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Obstetrics & Gynecology 2000;96:507-510
© 2000 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Relation Between Serum Uric Acid and Plasma Adenosine Levels in Twin Pregnancies

SHUNJI SUZUKI, MD, YOSHIO YONEYAMA, MD, RINTARO SAWA, MD and TSUTOMU ARAKI, MD

From the Department of Obstetrics and Gynecology, Nippon Medical School, Tokyo, Japan.

Address reprint requests to: Shunji Suzuki, MD Department of Obstetrics and Gynecology Nippon Medical School 1-1-5 Sendagi, Bunkyo-ku Tokyo 113 Japan


   Abstract
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Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To examine the relationship between plasma adenosine and serum uric acid levels in women with singleton and twin pregnancies.

Methods: We sampled maternal arterial blood and measured serum uric acid and plasma adenosine levels in 22 singleton pregnancies and nine twin pregnancies at 33 to 38 weeks’ gestation.

Results: The average plasma adenosine levels were 0.31 ± 0.12 µmol/L in the singleton pregnancy group and 0.45 ± 0.09 µmol/L in the twin pregnancy group (P < .001). The mean serum uric acid level in women with twin pregnancy was 5.7 ± 0.44 mg/dL which was higher than that in the singleton pregnant women (4.4 ± 0.69 mg/dL, P < .001). Positive correlations were found between serum uric acid and plasma adenosine levels in both the singleton (r2 = 0.54, P < .001) and the twin pregnancy groups (r2 = 0.65, P = .009). Moreover, there was also a significant correlation between serum uric acid and plasma adenosine levels overall (r2 = 0.66, P < .001).

Conclusion: Our results suggest that higher adenosine levels are a contributing source of hyperuricemia in twin pregnancies.

An association between twin pregnancy and elevated maternal serum uric acid levels has been noted.1,2 However, the reasons why twin pregnancy is a source of increased uric acid production have not been determined.

Adenosine is a precursor for the synthesis of adenosine triphosphate, which is a potent vasodilator and a metabolic regulator in the cardiovascular system. In our previous study,3 we found elevated maternal plasma adenosine levels accompanied by low platelet count in preeclampsia. Twin pregnancies are associated with an increased risk of preeclampsia.4 In general, the maternal physiologic change is greater in twin than in singleton pregnancy. A decrease in platelet count associated with latent preeclampsia has been observed during the last month of twin pregnancies, irrespective of the presence or absence of clinical signs of preeclampsia.5 Extracellular adenosine is taken up by cells to form adenine nucleotides or is degraded to other purine metabolites, such as hypoxanthine and uric acid.6,7 An increase in the breakdown of the purine nucleotides has been reported to occur with the increased oxidative stress present in preeclampsia.8

Thus, we hypothesized that maternal plasma adenosine levels in twin pregnancies are higher than those in singleton pregnancies, and the increased levels of serum uric acid in women with twin compared with singleton pregnancy are correlated with increased levels of plasma adenosine. The aim of this study was to examine the relationship between plasma adenosine and serum uric acid levels in women with singleton and twin pregnancies.


   Materials and Methods
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Abstract
 Materials and Methods
Results
 Discussion
 References
 
We sampled maternal arterial blood (5.0 mL) in 22 women with singleton pregnancies and nine women with twin pregnancies at 33 to 38 weeks’ gestation at Nippon Medical School. Patients were recruited consecutively between January 1997 and December 1998. Patients with preeclampsia, chronic hypertension, multiple gestation, diabetes mellitus, renal disease, idiopathic thrombocytopenia, and other systemic illnesses were excluded. Ten patients with twin pregnancies volunteered for this study, and nine of them gave informed consent for the procedures. We also recruited normal pregnant women who were of similar maternal age and parity and who carried fetuses of similar gestational age to serve as a control group. Twenty-four patients volunteered for entry to the study, 22 of whom gave informed consent.

Blood samples were obtained at 7:00 to 8:00 AM after an overnight fast. Maternal blood (2.0 mL) was taken from the left radial artery with a syringe containing an equal volume of ice-cold stop solution (120 µmol/L erythro-9-2(2-hydroxy-3-nonyl)adenine, 20 mmol/L dipyridamole, 60 mmol/L {alpha}, ß-methylene adenosine-5'-diphosphate, and 4.2 mmol/L Na2 ethylenediaminetetra-acetic acid. The blood and stop solution mixture was then immediately centrifuged for 5 minutes at 10,000 g at 4C, and the plasma was removed and frozen at -70C until assayed. Plasma adenosine levels were assayed with a modified high-performance liquid chromatographic method, as described previously.9 Adenosine peaks were identified by retention time, coelution of standards, and enzyme peak shifts. Plasma adenosine was calculated from the measured concentrations after correction for dilution. The detection limit was 10 nmol/L, and the intra-assay and interassay coefficients of variation were less than 4.8% and 6.7%, respectively.

