Title: Antioxidants in Pre-eclampsia
Key words: Antioxidants, pregnancy,
oxidative stress, clinical predictors,
Date: June 1999
Category: 13. Specific Conditions
Author: Dr van Rhijn
Antioxidants in Pre-eclampsia
Pre-eclampsia is a systemic pregnancy
syndrome, characterised by reduced uteroplacental blood flow, diffuse endothelial
dysfunction, increased peripheral vascular resistance, hypertension, coagulation
abnormalities, elevations of maternal leukocyte-derived cytokines, hyperlipidemia,
proteinuria, and oedema. The hypotheses suggest reactive oxygen species or their
metabolites (oxidative stress) ultimately compromise the "defensive" vasodilatory,
anti-aggregatory, and barrier functioning of the vascular endothelium1
due to uncontrolled lipid oxidation.
Diminished Antioxidant Protection
Oxidative stress in the maternal
compartment may be due to pre-existing factors (e.g., obesity, diabetes, hyperlipidemia)
or caused by placental lipid peroxides. Decreased placental antioxidant enzyme
protection is followed by a cascade of events of uncontrolled lipid peroxidation
with increased thromboxane production, increased tumor necrosis factor (TNF-alpha)
production, cytokine interleukin (IL-6, IL-8) and TNF-alpha, which are of monocytic
origin2 and decreased prostacyclin3. Activated intervillous
leucocytes serve as mediators linking increased placental oxidative stress with
increased maternal oxidative stress and endothelial dysfunction. Antioxidant
capacity in the third trimester (rapid placental growth) fails and leads to
membrane instability, failure of foetal protection systems and clinical symptoms
of preeclampsia4. Increased lipid peroxidation is correlated with
hypertension and serum uric acid levels5, but not with clinical severity6.
Shallow implantation, hypoxic maternal-fetal interface, and increased turnover
of trophoblast tissue, result in higher hypoxanthine, xanthine concentrations
and hyperuricemia characterize preeclampsia7.
Studies have confirmed the imbalance
between increased lipid peroxidation (MDA) and reduced8, 9, 10 sera
antioxidant activity [vitamin E11, C12,
13 & A14] in preeclampsia. Reduced plasma superoxide dismutase
(CuZn-SOD)15 and glucose 6-phosphate-dehydrogenase16 levels
and increased placenta activities of catalase17, glutathione-S-transferase
and glutathione peroxidase (Gpx) were found in preeclampsia, associated with
fetal growth retardation or asphyxia18.
- A 15% increase in the ratio of
omega-3 to omega-6 fatty acids was associated with a 46% reduction in risk
of preeclampsia19. Higher levels of beta-carotene (0.5 - 1 mumol/L)
inhibited peroxide-induced vasoconstriction and lipid peroxide and thromboxane
secretion20, but results from antioxidant treatment with vitamin
E21, vitamin C and allopurinol was not encouraging22.
Low-dose aspirin in pre-eclamptic placentas inhibits lipid peroxides and thromboxane
without affecting prostacyclin23. The oxidation of erythrocyte
glutathione was inhibited by the presence of the cyclooxygenase inhibitor
indomethacin, and may be of value in the treatment of oxidative pathologies24.
Clinical Predictors of Pre-eclampsia
- Prediction of risk or identification
of subclinical disease is desirable because of the lack of proven prophylaxis
- Potential candidate markers would
- renal function (kallikrein-creatinine)
- coagulation and fibrinolytic
systems and platelet activation (platelet volume); vascular function (fibronectin,
- oxidant stress (lipid peroxides,
8-isoprostane, antioxidants, anticardiolipin antibodies, haemoglobin,
iron, transferrin25, homocysteine, hypertriglyceridemia, albumin
- placental peptide hormones
(CRH, CRHbp, activin, inhibin, hCG)
- vascular resistance (uteroplacental
flow velocity waveforms)
- genetic markers, insulin resistance,
and glucose intolerance26.
Preeclampsia is associated with premature
delivery, foetal growth retardation, increased maternal and neonatal morbidity
and mortality. Prospective longitudinal studies are required to evaluate potential
predictive markers useful for early identification and successful therapeutic
antioxidative prevention27, as currently conducted in the Vitamins
In Pre-eclampsia (VIP) study in London.
- Hubel, C.A. Dyslipidemia, iron,
and oxidative stress in preeclampsia: assessment of maternal and feto-placental
interactions. Semin. Reprod. Endocrinol. 1998; 16:1, 75 – 92.
- Walker, J.J. Antioxidants and
inflammatory cell response in preeclampsia. Semin. Reprod. Endocrinol. 1998;16:1,
47 – 55.
- Rayman M.P. et al. Comparison
of selenium levels in pre-eclamptic and normal pregnancies. Biol. Trace. Elem.
Res. 1996; 55:1-2, 9 – 20.
