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Obstetrics & Gynecology 2001;97:62-65
© 2001 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Etiology of Third-Trimester Maternal Hyperuricemia in Nonpreeclamptic Twin Gestations

RICHARD L. FISCHER, MD, LAWRENCE S. WEISBERG, MD and MARY L. HEDIGER, PhD

From the Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, and the Division of Nephrology, Department of Medicine, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School at Camden, Cooper Hospital/University Medical Center, Camden, New Jersey.

Address reprint requests to: Richard L. Fischer, MD Division of Maternal-Fetal Medicine Department of Obstetrics and Gynecology Cooper Hospital/University Medical Center One Cooper Plaza, Room 623, Dorrance Building Camden, NJ 08103 E-mail: fischerl{at}umdnj.edu


   Abstract
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Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To determine whether the higher maternal serum uric acid levels observed in the third trimester of nonpreeclamptic twin gestations result from increased uric acid production or decreased renal excretion.

Methods: Thirty-four nonpreeclamptic subjects with twin gestations were analyzed, along with 34 singleton controls matched for age, ethnicity, prepregnancy weight, height, and gestational age. For each subject, a serum sample and 24-hour urine specimen were obtained in the third trimester. Serum and urine uric acid and creatinine levels were determined, as well as total 24-hour urine uric acid, uric acid clearance, creatinine clearance, fractional uric acid clearance, and net tubular uric acid absorption.

Results: The twin gestation group had significantly higher maternal serum uric acid levels (5.2 ± 1.2 compared with 4.0 ± 1.0 mg/dL, P < .001) and maternal serum creatinine levels (0.7 ± 0.2 compared with 0.5 ± 0.1 mg/dL, P < .001) than the paired singleton group. This was associated with greater 24-hour urine uric acid excretion (688.7 ± 167.0 compared with 597.7 ± 164.2 mg, P = .04) and 24-hour urine creatinine excretion (1268.4 ± 249.9 compared with 1161.2 ± 277.1 mg, P = .03) in the twin group. No differences were seen between the groups in uric acid clearance, creatinine clearance, fractional uric acid clearance, filtered uric acid load, or net uric acid absorption.

Conclusion: The higher maternal serum uric acid levels observed in the third trimester of nonpreeclamptic twin gestations result in part from increased uric acid production, as reflected in the increased daily uric acid excretion.

Uric acid is the primary end product of purine metabolism. During pregnancy, maternal serum uric acid levels initially fall, with a subsequent rise to prepregnancy levels near term.1 The third-trimester rise in uric acid levels may be related to an increase in fetal uric acid production or a decrease in uric acid clearance.2 Urinary excretion of uric acid is a complex process, with complete filtration at the glomerulus, proximal tubule reabsorption, distal tubule secretion, and postsecretion reabsorption.3 Elevated serum uric acid levels have been associated with preeclampsia4,5 and adverse perinatal outcome,6–9 although others have challenged their predictive value.10–12 The mechanism for hyperuricemia with preeclampsia has not yet been elucidated, but has been postulated to result from decreased glomerular filtration or increased net tubular reabsorption, as well as increased fetal production as a result of fetal hypoxia.3,13

Women with twin gestations are at increased risk for preeclampsia, with a reported incidence of 17.9–37%.14–16 In a previous study, we demonstrated that third-trimester maternal serum uric acid levels were higher in women with twin gestations compared with singleton gestations, in both the nonpreeclamptic and preeclamptic subgroups.17 The origin of this difference, however, was not evaluated. The purpose of this prospective study was to compare women with twin and singleton gestations with respect to both serum and urine uric acid and creatinine levels in the third trimester to determine whether the previously observed difference in maternal serum uric acid levels was the result of increased production, diminished renal excretion, or a combination of these two factors. We hypothesized that the additional fetus of a twin gestation would result in greater uric acid production, as measured by increased 24-hour urine uric acid excretion.


