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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.
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.
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