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Preeclampsia

Also indexed as: Pregnancy-Induced Hypertension (PIH), Proteinuric Gestational Hypertension, Toxemia (Pregnancy)

Preeclampsia 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.1 Preeclampsia ranges in severity from mild to severe; the mild form is sometimes called proteinuric pregnancy-induced hypertension2 or proteinuric gestational hypertension.3

Women with even mild preeclampsia must be monitored carefully by a healthcare professional. Hospitalization may be necessary to enable close observation.4

The cause of preeclampsia is unknown, although several factors have been shown to contribute.5 6 Preeclampsia is more common in women during their first pregnancy,7 as well as in women who are obese,8 9 who have diabetes,10 or who have gestational hypertension.11 12 13 Women who have had preeclampsia during a previous pregnancy are also at increased risk.14 Preeclampsia has also been associated with calcium deficiencies,15 antioxidant deficiencies,16 17 18 older maternal age,19 and job stress.20 21 22

Checklist for Preeclampsia

Rating Nutritional Supplements Herbs
3Stars Calcium (for high-risk only)  
2Stars Folic acid
Vitamin C and Vitamin E (in combination; for high-risk only)		  
1Star Fish oil
Magnesium
Vitamin B12
Vitamin B2
Vitamin B6
Zinc		  
3Stars Reliable and relatively consistent scientific data showing a substantial health benefit.
2Stars Contradictory, insufficient, or preliminary studies suggesting a health benefit or minimal health benefit.
1Star An herb is primarily supported by traditional use, or the herb or supplement has little scientific support and/or minimal health benefit.

What are the symptoms of preeclampsia? Symptoms, which typically appear after the 20th week of pregnancy, include swelling of the face and hands, visual disturbances, headache, and high blood pressure. In severe preeclampsia, symptoms are more pronounced. Jaundice may also be present. Severe preeclampsia may lead to seizures (eclampsia) and may cause death to both mother and fetus if left untreated.23 Like eclampsia, severe preeclampsia is a medical emergency requiring hospitalization.24 25

Conventional treatment options: Conventional treatment for preeclampsia includes strict bed rest, maintenance of normal salt intake, medicines to reduce high blood pressure (e.g., intravenous magnesium sulfate), and possibly hospitalization for observation. The definitive conventional treatment of preeclampsia is induced delivery or cesarean section.

Dietary changes that may be helpful: Unlike other conditions that cause high blood pressure, salt restriction and use of diuretics can worsen preeclampsia by reducing blood flow to the kidneys and placenta.26 In preeclampsia, unrestricted use of salt and an increased consumption of water are needed to maintain normal blood volume and circulation to the placenta.27

Data from one preliminary study suggest diets high in trans fatty acids are associated with an increased risk of preeclampsia.28 Trans fatty acids are found in foods that contain partially hydrogenated vegetable oils, such as margarine. Foods that have been deep-fried (e.g., French fries) are also rich sources of trans fatty acids.

Lifestyle changes that may be helpful: Regular prenatal care is essential for the prevention and early detection of preeclampsia.

Job stress (lack of control over work pace and the timing and frequency of breaks) may be detrimental, and reducing job stress may be beneficial in the prevention of preeclampsia.29 In a preliminary study, women exposed to high job stress were found to be at greater risk of developing preeclampsia and, to a lesser extent, gestational hypertension than were women exposed to low job stress. In this study, evaluation of job stress was based on scores assessing on-the-job psychological demand and decision-making latitude. High stress was defined as high psychological demand with low decision latitude, and low stress was defined as low-demand, high-latitude.30

For women with preeclampsia, obstetricians and midwives often recommend bed rest and lying on the left side; this position helps reduce edema and lower blood pressure by increasing urinary output.31 However, a review of clinical trials concluded that bed rest can significantly worsen pregnancy-induced hypertension.32 Women with preeclampsia should discuss the pros and cons of bed rest with their doctors.

