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Pre-eclampsia and Eclampsia Initiatives
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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.
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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 preeclampsia 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.”
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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 underdeveloped 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.
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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 preeclampsia and eclampsia in the third world. This can only be prevented by improving the healthservice 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.
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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 preeclampsia. 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.
Sibai, 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: 18771890.
Wynn A, Wynn M. Magnesium and other nutrient deficiencies as possible causes of hypertension and low
birth weight. Nutr Health 1988;6:69–88.
-- 0 -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.
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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.
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