Pre-eclampsia and Eclampsia Initiatives
IPRS Website Version with References

Description

Pre-eclampsia is defined as the combination of high blood pressure (hypertension), swelling (edema), and protein in the urine (albuminuria, proteinuria) developing after the 20th week of pregnancy (Roberts, 2001).  Pre-eclampsia ranges in severity from mild to severe; the mild form is sometimes called proteinuric pregnancy-induced hypertension (Roberts & Cooper, 2001) or proteinuric gestational hypertension (Page, 2000).

In severe pre-eclampsia, symptoms are more pronounced. Severe pre-eclampsia may lead to eclampsia, which causes seizures and can cause death of both the mother and fetus if left untreated.  Like eclampsia, severe pre-eclampsia is a medical emergency requiring hospitalization.  Pre-eclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality.

Impact

Around 210 million women become pregnant annually around the world and every minute a woman dies in pregnancy or childbirth, with a quarter of these deaths due to a condition called pre-eclampsia which can lead to the more severe and mortal condition called eclampsia. Women may develop high blood pressure during pregnancy (pre-eclampsia) and during or prior to birth may experience life-threatening seizures (eclampsia).  About 5-10 percent of women in their first pregnancy develop pre-eclampsia.

Women with even mild pre-eclampsia should be monitored carefully by a healthcare professional. Hospitalization may be necessary to enable close observation.  This is problematic for many women throughout the world who have limited access to both healthcare professionals and medical/laboratory facilities.

In the majority of third world countries there is a high incidence of maternal and neonatal deaths.  In these mostly rural locations people often have few resources, little or no electricity, lack of clean water, poor transportation, and there are few trained health professionals or functional hospitals.  Through a better understanding and implementation of knowledge about the role of magnesium ions in hypertension and convulsions, millions of lives can be saved.  Developing an inexpensive means to deliver a treatment that will substantially reduce the occurrence and severity of both pre-eclampsia and eclampsia may save both mother and child. 

 In addition to treatment of pregnant women, there are many other diseases that may be alleviated by monitoring Mg levels in people and providing supplementation as needed.  A 1994 Gallup poll found that 72 percent of Americans don't consume sufficient amounts of magnesium. The widespread consumption of processed foods has led to a progressive decline in dietary magnesium.  The availability of Mg in the water supply is another area of increasing concern both in the U.S. and especially in most third world countries.  If Mg is absent from the water and also from the diet, individuals are even more likely to be suffering from hypomagnesemia which can impact not only eclampsia can lead to or exacerbate dozens of other illnesses as well.

Cause

The pathophysiology of pre-eclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. (Maynard, et al., 2003).   There is evidence of a genetic component that increases the risk of having pre-eclampsia/eclampsia (Mützea, et al., 2008; Roberts, 2001).

Many of the deaths may be attributed to hypertensive disorders (pre-eclampsia) leading to hemorrhage and convulsions (eclampsia) for mothers and subsequent premature delivery for infants.  Several factors have been shown to contribute. Pre-eclampsia has been found to be more common in women during their first pregnancy (Mounier-Vehier et al., 1999), and in women who are obese, diabetic, gestationally hypertensive (Saudan, 1998; Myatt; 1999; and Sibai, 1997), and who have had pre-eclampsia during a previous pregnancy.  Pre-eclampsia has also been associated with calcium deficiencies (Hojo, 1997), antioxidant deficiencies (Gulmezoglu et al. 1997) and older maternal age.   Magnesium deficiency has been implicated as a possible cause of pre-eclampsia. (Wynn, 1988; Spatling, 1988; Sibai, et al. 1989; Standley et al., 1997; Handwerker et al., 1995).  Magnesium supplementation has been shown to reduce the incidence of pre-eclampsia in high-risk women in one study (Conradt, et al., 1985), but not in another double-blind trial (Spatling et al., 1988). 

Hypomagnesemia (low concentrations of magnesium ions (Mg++) in the blood) is an increasingly  prevalent condition in contemporary cultures that rely on processed drinking water – a heretofore important source (as much as half) of minimum daily requirements for the essential minerals Ca++ and Mg++.

Treatment

A recently released study of 10,141 women in 33 countries has shown beyond a "reasonable doubt" that intravenous magnesium reduces the risks of eclampsia among women with pre-eclampsia. The relative risk of eclampsia was reduced by 58 percent and the mortality rate nearly cut in half among women receiving magnesium compared to those who received a saline drip. The authors of the study concluded that "magnesium sulfate is remarkably effective at reducing the risk of eclampsia." [The Lancet 359: 1877-90, June 1, 2002]

Magnesium supplementation via daily ingested tablets has been shown to reduce the incidence of pre-eclampsia in high-risk women in one study (Conradt et al., 1985), but not in another double-blind trial (Spatling et al., 1988).

Current methods for measuring Mg++ levels in body fluids require skilled technicians and expensive laboratory-based equipment (over $5K).  An inexpensive, consumer friendly means of determining “nutritional value” of one’s drinking water would be an important adjunct to effective treatment.  Similarly, a simple method to monitor Mg levels in body fluids would also be an important companion device to guide one in determining whether to take mineral supplements or make dietary adjustments. 