Nutritional supplements that may be helpful: Calcium deficiency has been associated with preeclampsia.33 In numerous controlled trials, oral calcium supplementation has been studied as a possible preventive measure.34 35 36 37 While most trials have found a significant reduction in the incidence of preeclampsia with calcium supplementation,38 39 40 41 42 43 some have reported no change.44

An analysis of double-blind trials45 found calcium supplementation to be highly effective in preventing preeclampsia. However, a large and well-designed double-blind trial46 and a critical analysis47 of six double-blind trials48 49 50 51 52 53 concluded that calcium supplementation did not reduce the risk of preeclampsia in healthy women at low risk for preeclampsia. For healthy, high-risk (i.e., calcium deficient) women, however, the data show a clear and statistically significant beneficial effect of calcium supplementation in reducing the risk of preeclampsia.54 55 56

The National Institutes of Health recommends an intake of 1,200 to 1,500 mg of elemental calcium daily during normal pregnancy.57 In women at risk of preeclampsia, most trials showing reduced incidence have used 2,000 mg of supplemental calcium per day.58 Nonetheless, many doctors continue to suggest amounts no higher than 1,500 mg per day.

Women with preeclampsia have been shown to have elevated blood levels of homocysteine.59 60 61 62 Research indicates elevated homocysteine occurs prior to the onset of preeclampsia.63 Elevated homocysteine damages the lining of blood vessels,64 65 66 67 68 69 70 which can lead to the preeclamptic signs of elevated blood pressure, swelling, and protein in the urine.71

In one preliminary trial, women with a previous pregnancy complicated by preeclampsia and high homocysteine supplemented with 5 mg of folic acid and 250 mg of vitamin B6 per day, successfully lowering homocysteine levels.72 In another trial studying the effect of vitamin B6 on preeclampsia incidence, supplementation with 5 mg of vitamin B6 twice per day significantly reduced the incidence of preeclampsia. Women in that study were not, however, evaluated for homocysteine levels.73 In fact, no studies have yet determined whether lowering elevated homocysteine reduces the incidence or severity of preeclampsia. Nevertheless, despite a lack of proof that elevated homocysteine levels cause preeclampsia, many doctors believe that pregnant women with elevated homocysteine should attempt to reduce those levels to normal.

A marginal zinc deficiency has been reported in some women with preeclampsia.74 75 The common practice of prescribing iron and folic acid supplements to pregnant women can lead to reduced zinc absorption.76 Trials studying the relationship between zinc supplementation and preeclampsia incidence have produced conflicting results. In one double-blind trial, the incidence of preeclampsia was significantly lower in women receiving a multivitamin-mineral supplement, which provided 20 mg of zinc per day, than in women who received the same supplement without zinc.77 However, in another double-blind trial, a higher incidence of preeclampsia was reported in pregnant women given 20 mg of zinc per day than was reported in women given a placebo.78 In yet another trial, zinc supplementation failed to prevent preeclampsia. 79 Therefore, current evidence does not sufficiently support the use of zinc as a way to protect against preeclampsia.

Fish oil supplementation has been proposed to lower the incidence of preeclampsia.80 81 However, controlled clinical trials suggest that fish oil does not reduce symptoms82 or protect against preeclampsia.83 84

Women with preeclampsia have been found to be depleted in antioxidants.85 86 Some87 88 but not all studies89 have reported deficiencies in vitamin C, vitamin E, and beta-carotene in preeclampsia patients. In a double-blind trial, supplementation of vitamin C (one gram per day) and vitamin E (400 IU per day) reduced the incidence of preeclampsia by 76% in women at high risk.90 However, for those already suffering from this condition, supplementation with these same vitamins has led to only insignificant effects.91

Magnesium deficiency has been implicated as a possible cause of preeclampsia.92 93 94 95 96 Magnesium supplementation has been shown to reduce the incidence of preeclampsia in high-risk women in one trial,97 but not in another double-blind trial.98

Women who are deficient in vitamin B2 (riboflavin) are more likely to develop preeclampsia than women with normal vitamin B2 levels.99 These results were observed in a developing country, where vitamin B2 deficiencies are more common than in the United States. Nevertheless, insufficient vitamin B2 may contribute to the abnormalities underlying the disease process.