Other blood samples (3.0 mL) were obtained immediately to determine serum uric acid levels by the uricase-peroxidase method (Determiner L UA; Kyouwamedix, Tokyo, Japan) using an autoanalyzer (Hitachi 7350; Hitachi, Tokyo, Japan).

Data are presented as means ± standard deviation (SD). Statistical comparison between the two groups was determined by the unpaired Student t test. Linear regression was performed by the least-squares method. Differences were considered significant at P < .05.


   Results
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Abstract
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The clinical characteristics of patients is given in Table 1Go. There were no measurable differences in maternal age, parity, and gestational age between women with singleton and twin pregnancies.


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  		Table 1. Clinical Characteristics of Patients
 
Maternal arterial plasma adenosine levels averaged 0.31 ± 0.12 µmol/L in the singleton pregnancy group and 0.45 ± 0.09 µmol/L in the twin pregnancy group (P < .001). The mean serum uric acid level in women in the twin pregnancy group was 5.7 ± 0.44 mg/dL, which was significantly higher than that in women in the singleton pregnancy group (4.4 ± 0.69 mg/dL, P < .001).

Positive correlations were found between serum uric acid levels (mg/dL) and plasma adenosine levels (µmol/L) in both the singleton and twin pregnancy groups (line A (singleton pregnancy), serum uric acid = 3.2 + 4.1x adenosine, r2 = .54, P < .001; line B (twin pregnancy), serum uric acid = 3.9 + 4.1x adenosine, r2 = .65, P = .009) as shown in Figure 1Go. Furthermore, there was also a significant correlation between serum uric acid and plasma adenosine levels on the whole (line C, serum uric acid = 3.0 + 5.3x adenosine, r2 = .66, P < .001).



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  		Figure 1. Correlation of serum uric acid and plasma adenosine level in women with singleton pregnancies (open circles, n = 22) and twin pregnancies (closed circles, n = 9).

 

   Discussion
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Abstract
 Materials and Methods
 Results
 Discussion
References
 
In this study, mean serum uric acid levels and plasma adenosine levels were significantly higher in women with twin compared with singleton pregnancies. Furthermore, there were positive correlations between serum uric acid levels and plasma adenosine levels in both twin and singleton pregnancies. These results are consistent with our hypothesis and suggest that higher adenosine levels are a possible contributing source of hyperuricemia in twin pregnancies.

In our previous study,3 plasma adenosine in women with preeclampsia was found to be related to the presence of a protodiastolic notch in the uterine artery Doppler waveforms, indicating uteroplacental circulatory insufficiency, although adenosine acts as a vasodilator. Endothelial cell damage is caused by trophoblast deportation in severe preeclampsia, which can interfere with systemic cardiovascular function.10 Thus, increased plasma adenosine in preeclampsia was postulated to be a physiologic feedback inhibitor protecting maternal circulation. Preeclampsia has also been reported to be characterized by shallow implantation, which produces a relatively hypoxic maternal-fetal interface, and by increased turnover of trophoblast tissue, which can result in higher oxypurine concentrations.8 In addition, tubular defect of uric acid excretion caused by decreased maternal glomerular filtration has also been proposed to contribute to hyperuricemia in preeclampsia.11 Thus, increased adenosine might be a contributing source of preeclamptic hyperuricemia.

In twin pregnancies, on the other hand, the increased levels of maternal serum uric acid compared with those in singleton pregnancy could be associated with the amount of uric acid produced by two fetuses, which might exceed that produced by a single fetus.1,2 The reason for this is because uric acid enters the maternal circulation to be excreted. In an earlier study with guinea-pig placenta,12 however, transplacental transfer after administration of adenosine into maternal or fetal circulation was only 5–20% of the dose. Thus, if increased adenosine is a major source of uric acid in twin pregnancies, our results might be contrary to the previous hypothesis.1,2 Otherwise, the increased plasma adenosine might be a positive feedback inhibitor protecting maternal circulation in twin pregnancies complicated by hyperuricemia.

In twin pregnancies, pathophysiologic changes such as cardiac output and vascular tone are greater than those in singleton pregnancies13 because the increase in maternal blood volume in twin pregnancies is larger than in singleton pregnancies. In a study using Doppler ultrasound,14 for example, the resistance to flow in the uterine artery in twin pregnancies was shown to be lower than in singleton pregnancies. In addition, a decrease in platelet count has been observed during the last month of twin pregnancies, irrespective of the presence or absence of clinical signs of preeclampsia.5 In our earlier study,3 we found elevated maternal plasma adenosine levels accompanied by the low platelet count in preeclampsia. These conditions also could be associated with the high incidence of preeclampsia in twin pregnancies during the third trimester.13,15 Under these conditions, plasma adenosine can be released without hypoxia in humans,16,17 and it can suppress maternal metabolic activity through adenosine receptors; attenuate release of catecholamine, ß-adrenergic receptor-mediated myocardial hypercontraction, and Ca+ overload through A1 receptors; and increase coronary blood flow and inhibit platelet and leukocyte activation through A2 receptors.18–20 Uric acid is considered a metabolically inert endproduct of purine metabolism that preserves the ability of the endothelium to mediate vascular dilation.21 Therefore, our results suggest that increased adenosine is a contributing source of hyperuricemia in twin pregnancies, although further studies are needed to determine the mechanism.


