsia

Several studies have recently examined inflammatory proteins involved in the immune responses that are often overactive during preeclampsia. Elevations in CRP have been linked to increased cardiovascular disease risk. Preeclampsia shares some of its underlying pathologies, including high blood pressure, with cardiovascular disease. Preeclampsia is also a risk factor for the development of cardiovascular disease. Because of the links between preeclampsia and cardiovascular disease, CRP represents a possible marker for preeclampsia.

One of the risk factors for preeclampsia is a history of preeclampsia with previous pregnancies, called recurrernt preeclampsia. In one study, researchers from the MFMU Network investigated whether CRP predicts recurrent preeclampsia during subsequent pregnancies. Researchers collected blood samples from 255 pregnant women who developed preeclampsia during a previous pregnancy.

Approximately 20% of the women developed recurrent preeclampsia. The women who did not develop recurrent preeclampsia served as a control group. CRP levels were measured in the serum samples collected earlier in the study (7 to 26 weeks of pregnancy) and at a period close to delivery (34 to 38 weeks of pregnancy). There were no differences in CRP levels indicating that CRP is not a useful marker for identifying recurrent preeclampsia risk. For details on this finding, visit PubMed ID: 20701468.

Studies of the Maternal Effects of Preeclampsia

Preeclampsia May Damage Thyroid Function

Soluble fms-like tyrosine kinase (sFlt1) is a protein that inhibits blood vessel growth. Blood concentrations of sFlt1 normally increase during the last two months of pregnancy, but concentrations are much higher in women with preeclampsia. Among its activities, sFlt1 inhibits the action of several different proteins, including vascular endothelial growth factor (VEGF). Certain drugs, called VEGF inhibitors, function similarly to sFlt1 and inhibit VEGF. These drugs, which are used to treat various illnesses and other conditions, including cancer, can cause side effects, such as increased blood pressure and reduced thyroid activity (hypothyroidism).

 

Because VEGF inhibitors can cause hypothyroidism, researchers studying the effects of increased sFlt1 in preeclampsia examined whether excess sFlt1 during preeclampsia is associated with hypothyroidism. The researchers in the NICHD's DESPR analyzed blood samples taken from 141 pregnant women at baseline (21 weeks of pregnancy) and again after the onset of preeclampsia. These women were participants in the Calcium for Preeclampsia Prevention trial. The women who developed preeclampsia had evidence of reduced thyroid function, which included increased blood levels of thyroid-stimulating hormone (TSH).

The researchers next measured TSH levels from a large group of women (7,121 women) who previously had preeclampsia to test whether preeclampsia was associated with hypothyroidism later in life. These women were from the Nord-Trondelag Health Study. Blood samples for TSH measurements were collected approximately 20 years after pregnancy. Blood samples from a group of women who did not have preeclampsia served as the controls. Similar to the earlier findings that TSH was increased during pregnancy in preeclamptic women, TSH was also increased 20 years after preeclamptic women had given birth, indicating long-lasting thyroid function effects.

These findings indicate that preeclampsia is associated with reduced thyroid function during and many years after pregnancy. For details on this finding, visit PubMed ID: 19920004.

Other Supported Research on Preeclampsia

  • Maternal-Fetal Medicine Units (MFMU) Network
    The NICHD established the MFMU Network in 1986 to focus on clinical questions in maternal fetal medicine and obstetrics. The Network, funded through the PP Branch, has completed or is currently conducting more than 36 randomized clinical trials, cohort studies, and registries. Clinical studies conducted by the Network have included the following areas of research: maternal health; fetal health and development; gestational diabetes, asthma, and thyroid disorders; and preterm labor. Several of these research areas include studies of preeclampsia, including those examining therapies for preeclampsia prevention; risk factors for preeclampsia, including diabetes; markers of preeclampsia; and adverse perinatal outcomes for women with preeclampsia.
     
  • Investigation of Biomarkers Associated with Preeclampsia and Gestational Diabetes Mellitus
    Preeclampsia and gestational diabetes mellitus (GDM) are common pregnancy complications that increase risks of morbidity and mortality for the mother and fetus. A case cohort study, using stored serum samples from the Calcium for Preeclampsia Prevention trial, has been established to investigate several biomarkers associated with development of preeclampsia and GDM. These investigations, conducted by DESPR, can shed light on whether these biomarkers could be useful for identifying women at higher risk of preeclampsia or GDM and bring understanding to their possible shared causes.
  • NICHD Workshop Identifies Research Gaps
    In 2006, the NICHD held a workshop, titled Preeclampsia—A Pressing Problem, that brought together leaders in the field to discuss their diverse research on preeclampsia, ranging from basic science to clinical trials and management, and to identify scientific gaps. The NICHD published a paper in 2007, Preeclampsia—a pressing problem: An executive summary of an NICHD workshop External Web Site Policy (PDF – 165 KB), in the journal Reproductive Sciences, in which research gaps and future research pathways identified during the workshop were reviewed. The workshop also guided researchers in setting an agenda for future research on preeclampsia that continues to provide a framework for NICHD efforts to help better understand the disease, with the ultimate goal of preventing the disorder. To read more about the workshop, visit PubMed ID: 17959880.

For more information on preeclampsia and on research at the NICHD, select one of the following links:

 

Originally Posted: October 18, 2012

 

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