Are there any side effects or interactions? Refer to the individual supplement for information about any side effects or interactions.

References:

1. Myatt L, Miodovnik M. Prediction of preeclampsia. Semin Perinatol 1999;23:45–57.

2. Smith GN, Walker M, Tessier JL, Millar KG. Increased incidence of preeclampsia in women conceiving by intrauterine insemination with donor versus partner sperm for treatment of primary infertility. Am J Obstet Gynecol 1997;177:455–8.

3. Rey E, LeLorier J, Burgess E, et al. Report of the Canadian Hypertension Society Consensus Conference: 3. Pharmacologic treatment of hypertensive disorders in pregnancy. CMAJ 1997;157:1245–54.

4. Rath W Z. Treatment of hypertensive diseases in pregnancy—general recommendations and long-term oral therapy. Geburtshilfe Neonatol 1997;201:240–6 [in German].

5. Myatt L, Miodovnik M. Prediction of preeclampsia. Semin Perinatol 1999;23:45–57.

6. Sibai B. Prevention of preeclampsia: a big disappointment. Am J Obstet Gynecol 1998;179:1275–8 [review].

7. 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].

8. 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].

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

10. Persson B, Hanson U. Neonatal morbidities in gestational diabetes mellitus. Diabetes Care 1998;Suppl 2:B79–84.

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

12. Myatt L, Miodovnik M. Prediction of preeclampsia. Semin Perinatol 1999;23:45–57.

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

14. Myatt L, Miodovnik M. Prediction of preeclampsia. Semin Perinatol 1999;23:45–57.

15. Hojo M, August P. Calcium Metabolism in Preeclampsia: Supplementation may help. Medscape Womens Health 1997;2:5.

16. Mikhail MS, Anyaegbunam A, Garfinkel D, et al. Preeclampsia and antioxidant nutrients: decreased plasma levels of reduced ascorbic acid, alpha-tocopherol and beta carotene in women with preeclampsia. Am J Obstet Gynecol 1994;171:150–7.

17. 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.

18. Valsecchi L, Fausto A, Grazioli V. Severe preeclampsia and antioxidant nutrients. Am J Obstet Gynecol 1995;173:673 [letter].

19. Bianco A, Stone J, Lynch L, et al. Pregnancy outcome at age 40 and older. Obstet Gynecol 1996;87:917–22.

20. Marcoux S, Berube S, Brisson C, Mondor M. Job strain and pregnancy-induced hypertension. Epidemiology 1999;10:376–82.

21. Wergeland E, Strand K. Work pace control and pregnancy health in a population-based sample of employed women in Norway. Scand J Work Environ Health 1998;24:206–12.

22. 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].

23. Rath W Z. Treatment of hypertensive diseases in pregnancy—general recommendations and long-term oral therapy. Geburtshilfe Neonatol 1997;201:240–6 [in German].

24. Rey E, LeLorier J, Burgess E, et al. Report of the Canadian Hypertension Society Consensus Conference: 3. Pharmacologic treatment of hypertensive disorders in pregnancy. CMAJ 1997;157:1245–54.

25. Sibai BM, Frangieh AY. Management of severe preeclampsia. Curr Opin Obstet Gynecol 1996;8(2):110–3.

26. Franx A, Steegers EA, de Boo T, et al. Sodium-blood pressure interrelationship in pregnancy. J Hum Hypertens 1999;13:159–66.

27. Moutquin JM, Garner PR, Burrows RF, et al. Report of the Canadian Hypertension Society Consensus Conference: 2. Nonpharmacologic management and prevention of hypertensive disorders in pregnancy. CMAJ 1997;157:907–19.

28. Williams MA, King IB, Sorensen TK, et al. Risk of preeclampsia in relation to elaidic acid (trans fatty acid) in maternal erythrocytes. Gynecol Obstet Invest 1998;46:84–7.

