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Oxidative stress, diet, and the etiology of preeclampsia^1,2,3

¹ From the Department of Obstetrics and Gynecology (TOS and XC) and the Department of Surgery (ML, MS, and TPS), University of Medicine and Dentistry of New Jersey–School of Osteopathic Medicine, Stratford, NJ

² Supported by grant HD38329 from the National Institutes of Health.

³ Reprints not available. Address correspondence to TO Scholl, UMDNJ–SOM, Department of Obstetrics and Gynecology, Science Center, Suite 390, Stratford, NJ 08104. E-mail: scholl{at}umdnj.edu

	ABSTRACT

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Background: A current theory holds that oxidative stress, ie, an imbalance between maternal prooxidants and antioxidants, is a component of preeclampsia. It is uncertain whether such an imbalance occurs before clinical recognition of the syndrome or whether it is related to diet.

Objective: We measured urinary excretion of the isoprostane 8-iso-prostaglandin F₂, which is an indicator of oxidative damage to lipids, and the total antioxidant power, which is a global measure of antioxidant status, at the entry to prenatal care. We also examined the relation of these indexes to diet during pregnancy.

Design: A cohort of 307 gravidae from Camden, NJ, was studied from entry to prenatal care (at 15.0 ± 0.49 wk gestation). Measures of the maternal diet were obtained by 24-h recall.

Results: Risk of preeclampsia was increased 5-fold with higher urinary isoprostane excretion and decreased 3-fold with higher total antioxidant power. Over the course of pregnancy, there were significant trends for an association of higher isoprostane excretion with increased consumption of energy-adjusted fat, polyunsaturated fat, and polyunsaturated fatty acids (n–3, n–6, and linoleic and linolenic fatty acids), whereas total antioxidant power was not related to diet.

Conclusions: Increased urinary excretion of isoprostane and decreased antioxidant production is an imbalance that is consistent with oxidative stress, and it precedes clinical recognition of preeclampsia. The maternal diet is an underlying factor that provides an environment for free radical generation.

Key Words: Preeclampsia • diet • isoprostanes • total antioxidant capacity • total antioxidant power • oxidative stress • antioxidants • maternal nutrition • pregnancy

	INTRODUCTION

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Many pathophysiologic factors (eg, inflammation, cytokine production, dyslipidemia, elevated homocysteine, oxidative stress, reduced calcium intake and excretion, and an imbalance between thromboxane and prostacyclin) have been implicated in the etiology of preeclampsia (1-5). During uncomplicated pregnancy, there is an increased production of prooxidants that is balanced by the synthesis of antioxidants (6, 7). A current theory on the etiology of preeclampsia, an important cause of preterm delivery, fetal growth restriction, and maternal and infant mortality, holds that, in preeclampsia, there is an imbalance between prooxidant production and antioxidant defenses (8-10).

During pregnancy, the placenta is a major source of prooxidant and endogenous antioxidant synthesis (11). Chronic excess generation of free radicals will, in theory, deplete antioxidant pools and result in oxidative damage to lipids, protein, and DNA. Because most women with preeclampsia are identified after the syndrome has developed, it is uncertain whether an imbalance between prooxidants and antioxidants (oxidative stress) precedes preeclampsia or occurs after preeclampsia has developed.

Likewise, maternal factors may contribute to an imbalance between prooxidant and antioxidant forces that provides an environment for free radical generation (8). If oxidative stress is indeed a risk factor, then it is likely that the maternal diet—specifically, the intakes of antioxidants and polyunsaturated fats—is implicated (12). Therefore, we examined the influence of isoprostane excretion, an indicator of oxidative damage to lipids, and total antioxidant power or capacity, a global measure of antioxidant status—both measured at entry to prenatal care—on the risk of preeclampsia. We also examined their relation to the maternal diet during pregnancy.

	SUBJECTS AND METHODS

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Subjects
Participants in the Camden Study (13, 14) included pregnant young women (18 y old) and pregnant women in their early 20s who were enrolling for prenatal care at clinics in Camden, NJ. Gravidae with serious nonobstetric problems (eg, lupus, chronic hypertension, type 1 or 2 diabetes mellitus, seizure disorders, malignancies, or drug or alcohol abuse) were not eligible. Subjects included in this analysis enrolled in the oxidative stress protocol of the Camden Study between January 1999 and June 2002 and subsequently delivered a singleton infant.

