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Magee-Womens Research Institute and Department of Obstetrics, Gynecology and Reproductive Sciences (K.Y.L., N.M., R.B.N., J.M.R.), and Graduate School of Public Health, Department of Epidemiology (N.M., R.B.N., J.M.R.), University of Pittsburgh, Pittsburgh, Pennsylvania 15213
Address all correspondence and requests for reprints to: Kristine Y. Lain, M.D., University of Kentucky, 800 Rose Street, Room C365, Lexington, Kentucky 40536-0293. E-mail: kristine.lain{at}uky.edu.
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Abstract |
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Study Design: Plasma was obtained from 63 women throughout pregnancy who delivered at term. Smoking status was determined by urinary cotinine concentrations measured by HPLC. Uric acid, creatinine, free fatty acids, triglycerides, and total cholesterol were measured with diagnostic kits. Data were analyzed by repeated-measures ANOVA.
Results: The smoking groups were not different by delivery gestational age, maternal age, body mass index, or race. Uric acid, cholesterol, and triglyceride concentrations increased during pregnancy (significant for time, P < 0.0001). Mean uric acid and creatinine concentrations were different by smoking status (P < 0.001 and P = 0.046). Nonsmokers had the lowest concentrations of uric acid, and women who quit smoking had the highest concentrations. Uric acid concentrations remained significantly different controlling for serum creatinine
Conclusions: Women have changes in markers of the metabolic syndrome during pregnancy, and uric acid is further influenced by smoking. The difference in uric acid concentrations by smoking status may be secondary to increased production through the xanthine oxidase pathway but is not simply a result of altered glomerular function because the association persists after controlling for creatinine.
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Introduction |
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Hyperuricemia is a feature of the preeclampsia syndrome. In addition, uric acid is associated with metabolic risk factors such as hyperinsulinemia, impaired glucose tolerance (4), hypertension (5), cardiovascular mortality (6), and obesity (7) that increase cardiovascular disease. Hyperuricemia is also associated with hypertriglyceridemia independent of obesity and hyperinsulinemia (8, 9). Desai et al. (10) recently demonstrated an association between serum uric acid and increasing numbers of metabolic risk factors as well as a linear association between uric acid and triglycerides/high-density lipoprotein ratio, which has been demonstrated to be a marker of insulin resistance (11). Finally, hyperuricemia is associated with smoking in nonpregnant white females (12).
Information on the effect of smoking on metabolic markers during pregnancy is limited. The goal of this study was to compare metabolic markers among pregnant women grouped by smoking status. Despite the established negative association of smoking and preeclampsia, we hypothesized that selected metabolic markers (uric acid, creatinine, cholesterol, free fatty acids, and triglycerides) would be increased in smokers consistent with the effect of smoking in nonpregnancy. Thus, we expected that the metabolic markers would not explain the reduced risk of preeclampsia with smoking. To test this hypothesis we measured uric acid, creatinine, cholesterol, free fatty acids, and triglyceride concentrations in a cohort of healthy primigravidas with normal pregnancies who delivered at term and compared concentrations across pregnancy and by smoking status.
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Subjects and Methods |
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Healthy primiparous women who participated in an ongoing longitudinal study at Magee-Womens Hospital (Pittsburgh, PA) were eligible for study. The longitudinal study recruits women at the time of their first routine prenatal visit and collects blood and urine samples at additional times during pregnancy when they are undergoing routine obstetric blood collection in the second and third trimester (multiple marker screening, glucola testing, hemoglobin assessment, time of admission to labor and delivery, and postpartum). The Institutional Review Board at Magee-Womens Hospital approved this study, and informed consent was obtained from each participant at enrollment. Demographic data were obtained by interview and medical record abstraction. Abstracted charts were examined by a jury of clinicians to establish whether women were normal with normal outcomes or had medical or obstetrical complications.
The cohort studied in this project has been previously described (13). Briefly, a cohort of women who were juried as having a normal pregnancy and had self-reported smoking status available with a minimum of four plasma samples and urine samples obtained throughout pregnancy and the postpartum period were selected. Smoking status was confirmed by urinary cotinine, which is the major metabolite of nicotine. Concentrations were determined on urine samples collected at enrollment in the first trimester and at term. A concentration of greater than 100 ng/ml was considered positive and less than 50 ng/ml was considered negative. Sixty-three women were classified as smokers (urinary cotinine concentration positive at both visits), quitters (cotinine positive at first and negative at last visit), or nonsmokers (cotinine negative at both visits). Cotinine measurements assess both the direct intake of nicotine from active smoking as well as indirect intake from passive exposure (14), and urine cotinine has a half-life of approximately 18 h (15). The smoking habits reported by women during pregnancy do not necessarily provide an accurate measure of tobacco exposure and may result in a high rate of misclassification (16, 17). All women delivered at term, had no major medical problems, had normal glucose tolerance by glucola screening and oral glucose tolerance testing at 24–28 wk gestational age, and had no evidence of drug use including aspirin.
Samples
Blood and urine samples were obtained throughout pregnancy with most patients providing their first sample before 16 wk gestation. Sample time points were 14–16 wk, 16–25 wk, 25–34 wk, 34 wk to delivery, post delivery (6–24 h), and 6 wk postpartum. These time points were chosen to reflect the ranges of gestational ages of sample collection without overlap for individual patients and to use a repeated-measures analysis. Plasma was prepared from blood anticoagulated with EDTA. Plasma, serum, and urine samples were divided into aliquots under sterile conditions and stored until assayed at –80 C.
Assays
Uric acid and creatinine samples were determined from plasma samples and run in duplicate. Both assays were adapted for use in microtiter well plates from kits by Sigma Diagnostic, Inc. (St. Louis, MO). Interassay variability was no more than 6 and 8.5%, respectively.