29. Wergeland E, Strand K. Work pace control and pregnancy health in a population-based sample of employed women in Norway. Scand J Work Environ Health 1998;24:206–12.

30. Marcoux S, Berube S, Brisson C, Mondor M. Job strain and pregnancy-induced hypertension. Epidemiology 1999;10:376–82.

31. Katz VL, Ryder RM, Cefalo RC, et al. A comparison of bed rest and immersion for treating the edema of pregnancy. Obstet Gynecol 1990;75:147–51.

32. Allen C, Glasziou P, Del Mar C. Bed rest: a potentially harmful treatment needing more careful evaluation. Lancet 1999;354:1229–33 [review].

33. Hojo M, August P. Calcium metabolism in normal and hypertensive pregnancy. Semin Nephrol 1995;15:504–11 [review].

34. Hojo M, August P. Calcium Metabolism in Preeclampsia: Supplementation may help. Medscape Womens Health 1997;2:5.

35. Moutquin JM, Garner PR, Burrows RF, et. al. Report of the Canadian Hypertension Society Consensus Conference: 2. Nonpharmacologic management and prevention of hypertensive disorders in pregnancy. CMAJ 1997;157:907–19.

36. Levine RJ, Hauth JC, Curet LB, et al. Trial of calcium to prevent preeclampsia. N Engl J Med 1997;337:69–76.

37. Belizan JM. Calcium supplementation to prevent hypertensive disorders of pregnancy. N Engl J Med 1991;325:1399–405.

38. Hojo M, August P. Calcium Metabolism in Preeclampsia: Supplementation may help. Medscape Womens Health 1997;2:5.

39. Moutquin JM, Garner PR, Burrows RF, et al. Report of the Canadian Hypertension Society Consensus Conference: 2. Nonpharmacologic management and prevention of hypertensive disorders in pregnancy. CMAJ 1997;157:907–19.

40. Crowther CA, Hiller JE, Pridmore B, et al. Calcium supplementation in nulliparous women for the prevention of pregnancy-induced hypertension, preeclampsia, and preterm birth: an Australian randomized trial. FRACOG and the ACT study group. Aust N Z J Obstet Gynaecol 1999;39:12–8.

41. Bucher HC, Guyatt GH, Cook RJ, et al. Effect of calcium supplementation on pregnancy-induced hypertension and preeclampsia: a meta-analysis of randomized controlled trials. JAMA 1996;275:1113–7.

42. Belizan JM. Calcium supplementation to prevent hypertensive disorders of pregnancy. N Engl J Med 1991;325:1399–405.

43. Herrera JA, Arevalo-Herrera M, Herrera S. Prevention of preeclampsia by linoleic acid and calcium supplementation: a randomized controlled trial. Obstet Gynecol 1998;91:585–90.

44. Levine RJ, Hauth JC, Curet LB, et al. Trial of calcium to prevent preeclampsia. N Engl J Med 1997;337:69–76.

45. Bucher HC, Guyatt GH, Cook RJ, et al. Effect of calcium supplementation on pregnancy-induced hypertension and preeclampsia: a meta-analysis of randomized controlled trials. JAMA 1996;275:1113–7.

46. Levine RJ, Hauth JC, Curet LB, et al. Trial of calcium to prevent preeclampsia. N Engl J Med 1997;337:69–76.

47. Sibai BM. Prevention of preeclampsia: a big disappointment. Am J Obstet Gynecol 1998;179:1275–8.

48. Levine RJ, Hauth JC, Curet LB, et al. Trial of calcium to prevent preeclampsia. N Engl J Med 1997;337:69–76.

49. Lopez-Jaramillo P, Narvaez M, Weigel RM, Yepez R. Calcium supplementation reduces the risk of pregnancy-induced hypertension in an Andes population. Br J Obstet Gynaecol 1989;96:648–55.

50. Lopez-Jaramillo P, Narvaez M, Felix C, Lopez A. Dietary calcium supplementation and prevention of pregnancy hypertension. Lancet 1990;335:293. [letter]

51. Villar J, Repke JT. Calcium supplementation during pregnancy may reduce preterm delivery in high-risk populations. Am J Obstet Gynecol 1990;163:1124–31.