Written informed consent was obtained from all participants. The Institutional Review Board of the University of Medicine and Dentistry of New Jersey–School of Osteopathic Medicine approved the study.

Methods
Pregravid weight was recalled, and height was measured at entry to prenatal care. At entry, participants were interviewed to obtain socioeconomic, demographic, lifestyle, and dietary (24-h recall) data; the information was updated at 20 and 28 wk of gestation. At the same visits, blood was drawn by venipuncture, and a urine specimen was obtained. Samples were aliquoted and stored at –70 °C until they were assayed.

The recalls of the previous day's diet were processed with databases from the Campbell Institute of Research and Technology (Campbell Soup Company) in Camden. The three 24-h recalls were averaged to obtain a mean intake over the course of the pregnancy of nutrients including fat, calcium, folate, and dietary antioxidants (vitamins A, C, and E and ß-carotene). In Camden, the reliability of three 24-h recalls during the course of pregnancy is comparable to the reliability of those obtained in other published studies (15, 16). This reliability is based on statistical measures (16) indicating adequate stability [ coefficients (ie, Cronbach's ) for energy and nutrients: 0.5] and moderate variability [variance ratios (intraindividual:interindividual variance): 1.05–1.7] in nutrient intake across recalls (17; TO Scholl, unpublished observations, 1985–2004). When possible, nutrient intakes from Camden were confirmed with biomarkers (eg, folate or glycated hemoglobin) and, for energy intake, with gestational weight gain (13, 17-20).

The Campbell database used to process the recalls contains descriptions of and codes for 1875 foods consumed by women in Camden, along with information on serving size and weight in grams. It generated data for >70 nutrients and was updated from the United States Department of Agriculture's most current data set, the Nutrient Database for Standard Reference (Release 13; 2000; see http://www.nal.usda.gov/fnic/foodcomp) and the Continuing Survey of Food Intakes by Individuals (1994–1996; see http://www.barc.usda.gov/bhnrc/foodsurvey/products_9496.html), as well as from the scientific literature.

Information on past and current pregnancy outcomes, complications, and infant abnormalities was abstracted from the prenatal record, the delivery record, delivery logbooks, and the infant's chart. The time of gestation was based on the woman's recall of her last menstrual period as confirmed or modified by ultrasound. The diagnosis of preeclampsia was based on gestational hypertension (defined as systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg in a previously normotensive woman) occurring after 20 wk gestation and accompanied by new-onset proteinuria (1+ by dipstick) (8).

Urinary excretion of isoprostanes is a marker for oxidative damage to lipids (21, 22). An enzyme-linked immunosorbent assay (No. EA 85; Oxford Biomedical Research, Oxford, MI) was developed and validated for the assay for one of the isoprostanes, 8-iso-prostaglandin F₂ (23-25), and used to measure urinary isoprostane excretion in this study. The enzyme-linked immunosorbent assays were done in duplicate on 2 different plates; variation was further constrained by the exclusive use of plates from the same batch. Creatinine was measured by the picric acid method by using a kit (Sigma Chemical Co, St Louis, MO) and used to normalize urinary isoprostane excretion.

The measurement of total antioxidant power in plasma provides information on global antioxidant status that may include antioxidants that are not yet recognized or easily measured individually (26, 27). We used 2 batches of the Total Antioxidant Power Colorimetric Microplate Assay kit (No. TA 01; Oxford Biomedical Research) to assay total antioxidant power. The method measures colorimetrically the amount of Cu + derived from Cu ++ by the action of all antioxidant moieties in the sample. The Cu+ that is produced by the reaction complexes with bathocuptone to form a stable compound that is proportional to the concentration of all antioxidants in the sample. Batches of total antioxidant power were normalized against each other. Variation within and between assays was <10% for both analytes.

Statistical analysis
Linear regressions were computed to adjust urinary isoprostane excretion and total antioxidant power for week of gestation at entry (15). Residuals from these regressions were categorized into tertiles on the basis of data for the entire cohort; we added the overall mean to the residuals to make the data more interpretable. The chi-square test or analysis of variance was used to assess separately the relation between the tertiles, maternal background characteristics, and the maternal diet. A t test was used to compare entry concentrations of isoprostane (log₁₀) and of total antioxidant power (log₁₀) in gravidae who did and did not develop preeclampsia; the antilogs are reported.

