The transient increase of oxidative stress during normal pregnancy is higher and persists after delivery in women with pre-eclampsia

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Abstract

Objectives

Glutathione, an intracellular tripeptide, functions in the protection of cells against free radicals and toxins of endogenous and exogenous origin. To maintain the intracellular redox status in presence of reactive oxygen species, glutathione (GSH) and other thiols are oxidized. The oxidative status of thiols is reflected by the free-to-oxidized ratio and is a real-time measure for oxidative stress. Previously, we have reported abnormal ratios for the thiols cysteine (Cys), homocysteine (Hcy) and cysteinylglycine (CysGly) in women with pre-eclampsia. The aims of this study were to confirm our previous findings in a different case–control cohort and more importantly to determine whether these differences persist postpartum.

Study design

At onset of disease and at 6–8 weeks postpartum we analyzed whole blood of 41 women with pre-eclampsia and of 31 women with normotensive pregnancies for the free-to-oxidized ratio of thiols by the assessment of free and oxidized thiol levels using high performance liquid chromatography. Differences between values were determined using either the paired t-test (antepartum versus postpartum) or the t-test (pre-eclampsia versus normotensive pregnancy).

Results

Antepartum levels of free GSH as well as the free-to-oxidized ratios of Hcy were lower in pre-eclampsia and normotensive pregnancy when compared with corresponding postpartum values (P < 0.0001 and P < 0.01, respectively). Moreover, the free-to-oxidized ratio for Hcy was significantly lowered in pre-eclamptic compared with normotensive women, during as well as after pregnancy (both P  0.01).

Conclusion

The data suggest that pregnancy is a state of higher oxidative stress when compared to the postpartum period. In women with pre-eclampsia, oxidative stress is higher and persists in the postpartum period.

Introduction

In reproduction the glutathione/glutathione dependent enzyme system plays an important role in the defense against oxidative damage by scavenging of free radicals, thereby leading to oxidation of glutathione [1]. To maintain the cellular redox-balance the oxidized form of glutathione can either be converted to reduce glutathione or excreted when excessive amounts are formed [2]. The presence of the free sulfhydryl (–SH) group also confers potent antioxidant properties to other amino thiols including cysteine and homocysteine [3]. However, in presence of free transition metals (auto)oxidation of thiols will lead to the formation of superoxide, thus amino thiols may also contribute to oxidative stress. Cysteine is more easily oxidized than homocysteine in this process, but can subsequently be reduced by homocysteine. The dynamic equilibrium between reduced and oxidized amino thiols is termed the redox thiol status and elevated levels of oxidized thiols reflect a pro-oxidant environment [3].

Pre-eclampsia, classically defined by pregnancy-induced hypertension and concurrent proteinuria, is a severe complication of pregnancy with a prevalence of 5–7% and significant maternal as well as fetal mortality and morbidity [4]. Although the pathogenesis is not yet elucidated, disturbed trophoblast invasion and subsequent reduced placental perfusion are considered to contribute to a state of oxidative stress in the placenta [5]. At time of disease pre-eclampsia is characterized by maternal oxidative stress that has been proposed to give rise to the dysfunction of vascular endothelium, a hallmark of the disease [4]. It has been suggested that pregnancy may act as a vascular stress test for the development of cardiovascular diseases (CVD) in later life, since women who have previously experienced pre-eclampsia are more susceptible to CVD than those who have not [6], [7]. Although the mechanism remains unknown, both oxidative stress and endothelial activation are common characteristics [8], [9]. In addition, elevated plasma homocysteine is widely accepted to be one of the major risk factors of CVD [10] and has recently been associated with a pro-oxidant state [11].

Oxidative stress in women with pre-eclampsia has been investigated by many others. However, methodologies applied in these studies, such as estimating the levels of individual antioxidants or markers for lipid peroxides, all have the major drawback that only one side of the oxidative stress balance is investigated [12]. In contrast, the use of the free-to-oxidized ratio of thiols will provide a ‘real-time’ reflection of the oxidative stress balance. In an earlier study we have shown that the free-to-oxidized ratios for cysteine and homocysteine can be used as markers for oxidative stress in pre-eclampsia. However, no significant differences were found for glutathione, but there was a large inter-individual variation in free glutathione levels among subjects [13]. The principal aim of this study was to determine whether this oxidative stress persists postpartum in women who experienced pre-eclampsia and to confirm our previous findings in a newly recruited cohort. Therefore, we have assessed the antepartum and postpartum thiol redox status in blood of women with normotensive pregnancies and pregnancies affected by pre-eclampsia.

Section snippets

Materials and methods

The Institutional Medical Ethical Review Committee approved the study protocol and all subjects investigated provided written informed consent. Pre-eclampsia was defined as pregnancy-induced hypertension (diastolic blood pressure >90 mmHg on two or more occasions each more than 4 h apart) with proteinuria (protein/creatinine ratio ≥0.30 g/10 mmol) according to the standard of the International Society for the Study of Hypertension in Pregnancy [14]. Forty-one patients with pre-eclampsia were

Results

Women with pre-eclampsia were significantly younger (P < 0.001), were more often nulliparous (P < 0.001) and produced offspring with a lower birth weight (P < 0.0001). The latter, in part, is related to the lower gestational age as compared with normotensive pregnant controls (P < 0.0001). In Table 2 the results of the free and oxidized whole blood thiol concentrations as well as the free-to-oxidized ratios of cysteine, homocysteine, cysteinylglycine and glutathione are summarized.

In contrast with

Comment

Until now, there is no gold standard for the assessment of oxidative stress. The free-to-oxidized ratio of amino thiols, reflecting the dynamic redox status, could be an alternative measure for oxidative stress. Using a newly recruited cohort of women we confirm that this ratio can be used as an index for oxidative stress during pregnancy as previously reported by us [13]. We now have extended these observations to the postpartum period and found that the antepartum free-to-oxidized ratio of

Acknowledgement

This study was supported by grant no. 28-2801.1 from the Dutch “Praeventiefonds” (Zorg Onderzoek Nederland), The Hague, The Netherlands.

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