52. Belizan JM, Villar J, Gonzalez L. Calcium supplementation to prevent hypertensive disorders of pregnancy. N Engl J Med 1991;325:1399–405.

53. Sanchez-Ramos L, Briones DK, Kaunitz AM, et al. Prevention of pregnancy-induced hypertension by calcium supplementation in angiotensin II-sensitive patients. Obstet Gynecol 1994;84:349–53.

54. DerSimonian R, Levine RJ. Resolving discrepancies between a meta-analysis and a subsequent large controlled trial. JAMA 1999;282:664–70 [review].

55. Ritchie LD, King JC. Dietary calcium and pregnancy-induced hypertension: is there a relation? Am J Clin Nutr 2000;71(5 Suppl):1371–4S [review].

56. Villar J, Belizan JM. Same nutrient, different hypotheses: disparities in trials of calcium supplementation during pregnancy. Am J Clin Nutr 2000;71(5 Suppl):1375–9S [review].

57. NIH Consensus conference. Optimal calcium intake. NIH Consensus Development Panel on Optimal Calcium Intake. JAMA 1994;272(24):1942[review].

58. Moutquin JM, Garner PR, Burrows RF, et al. Report of the Canadian Hypertension Society Consensus Conference: 2. Nonpharmacologic management and prevention of hypertensive disorders in pregnancy. CMAJ 1997;157:907–19.

59. Leeda M, Riyazi N, de Vries JI, et al. Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction. Am J Obstet Gynecol 1998;179:135–9.

60. Powers RW, Evans RW, Majors AK, et al. Plasma homocysteine concentration is increased in preeclampsia and is associated with evidence of endothelial activation. Am J Obstet Gynecol 1998;179:1605–11.

61. Rajkovic A, Catalano PM, Malinow MR. Elevated homocyst(e)ine levels with preeclampsia. Obstet Gynecol 1997;90:168–71.

62. Laivuori H, Kaaja R, Turpeinen U, et al. Plasma homocysteine levels elevated and inversely related to insulin sensitivity in preeclampsia. Obstet Gynecol 1999;93:489–93.

63. Sorensen TK, Malinow MR, Williams MA, et al. Elevated second-trimester serum homocyst(e)ine levels and subsequent risk of preeclampsia. Gynecol Obstet Invest 1999;48:98–103.

64. Powers RW, Evans RW, Majors AK, et al. Plasma homocysteine concentration is increased in preeclampsia and is associated with evidence of endothelial activation. Am J Obstet Gynecol 1998;179:1605–11.

65. Ray JG, Laskin CA. Folic acid and homocyst(e)ine metabolic defects and the risk of placental abruption, pre-eclampsia and spontaneous pregnancy loss: A systematic review. Placenta 1999;20:519–29 [review].

66. Sorensen TK, Malinow MR, Williams MA, et al. Elevated second-trimester serum homocyst(e)ine levels and subsequent risk of preeclampsia. Gynecol Obstet Invest 1999;48:98–103.

67. Roberts JM. Endothelial dysfunction in preeclampsia. Semin Reprod Endocrinol 1998;16:5–15.

68. Hayman R, Brockelsby J, Kenny L, Baker P. Preeclampsia: the endothelium, circulating factor(s) and vascular endothelial growth factor. J Soc Gynecol Investig 1999;6:3–10.

69. Lyall F, Greer IA. The vascular endothelium in normal pregnancy and pre-eclampsia. Rev Reprod 1996;1:107–16.

70. Roberts JM, Redman CWG. Pre-eclampsia: more than pregnancy-induced hypertension. Lancet 1994;341:1447–54.

71. Taylor RN, de Groot CJ, Cho YK, Lim KH. Circulating factors as markers and mediators of endothelial cell dysfunction in preeclampsia. Semin Reprod Endocrinol 1998;16:17–31.