Potential confounding variables traditionally associated with preeclampsia [ie, nulliparity, maternal age, pregravid body mass index (in kg/m²), and ethnicity] were included in multivariable models. The maternal diet was adjusted for energy (15). Models for preeclampsia used tertiles of isoprostane or total antioxidant power; separate and joint models were fitted by using multiple logistic regression. Confounding was assessed by comparing crude and adjusted odds ratios. Adjusted odds ratios and their 95% CIs were computed from the logistic regression coefficients and their corresponding covariance matrices; P for trend was computed by using the same model (28, 29). The interaction between the isoprostanes and total antioxidant power was also examined and found not to be significant (P > 0.5). Likewise, there were no significant interactions (P = 0.35–0.92) between tertiles of isoprostane, tertiles of total antioxidant power, and any of the nutrients of interest. All computations were done with SAS software (version 8.0; SAS Corp, Cary, NC).

	RESULTS

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Background characteristics of the mother were examined for their association with urinary isoprostane excretion and total antioxidant power as potential confounding variables (Table 1 and Table 2). Univariate analysis suggested that gravidae in the lowest isoprostane tertile tended to have a lower mean pregravid body mass index than did the others (P = 0.10) and that ethnic differences were present (P = 0.11). Total antioxidant power also tended to be associated with maternal body mass index (P = 0.06) and ethnicity (P = 0.098). Gestation at entry to the study (15.0 ± 0.49 wk gestation) did not vary across tertiles of isoprostane or of total antioxidant power. Concentrations of isoprostane and total antioxidant power were not correlated (r = 0.02, P = 0.68).

Table 3

Table 4

Table 3

Table 3

Table 4

Table 3

The maternal diet was significantly related to isoprostane excretion (Table 5). After adjustment for energy, there were significant relations between higher intakes of total fat and polyunsaturated fat and increased isoprostane excretion. The intake of polyunsaturated fatty acids (energy-adjusted), including linolenic, linoleic, n–3, and n–6 fatty acids, also was significantly associated with isoprostane excretion over the course of pregnancy. There was no significant relation between the maternal diet and total antioxidant power (Table 5).

	DISCUSSION

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The isoprostanes are a specific marker for oxidative damage to lipids from endogenous lipid peroxidation. They are prostaglandin-like compounds derived by autooxidation of the arachidonic acid moiety (22, 31-33). With few exceptions, the research implicating isoprostanes in the etiology of preeclampsia took place after preeclampsia became clinically overt. Barden et al (33, 34), for example, found higher concentrations of free isoprostanes in the plasma of gravidae (n 20) with established preeclampsia than in that of control subjects; urinary isoprostane excretion was decreased in the cases, and total isoprostane showed no difference. In the postpartum period, gravidae who had been preeclamptic had significantly higher isoprostane concentrations in both plasma and urine (33). Other investigators have (35-37) and have not (38, 39) reported similar findings. As far as we are aware, only 2 prospective studies have examined isoprostane concentrations before clinical recognition of preeclampsia. Regan et al (39) studied urinary isoprostane excretion in 29 cases and control subjects. Isoprostane excretion was 7–10% higher in the cases in the weeks preceding diagnosis. As was previously seen in studies of overt preeclampsia, urinary isoprostane excretion fell and was 19% lower in the cases after preeclampsia was recognized. Whereas these differences were not significant, the sample size was small in this study and in the studies described above. Chappell et al (40, 41) conducted a clinical trial of supplementation with vitamins C and E in gravidae at high risk of preeclampsia. They compared baseline concentrations of isoprostane in high-risk women with those in low-risk control subjects before they were randomly assigned to receive antioxidant supplements or placebo. At baseline, isoprostane concentrations in the high-risk group were significantly (40%) higher than those in the low-risk group. During the remainder of gestation, isoprostane concentrations remained elevated in high-risk women on placebo but fell to those in the low-risk women in those assigned to antioxidant supplements (40).

In preeclampsia, antioxidant activity is generally but not uniformly low (40, 42, 43). When Chappell et al (41) compared antioxidant concentrations in high- and low-risk women, baseline concentrations of specific antioxidants were lower (vitamin C), higher (uric acid), or the same (-tocopherol). This suggests that the measurement of a single antioxidant in a particular biological fluid or tissue at a given point in pregnancy may not adequately reflect the balance between prooxidant and antioxidant forces.