   Materials and Methods
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Abstract
 Materials and Methods
Results
 Discussion
 References
 
Between January 1995 and October 1996, women with twin gestations were identified from the Antepartum Diagnostic Centers at Cooper Hospital/University Medical Center and Memorial Hospital of Burlington County, as well as from our free-standing ultrasound unit, all of which are located in southern New Jersey. Subjects were considered for inclusion if they had a well-dated twin gestation. Exclusion criteria consisted of twin-twin transfusion syndrome, chronic hypertension, pregnancy-induced hypertension or preeclampsia occurring within 1 week of urine collection, underlying renal disease (defined as a baseline serum creatinine greater than 1.0 mg/dL), diuretic use, or the use of parenteral tocolysis at the time of collection. Women with gestational diabetes or pregestational diabetes without renal disease were not excluded. The study was approved by the Institutional Review Boards of Cooper Hospital/University Medical Center and Memorial Hospital of Burlington County. Patients gave informed written consent before enrollment.

For those subjects agreeing to participate, 24-hour urine samples were collected at home, usually after 34 weeks’ gestation. Boric acid tablets were initially recommended by our laboratory as a preservative to prevent bacterial contamination. After initiation of the study, the laboratory changed their recommendation from boric acid to refrigeration. For the sake of consistency, we continued to use the boric acid tablets with unrefrigerated urine. Within 3 hours of completion of the 24-hour urine collection, each subject returned the urine sample, a weight was obtained, and blood was drawn for serum uric acid and creatinine levels.

For each subject with a twin gestation, a gravida with a singleton gestation was recruited to act as a control after the same exclusion criteria were applied. The singleton subjects were matched to their multiplegestation counterparts for age (± 5 years), ethnicity, prepregnancy weight (± 20 lb), height (± 2 inches), and gestational age at the time of collection (± 2 weeks). No attempt was made to control for dietary intake or maternal positioning during collection.

All urine and serum samples were analyzed by the laboratory at Cooper Hospital/University Medical Center. For each 24-hour urine sample, the urine volume was determined visually in a graduated cylinder. A 5–10 mL aliquot of urine was analyzed for uric acid levels by a colorimetric uricase assay, and urinary creatinine levels were determined by a modification of the Jaffé reaction, both performed on a Boehringer Mannheim/Hitachi 911 analyzer (Roche Diagnostics, Indianapolis, IN). The serum sample was centrifuged at 2800 rpm for 10 minutes, and the supernatant was analyzed for uric acid and creatinine levels in a similar fashion on the analyzer. From the serum and urine levels, the following values were calculated: 24-hour urine uric acid excretion, 24-hour urine creatinine excretion, uric acid clearance, creatinine clearance, fractional uric acid clearance (uric acid clearance divided by creatinine clearance), filtered uric acid load (serum uric acid multiplied by creatinine clearance), and net tubular uric acid absorption (filtered uric acid load minus 24-hour uric acid excretion).

Statistical analysis was performed with SAS (Statistical Analysis System, Cary, NC) and SPSS 8.0 (SPSS Inc., Chicago, IL) including the McNemar test for paired proportional data and the paired t test for continuous data. All statistical tests were two-tailed, with significance defined as P < .05.


   Results
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Abstract
 Materials and Methods
 Results
Discussion
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A total of 35 women with twin gestations were initially recruited into the study, along with 35 singleton controls. One subject with twins, along with her singleton control, was subsequently excluded because preeclampsia developed within a week of serum and urine collection. The characteristics of the remaining 34 pairs are shown in Table 1Go. The two groups were well matched except for a significantly shorter interval from serum and urine collection to delivery in the twin-gestation group because of an earlier gestational age at delivery. The subjects in the twin-gestation group were also slightly older and heavier at the time of collection. Two subjects in the twin-gestation group, as well as three in the singleton group, developed preeclampsia more than 1 week after their urine collections, with two in each group requiring intrapartum or postpartum magnesium sulfate.


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  		Table 1. Subject Characteristics
 
The results of the analyses of serum and urine are shown in Table 2Go. The two groups were equivalent with regard to adequacy of 24-hour urine collections based on total creatinine to prepregnant weight ratios. There was a significantly higher uric acid level in subjects with twin gestations compared with singletons (5.2 ± 1.2 compared with 4.0 ± 1.0 mg/dL, P < .001). This was associated with an increase in 24-hour urine uric acid excretion in the twin group (688.7 ± 167.0 compared with 597.7 ± 164.2 mg, P = .04). Maternal serum creatinine was also significantly elevated in the twin group (0.7 ± 0.2 compared with 0.5 ± 0.1 mg/dL, P = .001), associated with a higher 24-hour urine creatinine excretion (1268.4 ± 249.9 compared with 1161.2 ± 277.1 mg, P = .03). No differences were seen in uric acid clearance, creatinine clearance, fractional uric acid clearance, filtered uric acid load, or net tubular uric acid absorption between the groups.