Triglyceride, cholesterol, and free fatty acid concentrations were determined by microplate colorimetric assays adapted from standard Sigma kits. The coefficient of variations between runs has been 6.1, 6.9, and 7.4%.
Cotinine concentrations were determined by HPLC as previously described (16, 18). One-milliliter standards and aliquots of urine were double extracted and reconstituted. The constituents of the specimens were separated using a calibrated C18 column (30 x 0.39 cm) with a column pressure of 20.7 Mpa (
2000 
) and a flow rate of 1 ml/min. Absorbance was measured at 258 nm and at pH 4.05. Peaks were integrated from baseline individually, and 2-phenylimidazole was used as an internal standard. Sensitivity is 20 ng/ml.
Statistical analysis
Demographic variables were compared among the three groups with ANOVA and 
2. Mean metabolic marker concentrations from the four pregnancy samples were analyzed over time and by smoking status controlling for race using repeated-measures ANOVA. In addition, creatinine was included in the uric acid model. Demographic data are presented as mean ± SD, and experimental data are presented as mean ± SEM. Statistical analysis was done using the SAS System for Windows (version 8.1; SAS Institute, Cary, NC) and SPSS for Windows (release 10.0.5) statistical software.
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Results |
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. The mean maternal age of the entire cohort was 22.0 ± 4.6 yr, and the mean body mass index was 24.4 ± 6.0. The mean gestational age at delivery was 40.1 ± 1.3 wk with a mean birthweight of 3357 g. The racial distribution was 33% African-American and 67% Caucasian. Maternal age, body mass index, gestational age at delivery, birthweight, or racial distribution was not different in the three groups.
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by smoking status and timing of the sample. As previously reported, uric acid concentrations increased during pregnancy (significant for time, P < 0.0001) from a mean of 3.2 mg/dl to 4.7 mg/dl before delivery (Fig. 1A), and creatinine concentrations did not change over time (Fig. 1B). When analyzed by smoking status, mean uric acid concentrations were consistently the lowest in women who did not smoke and highest in women who quit. Uric acid concentrations were statistically different by smoking status (P < 0.001) (Fig. 1A) and race (P = 0.03) controlling for serum creatinine. There were no significant interactions among race, smoking, or time in the repeated-measures ANOVA model. African-American women had lower uric acid concentrations than Caucasian women.
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Discussion |
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The effect of smoking to increase cardiovascular risk is postulated to be a result of endothelial dysfunction secondary to oxidative stress generated by xanthine oxidase. Inhibition of xanthine oxidase reverses endothelial dysfunction in smokers (19, 20). Furthermore, tobacco smoke condensate up-regulates xanthine oxidase transcription and activity in pulmonary endothelial cells (21).
Uric acid is a product of the xanthine oxidase reaction, and increased uric acid is also associated with cardiovascular disease. Whether the change in uric acid is only a marker of oxidative stress or whether uric acid has a direct mechanistic role is not clear. Uric acid also has both antioxidant and prooxidant characteristics, scavenging free radicals and generating aminocarbonyl radicals (22). Importantly, data suggest that lowering uric acid with losartan or allopurinol modifies cardiovascular risk (23, 24).
Uric acid is freely filtered by the glomeruli with reabsorption in the proximal tubule. In normal pregnancy, serum uric acid decreases by 25–35% but increases toward normal concentrations near term. These initial changes may be explained by an increase in glomerular filtration rate and filtered load with reduced tubular reabsorption. The increase in late pregnancy may be secondary to increased tubular reabsorption with falling renal clearance (25).
Preeclampsia is usually clinically diagnosed during pregnancy by the presence of hypertension and proteinuria. Uric acid, however, is often elevated, as it is in essential hypertension, and may be an important component of the syndrome. As with cardiovascular disease, the mechanism of hyperuricemia in preeclamspia is not clear. The higher uric acid concentration among smokers in this pregnant cohort is consistent with findings in nonpregnancy; however, the relationship does not help to explain the negative association of smoking with preeclampsia.
We included women who quit smoking because of the interesting finding that these women have even a lower risk of developing preeclampsia than smokers. Perhaps there are separate mechanisms of smoking affecting overall risk at different times of gestation such as an influence on implantation as well as on endothelial function. Women who do not smoke during pregnancy have the highest risk (26). Of interest, our data follow the opposite pattern. Women who quit have the highest concentrations of uric acid, and women who do not smoke have the lowest concentrations. Others have demonstrated an increase in several antioxidants with smoking cessation (27). Perhaps women who quit during pregnancy have an increase in antioxidants that alters the balance of oxidative stress and decreases the risk of endothelial dysfunction. Even if the effect of cessation is only temporary or immediate, given the short course of pregnancy, it may be sufficient.
Our current study is limited by detailed information regarding smoking habits such as the length of time an individual had smoked, age of initiation of smoking, or gestational age of cessation. Also, we were unable to determine whether those women who were categorized as nonsmokers had ever smoked or simply quit before the first urine sample.
This study demonstrates differences in one component of the metabolic syndrome, uric acid, among pregnant women grouped by smoking status. The increased uric acid may be secondary to increased production by the xanthine oxidase pathway but is not simply a result of altered glomerular function because the association persists after controlling for creatinine. We expected an increase in the uric acid in smokers during pregnancy given the increase in smokers who are not pregnant, but this change does not explain the reduced risk of preeclampsia in smokers. However, uric acid does have antioxidant effects that could be beneficial to reduce oxidative stress, posited to be important in the genesis of preeclampsia. It may therefore be important to evaluate the effects of smoking on endothelial function and uric acid in smokers who do develop preeclampsia.
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Acknowledgments |
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Footnotes |
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First Published Online July 26, 2005
Received February 24, 2005.
Accepted July 15, 2005.
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