Proteinuria (proteins in the urine) is an indicator condition for the onset of pre-eclampsia.  There is technology already in use to measure certain proteins (mostly albumin) in the urine.  An adaptation of dipstick technology to incorporate testing  into an integrated system - simple to use and simple to interpret would greatly increase the chances of successful diagnosis and treatment .

In developed countries, the modern therapy for eclampsia now includes calcium-blocking drugs and a host of anti-hypertensive agents. According to a noted researcher in the field “Drugs may reduce the risk of severe high blood pressure, but not the overall rate of hypertension nor the risk of eclampsia.”  Magnesium is a natural calcium antagonist and is much less expensive to provided compared to “modern” pharmaceuticals.

 A report endorsed by the World Health Organization (WHO), UNICEF and the WORLD BANK, magnesium sulfate is still not available to millions of women worldwide. British medical researchers are pleading with the World Bank and WHO to fund and disseminate treatment kits. [The Lancet 359: June 1, 2002]

Application

Pre-eclampsia and eclampsia is a significant cause of death and sickness of pregnant women and their unborn children.  While the cause is not certain, there are known and likely risk factors.  Given the risk factors, assessments can be made as to what appropriate interventions should be taken.  This may include no intervention; determining dietary intake of minerals; monitoring minerals (Ca and Mg) in blood and urine and protein in the urine; monitoring blood pressure; providing oral Mg supplementation throughout the pregnancy or just in the later stages of pregnancy; providing intravenous Mg sulfate in the late stages of pregnancy and during delivery as indicated by elevated blood pressure, proteinuria and/or onset of convulsions. 

The application of the different levels of intervention outlined in the preceding presupposes the development of adequate tools to monitor Ca, Mg (both in diet and in body fluids), blood pressure and protein in urine.  Adequate tools may need to be developed in order to implement the schema in under-developed and/or rural areas of the world where access to trained and laboratory-equipped health care providers is limited.  Decision-support tools may also be developed that could help assure that appropriate and timely interventions are made to maximize positive health outcomes for mother and child.

Research Background

A number of studies have been conducted that demonstrate that Mg++ plays an important role in dozens of metabolic pathways in the body, not the least of which is in the activation of enzymes including most of the kinases.  Recently, a tyrosine kinase 1 (sFlt1) has been associated with pre-eclampsia by S.E. Maynard’ group at Beth Israel Deaconess Medical Center, Boston, MA (Maynard, et al., 2003).  Others have found (Baker, et al. 1995) elevated serum levels of vascular endothelial growth factor in patients with pre-eclampsia.

Clinical studies show a correlation between low magnesium and incidence of pre-eclampsia (e.g.  see publications of B.M. Altura and B.T. Altura cited in Handwerker, 1995).  Blood tests for Mg however are highly variable since most of the Mg is bound (Cheung et al., 1999 ). Only red-blood cell magnesium levels accurately determine the risk for pre-eclampsia and/or magnesium deficiency, but this test is not commonly performed in laboratories.  Thus a test on urine would be preferred.  According to Susan Fisher a professor at the University of California at San Francisco ''A urine test is very valuable because that's what women are used to doing... 'Being able to identify women before this catastrophe (eclampsia) happens ... is hugely important in saving both the baby and the mother."  Hence the need for developing a test for urine. 

The role of drinking water in providing a significant portion of the essential minerals, Ca++ and Mg++ is well delineated in the recent study by Cotruvo et al., 2009.  It was concluded that a typical daily magnesium deficit is 125-175 mg.  This is the rationale for testing water.

 C.L. AbouZahr with the World Health Organization referencing The Eclampsia Trial Collaborative Group (AbouZahr, 1995) indicates that “A collaborative effort has shown conclusively that magnesium sulfate is the drug of choice in the management of eclampsia.”  This provides the rationale for developing safe and effective means of providing Mg supplementation and monitoring its use.

Some of the studies have lead to conflicting statements about the circumstances under which Mg is used.  The sources of the confusion may be several fold.  In a major study (The Magpie Trial), the emphasis was on treating critically ill women in a hospital setting.  In those cases an intravenous infusion of MgSulfate was found to be beneficial.  One researcher/clinician (Sibai, 2002, 1989) cautions that

“magnesium will not prevent most maternal and perinatal mortality and morbidity related to pre-eclampsia and eclampsia in the third world. This can only be prevented by improving the health-service infrastructure in these countries or preventing severe pre-eclampsia.” 

It is agreed that the health-service infrastructure is a very important aspect of increasing survival of mother and infant.  However, some of the deficits in that infrastructure can be over-come by providing an integrated approach that includes economical and simple field testing along with oral supplementation as indicated and timely referral to health care professionals for more severe cases.