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  		Table 2. Serum and Urine Analysis
 

   Discussion
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Abstract
 Materials and Methods
 Results
 Discussion
References
 
As seen in our previous study,17 nonpreeclamptic women with twin gestations in the third trimester had significantly higher serum uric acid levels than those with singletons. This was associated with a significantly higher 24-hour uric acid excretion. Because the sum of daily exogenous intake plus endogenous production must equal the daily uric acid excretion to maintain steady-state levels, this implies that uric acid production was increased in twin gestations, either from the contribution of the additional fetus or from increased cellular turnover in the placenta.13

The finding of a significantly higher maternal serum creatinine level in twin gestations was unexpected because the physiologic increase in glomerular filtration rate exhibited in a singleton pregnancy has traditionally been expected to be even greater with twins.18 Our study demonstrated that the elevated maternal serum creatinine level in twins was associated with increased urinary excretion of creatinine, which, like uric acid, implies increased creatinine production. Because endogenous creatinine production is a function of total muscle mass, this suggests that the additional fetus of the twin gestation was the source of the increased creatinine production.

The maternal serum uric acid level was 30.0% higher in the twin group, whereas the 24-hour urinary excretion of uric acid was only 15.2% higher. This implies that there may be another source for the difference in maternal serum levels, namely altered renal handling. It is possible that more subjects in the twin group might have had preclinical preeclampsia that never became apparent because of earlier delivery. It is known that women with twin gestations are at increased risk for preeclampsia14–16 and that uric acid rises with the development of preeclampsia because of a reduction in the glomerular filtration rate or an increase in net uric acid tubular reabsorption.3,13 We attempted to control for this by initially excluding any pair that developed preeclampsia within 1 week of collection, because Fay et al19 found a significant rise in serum uric acid levels in preeclamptic women only in the week before delivery. In contrast, others have observed elevated serum uric acid levels earlier in pregnancy, both in singleton9 and twin gestations.20 If we excluded the additional five pairs in whom one or both subjects developed preeclampsia after 1 week of collection, our findings remained unchanged. Additionally, if preclinical preeclampsia was a factor in causing altered renal handling, we were unable to demonstrate any statistically significant differences in glomerular or tubular function. Although the twin group had a 17.4% reduction in glomerular filtration rate as estimated by the creatinine clearance, this difference was not statistically significant. Similarly, net tubular uric acid reabsorption was not significantly different between the twin and singleton groups. Although this may indicate that no difference truly exists, the lack of significance may represent a type II error. The relatively small sample size, in addition to the reduced degrees of freedom required with paired t tests, contributed to a power of only 16% to detect a 15% difference in creatinine clearance.

One limitation of our study was our inability to assess the true adequacy of the outpatient 24-hour urine collections; patients have historically been known to both under- and overcollect. The adequacy of a 24-hour urine collection is usually based on total 24-hour urine creatinine per kilogram of body weight, with a normal value of 20.6 ± 2.3 mg/kg reported in nonpregnant, reproductive-aged women (Hansen JM, Kampmann J, Laursen H. Renal excretion of drugs in the elderly [letter]. Lancet 1970;1:1170). It is unclear whether this value is valid during pregnancy, in part because of the additional contribution of creatinine by the fetus(es), and which weight (ideal, prepregnant, or weight at collection) should be used in the calculation. We chose prepregnant weight because this value is known to correlate with total maternal muscle mass and was one of our matching variables. The creatinine to prepregnant weight ratios were similar to published norms and were comparable between the twin and singleton groups. Because of the similar group ratios, the lack of published norms in pregnancy, and the equal opportunity for both groups to adequately collect a 24-hour urine sample, no patient was excluded based on the creatinine-weight ratio.