   Footnotes
 
PII S0029-7844(00)00964-9

Received February 28, 2000. Received in revised form April 24, 2000. Accepted May 3, 2000.


   References
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Abstract
 Materials and Methods
 Results
 Discussion
 References
 
1. Fischer RL, Bilanculli KW, Hediger ML, Scholl TO. Maternal serum uric acid levels in twin gestations. Obstet Gynecol 1995;85:60–4.[Abstract]

2. Koike T, Minakami H, Takayama T, Ogawa S, Kuwata T, Sato I. Elevation of the serum uric acid level preceding the clinical manifestation of preeclampsia in twin pregnancies. Gynecol Obstet Invest 1997;44:97–101.[Medline]

3. Suzuki S, Yoneyama Y, Sawa R, Takeuchi T, Power GG, Araki T. Maternal plasma adenosine levels in pregnancies complicated by toxemia. Trophoblast Res 1999;13:407–14.

4. Minakami H, Watanabe T, Izumi A, Matsubara S, Koike T, Sayama M, et al. Association of a decrease in antithrombin III activity with a perinatal elevation in aspartate aminotransferase in women with twin pregnancies: Relevance to the HELLP syndrome. J Hepatol 1999;30:603–11.[Medline]

5. Long PA, Oats JN. Preeclampsia in twin pregnancy—Severity and pathogenesis. Aust N Z J Obstet Gynaecol 1987;27:1–5.[Medline]

6. Winn HR, Rubio R, Berne RM. Brain adenosine production in the rat during 60 seconds of ischemia. Circ Res 1979;45:486–92.[Abstract]

7. Becker BF. Towards the physiological function of uric acid. Free Radic Biol Med 1993;14:615–31.[Medline]

8. Many A, Hubel CA, Roberts JM. Hyperuricemia and xanthine oxidase in preeclampsia, revisited. Am J Obstet Gynecol 1996;174: 288–91.[Medline]

9. Yoneyama Y, Power GG. Plasma adenosine and cardiovascular responses to dipyridamole in fetal sheep. J Dev Physiol 1992;18: 203–9.[Medline]

10. Tykarski A, Gluszek J, Banaszak F. Value of oxypurines and uric acid in plasma, renal excretion oxypurines, and uric acid as well as plasma adenosine deaminase and AMP deaminase activity in patients with essential hypertension. Pol Arch Med Wewn 1993; 89:223–9.[Medline]

11. Seitchik J, Szutka A, Alper C. Further studies on the metabolism of N15-labeled uric acid in normal and toxemic pregnant women. Am J Obstet Gynecol 1958;76:1151–5.[Medline]

12. Wheeler CPD, Yudilevich DL. Transport and metabolism of adenosine in the perfused guinea-pig placenta. J Physiol 1988;405:511–26.[Abstract/Free Full Text]

13. Coonrod DV, Hickok DE, Zhu K, Eastering TR, Darling JR. Risk factors for preeclampsia in twin pregnancies: A population-based cohort study. Obstet Gynecol 1995;85:645–50.[Abstract]

14. Chen Q, Izumi A, Minakami H, Sato I. Comparative changes in uterine artery blood flow waveforms in singleton and twin pregnancies. Gynecol Obstet Invest 1998;45:165–9.[Medline]

15. Yoneyama Y, Sawa R, Suzuki S, Shin S, Power GG, Araki T. The relationship between uterine artery Doppler velocimetry and umbilical venous adenosine levels in pregnancies complicated by preeclampsia. Am J Obstet Gynecol 1996;174:267–71.[Medline]

16. Agarwal KC. Modulation of vasopressin actions on human platelets by plasma adenosine and theophylline: Gene differences. J Cardiovasc Pharmacol 1993;21:1012–8.[Medline]

17. Bardenheuer H, Schrader J. Supply-to-demand ratio for oxygen determines formation of adenosine by the heart. Am J Physiol 1986;250:H173–80.

18. Lagerkranser N, Sollevi A, Irestedt L, Tidgren B, Andreen M. Renin release during controlled hypotension with sodium nitroprusside, nitroglycerin, and adenosine: A comparative study in dogs. Acta Anaesthesiol Scand 1985;29:45–9.[Medline]

19. Bouma MG, Wildenberg FAJM, Buurman WA. Adenosine inhibits cytokine release and expression adhesion molecules by activated human endothelial cells. Am J Physiol 1996;270:C522–9.

20. Becker BF. Towards the physiological function of uric acid. Free Radic Biol Med 1993;14:615–31.




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