References

AbouZahr, C.L, Maternity Eclampsia  Reprinted from WORLD HEALTH FORUM
(World Health Organization) Sept. 21, 1998, pp. 253-260  Lessons On Safe Motherhood  by C.L. AbouZahr Referencing the following: 18. The Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet, 1995, 345: 1455-1463.

Baker, PN, Krasnow J, Roberts JM, Yeo KT. Elevated serum levels of vascular endothelial growth factor in patients with pre-eclampsia. Obstet. Gynecol. 1995  86:815–821.

Cotruvo, J. and J. Bartram (eds),  in Calcium and Magnesium in Drinking-Water: Public Health Significance, Geneva, World Health Organization, 2009 .  ISBN 978 92 4 156355 0
http://www.who.int/water_sanitation_health/publications/publication_9789241563550/en/print.html

 Choon, Nam Ong, A.C. Grandjean and R.P. Heaney.  The mineral composition of water and its contribution to calcium and magnesium intake.  (Chapter 3 in Cotruvo, 2009 above (WHO)).

Cheung, GT; Huijgen HJ; Sanders R.      Magnesium in disease: a review with special emphasis on the serum ionized magnesium.  Clin Chem Lab Med.  1999 37: 1011–1033.

 Conradt A, Weidinger H, Algayer G. Magnesium deficiency, a possible cause of pre-eclampsia: reduction of frequency of premature rupture of membranes and premature or small-for-date deliveries after magnesium supplementation. J Am Coll Nutr 1985 4:321.

Gulmezoglu AM, Hofmeyr GJ, Oosthuisen MM. Antioxidants in the treatment of severe pre-eclampsia: an explanatory randomised controlled trial. Br J Obstet Gynaecol 1997  104:689–96.

Handwerker SM, Altura BT, Altura BM. Ionized serum magnesium and potassium levels in pregnant women with pre-eclampsia and eclampsia. J Reprod Med 1995;40:201–8.

Hojo M, August P. Calcium Metabolism in Pre-eclampsia: Supplementation may help. Medscape Womens Health 1997  2:5.

 Mounier-Vehier C, Equine O, Valat-Rigot AS, et al. [Hypertensive syndromes in pregnancy. Physiopathology, definition and fetomaternal complications]. Presse Med 1999;28:880–5 [in French].  Pre-eclampsia has been found to be more common in women during their first pregnancy.

 Maynard, Sharon E.; Jiang-Yong Min; Jaime Merchan, Kee-Hak Lim, Jianyi Li, Susanta Mondal et al.; Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in pre-eclampsia.  J Clin Invest.  March 1; 111(5): 649–658, 2003

 Mütze S, Rudnik-Schöneborn S, Zerres K, Rath W.  Genes and the pre-eclampsia syndrome. J Perinat Med. 2008;36(1):38-58.     PMID: 18184097.  Immune maladaptation, placental ischemia and increased oxidative stress represent the main components discussed to be of etiologic importance, and they all may have genetic implications. 

Myatt L, Miodovnik M. Prediction of pre-eclampsia. Semin Perinatol 1999  23:45–57.

Page, NM, et al. Excessive placental secretion of neurokinin B during the third trimester causes pre-eclampsia. Nature. 2000 405:797–800.

Roberts, JM. Pre-eclampsia: what we know and what we do not know. Semin. Perinatol. 2000  24:24–28.

Roberts,  JM and Cooper DW. Pathogenesis and genetics of pre-eclampsia. Lancet. 2001 357:53–56.

Saudan P, Brown MA, Buddle ML, Jones M. Does gestational hypertension become pre-eclampsia? Br J Obstet Gynaecol 1998;105:1177–84.

Sibai BM, Ewell M, Levine RJ, et al. Risk factors associated with pre-eclampsia in healthy nulliparous women. The Calcium for Pre-eclampsia Prevention (CPEP) Study Group. Am J Obstet Gynecol 1997  177:1003–10.

Sibai BM, Villar MA, Bray E. Magnesium supplementation during pregnancy: a double-blind randomized controlled clinical trial. Am J Obstet Gynecol 1989  161:115–9.

Baha M  The Magpie Trial.  The Lancet. Volume 360, Issue 9342, Page 1329, 26 October,  2002 

Spatling L, Spatling G. Magnesium supplementation in pregnancy: a double-blind study. Br J Obstet Gynaecol 1988;950:120–5.

Standley CA, Whitty JE, Mason BA, Cotton DB. Serum ionized magnesium levels in normal and preeclamptic gestation. Obstet Gynecol 1997 89:24–7.

The Magpie Trial Collaborative Group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet 2002; 359: 1877-1890.

Wynn A, Wynn M. Magnesium and other nutrient deficiencies as possible causes of hypertension and low birth weight. Nutr Health 1988;6:69–88.

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For a more extensive list of publications relating to eclampsia and pre-eclampsia, its incidence worldwide, the role of Mg and water supplies and the recent studies on indicator proteins, contact IPRS regarding the following database:  EclampsiaRefs.

For a more extensive list of publications relating to the role of minerals (Ca, Mg, Na, K et al.) in living systems contact IPRS regarding the following database: CationRefs.