Title: Antioxidant status and pre-eclampsia in clinical practice
Key words: pre-eclampsia, antioxidant, hypertension, proteinuria, placental impairment, foetal, maternal, morbidity, perinatal, neonatal, death, obesity, diabetes, cardiovascular disease CVD, atherosclerosis, lipid peroxidation, atherogenesis, endothelial, eNOS, NO, nitric oxide, peroxynitrite, nitrotyrosine, superoxide, free radical, vasoactive, vasoconstrictive, catalase, glutathione peroxidase, selenium, vitamin C, folate, vitamin B12, supplementation, homocysteine, synergistic, betaine, B2, B6, vitamin E,
Date: Sept 2006
Category: Specific conditions
Author: Morgan, G
Antioxidant status and pre-eclampsia in clinical practice
Pre-eclampsia is a disease of pregnancy characterised by hypertension, proteinuria, placental impairment, foetal growth retardation and a high incidence of foetal and maternal morbidity. It remains a leading cause of neonatal and perinatal mortality, being the second commonest cause of maternal death in the UK (Roberts 1994). It is estimated that 7-10% of all pregnancies develop pre-eclampsia (Roggensack 1999). Multiple risk factors are involved, there being strong associations with obesity, diabetes and cardiovascular disease (Sibai 1995), illustrating the fact that pre-eclampsia exhibits many of the same features as atherosclerosis. These changes have been confirmed pathophysiologically, occlusive placental vascular changes being seen to precede the clinical features of the disease (Roberts 1999). The role of antioxidants in the pathophysiology and treatment of this disorder will be examined in this review.
Lipid peroxidation has been recognised for some time as a cardinal feature of atherogenesis. Similar markers of peroxidation have been found in pre-eclampsia cases (Hubel 1989). Endothelial damage is thought to be a precipitating event leading to the evolution of disordered lipid metabolism (Diaz 1997). One such factor may be homocysteine which is known to be toxic to endothelium (Dekker 1996, Ray 1999), and whose levels are raised in pre-eclampsia (Powers 1998). Endothelial damage has been shown to be associated with increased expression of eNOS (Davidge 1995, Myatt 1996), and with increased production of NO metabolites, including the highly reactive free radical peroxynitrite (Roggensack 1999).
Reduced antioxidant defences reflected in lower levels of SOD, for example, render increased NO production pathological, leading to lipid peroxidation (Roggensack 1999). Increased nitrotyrosine residues, reflecting DNA damage, has also been reported under such conditions (Myatt 1996, Roggensack 1999). Activation of peroxynitrite through the reaction of NO with the superoxide radical has been shown to lead to the biosynthesis of vasoconstrictive prostaglandins (Landino 1996). Release of such inflammatory and vasoactive compounds contributes to the reduction in blood flow and placental pathology seen in pre-eclampsia (Giles 1985, Myatt 1996).
Antioxidant enzyme expression is diminished in pre-eclampsia (Wang 1996). Apart from reduced SOD activity (Roggensack 1999), catalase and glutathione peroxidase have also been shown to be reduced (Wang 1996, Barrington 1996). Reduced antioxidant activity is linked to lipid peroxidation, DNA damage and a progression of the vasculopathy seen in pre-eclampsia (Barrington 1996, Hubel 1999). Reduced glutathione peroxidase activity reflects lower selenium levels, the essential cofactor (Barrington 1996, Rayman 2003). Reductions in other antioxidants have been observed (Davidge 1992, Cikot 2001).
Levels of vitamin C less than 85mgs a day have been associated with a doubling of the rate of pre- eclampsia (Zhang 2002). Vitamin cofactors associated with homocysteine metabolism, notably folate (Ray 1999, Sanchez 2001), vitamin B2 (Wacker 2000), and vitamin B6 (Cikot 2001) deficiencies, have also been linked to pre-eclampsia. The endothelial damage associated with hyperhomo- cysteinemia shares many of the features linked to oxidative damage. Vitamin B12 levels, though depressed and a key cofactor in homocysteinia metabolism, have not been found to be an independent factor in pre- eclampsia (Ray 1999, Sanchez 2001).
The above evidence linking oxidative stress with pre-eclampsia has promoted several trials of antioxidant treatment for this condition. In atherosclerosis, both in vitro and in vivo research has shown that vitamin E, or combinations of vitamin E and vitamin C, reduce lipid peroxidation and associated abnormal lipid profiles (Porkkala 2000, Kontusch 2001). In pre- eclampsia the use of these agents have yielded mixed results. Two trials using vitamin E or combinations of vitamin E and C led to negative results(Stratta 1994, Gulmezoglu 1997), but have been criticised on methodological grounds by Chappell (Chappell 1999). Chappell’s own study (Chappell 1999), which instituted supplementation at 14 weeks gestation, showed both a clinical benefit and an improvement in biochemical markers associated with the disease. Another trial looking at the effect of B12 and folate supplementation showed a reduction in homocysteine levels, pre-eclampsia and foetal growth retardation (Leeda 1998).
The results of cross-sectional and prospective studies have confirmed that the aetiology of pre-eclampsia is multifactorial (Roberts 1999). With respect to antioxidants, a synergistic action between cofactors has frequently been demonstrated. The ability of vitamin C to regenerate vitamin E is illustrated by the increased efficacy of these two vitamins in combination in cardiovascular trials (Porkkala-Sarataho 2000). The same applies to the interaction of vitamins B2, B6, B12, folate and methyl donors such as betaine in hyperhomocysteinemia (Koyama 2002, McGregor 2002).
Combinations of these vitamins have been shown to redress the biochemical and clinical parameters of pre-eclampsia (Leeda 1998), even though only folate has been shown to be an independent risk factor (Sanchez 2001). These studies call to attention the need to conduct larger scale randomised controlled trials utilising a broad spectrum of the antioxidants implicated in pre-eclampsia, namely selenium, folate and the vitamins B2, B6, B12, C and E. The trials would need to be commenced at an early stage of gestation at a stage when the pre-eclamptic process was reversible (Chappell 1999). No toxicity problems have been reported in using such therapeutic doses, either singly or in combination.
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