72. Leeda M, Riyazi N, de Vries JI, et al. Effects of folic acid and vitamin B6 supplementation on women with hyperhomocysteinemia and a history of preeclampsia or fetal growth restriction. Am J Obstet Gynecol 1998;179:135–9.

73. Wachstein M, Graffeo LW. Influence of Vitamin B6 on the incidence of preeclampsia. Obstet Gynecol 1956;8:177–80.

74. Lazebnik N, Kuhnert BR, Kuhnert PM. Zinc, cadmium, and hypertension in parturient women. J Obstet Gynecol 1989;161:437–40.

75. Cherry FF, Bennett EA, Bazzano GS, et al. Plasma zinc in hypertension/toxemia and other reproductive variables in adolescent pregnancy. Am J Clin Nutr 1981;34:2367–75.

76. Simmer K, Iles CA, James C, Thompson RP. Are iron-folate supplements harmful? Am J Clin Nutr 1987;45:122–5.

77. Hunt IF, Murphy NJ, Cleaver AE, et al. Zinc supplementation during pregnancy: effects on selected blood constituents and on progress and outcome of pregnancy in low-income women of Mexican descent. Am J Clin Nutr 1984;40:508–21.

78. Mahomed K, James DK, Golding J, McCabe R. Zinc supplementation during pregnancy: a double-blind randomised controlled trial. BMJ 1989;299:826–9.

79. Jonsson B, Hauge B, Larsen MF, Hald F. Zinc supplementation during pregnancy: a double blind randomised controlled trial. Acta Obstet Gynecol Scand 1996;75:725–9.

80. Sibai BM. Prevention of preeclampsia: A big disappointment. Am J Obstet Gynecol 1998;179:1275–8 [review].

81. Williams MA, Zingheim RW, King IB, Zebelman AM. Omega-3 fatty acids in maternal erythrocytes and risk for preeclampsia. Epidemiology 1995;6:232–7.

82. Laivuori H, Hovatta O, Viinikka L, Ylikorkala O. Dietary supplementation with primrose oil or fish oil does not change urinary excretion of prostacyclin and thromboxane metabolites in pre-eclamptic women. Prostaglandins Leukot Essent Fatty Acids 1993;49:691–4.

83. Onwude JL, Lilford RJ, Hjartardottier H, et. al. A randomised double blind placebo controlled trial of fish oil in high risk pregnancy. Br J Obstet Gynaecol 1995;109:95–100.

84. Salvig JD, Olsen SF, Secher NJ. Effects of fish oil supplementation in late pregnancy on blood pressure: a randomised controlled trial. Br J Obstet Gynaecol 1996;103:529–33.

85. Tabacova S, Balabaeva L, Little RE. Maternal exposure to exogenous nitrogen compounds and complications of pregnancy. Arch Environ Health 1997;52:341–7.

86. Mutlu-Turkoglu U, Ademoglu E, Ibrahimoglu L, et al. Imbalance between lipid peroxidation and antioxidant status in preeclampsia. Gynecol Obstet Invest 1998;46:37–40.

87. Mikhail MS, Anyaegbunam A, Garfinkel D, et al. Preeclampsia and antioxidant nutrients: decreased plasma levels of reduced ascorbic acid, alpha-tocopherol and beta carotene in women with preeclampsia. Am J Obstet Gynecol 1994;171:150–7.

88. Valsecchi L, Fausto A, Grazioli V. Severe preeclampsia and antioxidant nutrients. Am J Obstet Gynecol 1995;173:673 [letter].

89. Schiff E, Friedman SA, Stampfer M, et al. Dietary consumption and plasma concentrations of vitamin E in pregnancies complicated by preeclampsia. Am J Obstet Gynecol 1996;175:1024–8.

90. Chappell LC, Seed PT, Briley AL, et al. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet 1999;354:810–6.

91. 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.

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

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

94. 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.

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

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

97. 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.

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

99. Wacker J, Fruhauf J, Schulz M, et al. Riboflavin deficiency and preeclampsia. Obstet Gynecol 2000;96:38–44.