During uncomplicated pregnancy, an increase in total antioxidant power accompanies a rise in lipid peroxides (7). A recent study showed alterations in plasma oxidants and antioxidants with overt preeclampsia, including total antioxidant power, which was reduced, and the concentration of malondialdehyde, which was increased (43). High concentrations of prooxidants and low total antioxidant power were shown in placental and decidual tissue from women whose preeclampsia was complicated by the hemolysis, elevated liver enzymes, and low platelets syndrome, but not in the tissue from other gravidae with preeclampsia (44). A limitation of the current study is that we do not know which of the antioxidants measured collectively was associated with the reduction in risk that we observed.

The maternal diet has long been implicated in the etiology of preeclampsia (45, 46). Our observations were again limited by reduced statistical power to detect significant differences when all the tertiles were compared. However, we found higher isoprostanes in association with increased intakes of fat, polyunsaturated fat, and specific polyunsaturated fatty acids (ie, linolenic, linoleic, n–3, and n–6). The relation between polyunsaturated fat intake and isoprostane excretion has high biological plausibility. Oxidative damage to lipids increases the formation of lipid peroxides. Because the substrate for lipid peroxidation is polyunsaturated fatty acids, it seems reasonable that diets high in polyunsaturates could contribute to the oxidative stress associated with preeclampsia (12, 47). However, we did not directly assay circulating concentrations of these substrates.

More than 5 decades ago, Burke (46) noted that a deficient diet was related to a greater risk of preeclampsia. More than 2 decades ago, Chung et al (48) observed that low-income African American women from Alabama with toxemia had increased intake of total fat as well as increased intakes of specific polyunsaturated, monounsaturated, and saturated fatty acids. Clausen et al (49) confirmed and extended this finding in a prospective study in 3133 Norwegian women. They reported a significant trend for preeclampsia to increase with increasing energy intake and with increasing (energy-adjusted) intakes of polyunsaturated fat, including n–3 and n–6 fatty acids. However, dietary data from a clinical trial that used a single 24-h recall suggested no difference in any energy-adjusted nutrient between women with preeclampsia and control subjects (50).

Perhaps as a result of limited statistical power, we did not find significant associations between antioxidants from diet and the isoprostanes. Vitamin C is the first antioxidant exhausted by oxidative stress (51). Folate may protect against oxidative stress directly or by reducing the production of homocysteine (52, 53). Likewise, we found little relation between diet and total antioxidant power. Prior research suggested that excessive intakes of polyunsaturated fat reduce antioxidant power (54) and thus increase oxidative stress.

Our research thus supports the hypothesis that high excretion of isoprostane along with low antioxidant production, an imbalance consistent with oxidative stress, precedes the recognition of preeclampsia. In some disorders, oxidative stress follows an acute event or injury (55). Whereas we do not know the cause (or causes) of preeclampsia, reduced placental perfusion is considered to be the fundamental source (8, 9). It is thought that, in response to poor placental perfusion, substances are released from the placenta that access the maternal circulation and that, in the right environment, initiate a generalized endothelial dysfunction that gives rise to maternal hypertension and proteinuria (8-10).

The isoprostanes are biologically active, and they function as vasoconstrictors in the placenta as well as in maternal organs to stimulate the production of endothelin-1 from endothelial cells and to trigger platelet activation (32). Several researchers hypothesized that, in women at risk of preeclampsia, the placenta produced an excess of reactive oxygen species (8-10). Thus, it is possible that an imbalance between the isoprostanes and other prooxidants with antioxidant forces may be part of the mechanism that underlies the development of preeclampsia.

	ACKNOWLEDGMENTS

 
We thank the staffs of the Osborn Family Health Center, the St John the Baptist Prenatal Clinic, and Our Lady of Lourdes Hospital in Camden, NJ, for facilitating this research.

TOS and TPS designed the research and obtained the funding; TOS supervised collection of the data. XC ran the database and assisted with the analysis. TPS, ML, and MS developed and performed the assays. All of the authors participated in writing the manuscript. None of the authors had any personal or financial conflict of interest.

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TOP ABSTRACT INTRODUCTION SUBJECTS AND METHODS RESULTS DISCUSSION REFERENCES

 

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