- Walsh, S.W. Maternal-placental
interactions of oxidative stress and antioxidants in preeclampsia. Semin.
Reprod. Endocrinol. 1998; 16:1, 93 – 104.
- Yanik, F.F. et al. Pre-eclampsia
associated with increased lipid peroxidation and decreased serum vitamin E
levels. Int. J. Gynaecol. Obstet. 1999; 64:1, 27 – 33.
- Ozan, H. et al. Plasma
ascorbic acid level and erythrocyte fragility in preeclampsia and eclampsia.
Eur. J. Obstet. Gynecol. Reprod. Biol. 1997; 71:1, 35 – 40.
- Many, A. Hyperuricemia and xanthine
oxidase in preeclampsia, revisited. Am. J. Obstet. Gynecol. 1996; 174:1 Pt
1, 288 – 291.
- Shaarawy, M. et al. Radical-scavenging
antioxidants in pre-eclampsia and eclampsia. Int. J. Gynaecol. Obstet. 1998;
60:2, 123 – 128.
- Sagol, S. et al. Impaired
antioxidant activity in women with pre-eclampsia. Int. J. Gynaecol. Obstet.
1999; 64:2, 121 – 127.
- Davidge, S.T. et al. Sera
antioxidant activity in uncomplicated and preeclamptic pregnancies. Obstet.
Gynecol. 1992; 79:6, 897 – 901.
- Morris, J.M. et al. Circulating
markers of oxidative stress are raised in normal pregnancy and pre-eclampsia.
Br. J. Obstet. Gynaecol. 1998; 105:11, 1195 – 1199.
- Mutlu Türkoglu, U. et
al. Imbalance between lipid peroxidation and antioxidant status in preeclampsia.
Gynecol. Obstet. Invest. 1998; 46:1, 37 – 40.
- Mikhail, M.S. 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; 171:1, 150 – 157.
- Ziari, S.A. et al. Serum
vitamin A, vitamin E, and beta-carotene levels in preeclamptic women in northern
Nigeria. Am. J. Perinatol. 1996; 13:5, 287 – 291.
- Poranen, A.K. The effect of vitamin
C and E on placental lipid peroxidation and antioxidative enzymes in perfused
placenta. Acta. Obstet. Gynecol. Scand. 1998; 77:4, 372 – 276.
- Poranen, A.K. et al. Lipid
peroxidation and antioxidants in normal and pre-eclamptic pregnancies. Placenta.
1996; 17:7, 401 – 405.
- Wang, Y. 7 Walsh, S.W. Antioxidant
activities and mRNA expression of superoxide dismutase, catalase, and glutathione
peroxidase in normal and preeclamptic placentas. J. Soc. Gynecol. Investig.
1996; 3:4, 179 – 184.
- Uotila, J.T. Findings on lipid
peroxidation and antioxidant function in hypertensive complications of pregnancy.
Br. J. Obstet. Gynaecol. 1993; 100:3, 270 – 176.
- Williams, M.A. et al. Omega-3
fatty acids in maternal erythrocytes and risk of preeclampsia. Epidemiology.
1995; 6:3, 232 –237.
- Cueto, S.M. et al. beta-Carotene
attenuates peroxide-induced vasoconstriction in the human placenta. J. Soc.
Gynecol. Investig. 1997; 4:2, 64 – 71.
- Schiff, E. et al. Dietary
consumption and plasma concentrations of vitamin E in pregnancies complicated
by preeclampsia. Am. J. Obstet. Gynecol. 1996; 175:4 Pt 1, 1024 – 1028.
- Gülmezoglu, A.M. Antioxidants
in the treatment of severe pre-eclampsia: an explanatory randomised controlled
trial; Br. J. Obstet. Gynaecol. 1997; 104:6, 689 – 696.
- Wang, Y. & Walsh, S.W. Aspirin
inhibits both lipid peroxides and thromboxane in preeclamptic placentas. Free
Radic. Biol. Med. 1995; 18:3, 585 – 591.
- Spickett, C.M. et al. Oxidation
of erythrocyte glutathione by monocytes stimulated with interleukin-6. Analysis
by 1H spin echo. Clin. Chim. Acta. 1998; 270:2, 115 – 124.
- Hubel, C.A. et al. Decreased
transferrin and increased transferrin saturation in sera of women with preeclampsia:
implications for oxidative stress. Am. J. Obstet. Gynecol. 1996; 175:3 Pt
1, 692 – 700.
- Myatt, L. & Miodovnik, M.
Prediction of preeclampsia. Semin. Perinatol. 1999; 23:1, 45 – 57.
- Dekker, G.A. & van Geijn,
H.P. Endothelial dysfunction in preeclampsia. Part I: Primary prevention.
Therapeutic perspectives. J. Perinat. Med. 1996; 24:2, 99 – 117.