Although the serum and urine analyses of uric acid and creatinine were not evaluated as predictive tests for preeclampsia, the finding of increased daily uric acid excretion helps to account for the difference observed in maternal serum uric acid levels between nonpreeclamptic twin and singleton gestations in the third trimester. Any future studies involving serum uric acid surveillance in pregnancy should avoid combining women with twin and singleton gestations because they clearly have different serum and urine profiles.


   Footnotes
 
Funded through a Faculty Practice Research Grant from Cooper Hospital/University Medical Center.

PII S0029-7844(00)01106-6

Received April 19, 2000. Received in revised form July 19, 2000. Accepted August 10, 2000.


   References
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Abstract
 Materials and Methods
 Results
 Discussion
 References
 
1. Lind T, Godfrey KA, Otun H, Philips PR. Changes in serum uric acid concentrations during normal pregnancy. Br J Obstet Gynaecol 1984;91:128–32.[Medline]

2. Dunlop W, Davison JM. The effect of normal pregnancy upon the renal handling of uric acid. Br J Obstet Gynaecol 1977;84:13–21.[Medline]

3. Hill LM. Metabolism of uric acid in normal and toxemic pregnancy. Mayo Clin Proc 1978;53:743–51.[Medline]

4. Lim KH, Friedman SA, Ecker JL, Kao L, Kilpatrick SJ. The clinical utility of serum uric acid measurements in hypertensive diseases of pregnancy. Am J Obstet Gynecol 1998;178:1067–71.[Medline]

5. Voto LS, Illia R, Darbon-Grosso HA, Imaz FU, Margulies M. Uric acid levels: A useful index of the severity of preeclampsia and perinatal prognosis. J Perinat Med 1988;16:123–6.[Medline]

6. Schuster E, Weppelmann B. Plasma urate measurements and fetal outcome in preeclampsia. Gynecol Obstet Invest 1981;12:162–7.[Medline]

7. Shah DM, Reed G. Parameters associated with adverse perinatal outcome in hypertensive pregnancies. J Hum Hypertens 1996;10: 511–5.[Medline]

8. Sagen N, Haram K, Nilsen ST. Serum urate as a predictor of fetal outcome in severe preeclampsia. Acta Obstet Gynecol Scand 1984;63:71–5.[Medline]

9. Redman CWG, Beilin LJ, Bonnar J, Wilkinson RH. Plasmaurate measurements in predicting fetal death in hypertensive pregnancy. Lancet 1976;1:1370–3.[Medline]

10. O’Brien WF. Predicting preeclampsia. Obstet Gynecol 1990;75:445–52.[Abstract/Free Full Text]

11. Calvert SM, Tuffnell DJ, Haley J. Poor predictive value of platelet count, mean platelet volume and serum urate in hypertension in pregnancy. Eur J Obstet Gynecol Reprod Biol 1996;64:179–84.[Medline]

12. Merviel P, Ba R, Beaufils M, Breart G, Salat-Baroux J, Uzan S. Lone hyperuricemia during pregnancy: Maternal and fetal outcomes.Eur J Obstet Gynecol Reprod Biol 1998;77:145–50.[Medline]

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

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

15. Thompson SA, Lyons TI, Makowski EL. Outcomes of twin gestations at the University of Colorado Health Sciences Center, 1973-1983. J Reprod Med 1987;32:328–39.[Medline]

16. McMullan PF, Norman RJ, Marivate M. Pregnancy-induced hypertension in twin pregnancy. Br J Obstet Gynaecol 1984;91:240–3.[Medline]

17. Fischer RL, Bianculli KW, Hediger ML, Scholl TO. Maternal serum uric acid levels in twin gestations. Obstet Gynecol 1995;85:60–4.[Abstract]

18. Malone FD, D’Alton ME. Multiple gestation: Clinical characteristics and management. In: Creasy RK, Resnik R, eds. Maternal-fetal medicine. 4th ed. Philadelphia: WB Saunders, 1999:599.

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20. 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]




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S. Suzuki, R. L. Fischer, L. S. Weisberg, and M. L. Hediger
ETIOLOGY OF THIRD-TRIMESTER MATERNAL HYPERURICEMIA IN NONPREECLAMPTIC TWIN GESTATIONS
Obstet. Gynecol., April 1, 2001; 97(4): 641 - 642.
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