Uric acid: is it time to give up routine testing in management of pre-eclampsia?

Abstract

Ever since it was first linked with the pathophysiology of pre-eclampsia, uric acid has been a routine test requested by many care-givers managing pregnant women with hypertensive disease of pregnancy for almost 100 years. Existing evidence however suggests that it has no definitive role in prediction, diagnosis or management of pre-eclampsia. We argue against routine uric acid testing in pregnancies complicated by hypertension not only because it has become a fruitless academic exercise but also because ceasing its routine use will ensure cost-savings for the health services.

INTRODUCTION

Uric acid is a product of purine degradation catalysed by the enzyme xanthine oxidase/xanthine dehydrogenase.¹ Unlike in most other mammals, in humans, uric acid is the final oxidation product of purine metabolism and is chiefly excreted in the urine.² Renal pathway accounts for up to 70% of daily uric acid excretion. It is freely filtered by the glomeruli with re-absorption and secretion in the proximal convoluted tubule of the kidney. Although some new guidelines^3,4 for diagnosis and management of pre-eclampsia do not include uric acid as a mandatory test, serum uric acid testing still continues to form a part of routine investigations performed for hypertensive disorders of pregnancy by other guidelines⁵ or hospital protocols. A review of recent evidence raises questions over such a policy of routine testing.

URIC ACID AND NORMOTENSIVE PREGNANCY

Due to the physiological adaptations of a normal pregnancy, glomerular filtration rate (GFR) and renal plasma flow increase by at least 50%, starting soon after conception and lasting until term. There is a gradual fall (25–35%) in serum uric acid level in normal pregnancy until 16 weeks of gestation. The uric acid levels then tend to stabilize between 17 and 28 weeks of pregnancy and start rising during the third trimester.^6–8 The normal ranges of serum uric acid values for each trimester of pregnancy are shown in Table 1. The initial drop in levels is explained by an increase in GFR and filtered load with reduced tubular re-absorption as well as the uricosuric action of oestrogen.¹ The rise in late pregnancy may be secondary to increased fetal production, decreased binding to albumin and increased tubular re-absorption with falling renal clearance.

Table 1.

Normal ranges of serum uric acid values for each trimester of pregnancy⁹

	Non-pregnant	First trimester	Second trimester	Third trimester
Uric acid (mmol/L)	0.18–0.35	0.14–0.23	0.14–0.28	0.21–0.38

SI units for uric acid measurements are either mmol/L or more commonly μmol/L. Multiply the mmol/L value by 1000 to get μmol/L value and then divide the μmol/L value by 59.48 (conversion factor) to get the mg/dL value

A study that attempted to evaluate serial changes in serum uric acid concentrations in healthy women before conception, at regular intervals throughout pregnancy and finally 12 weeks after delivery, found that after 24 weeks, uric acid concentrations increased and by term, they were greater than the prepregnancy values in the majority of patients and remained elevated until 12 weeks postpartum.⁹ The authors cautioned that clinical management based on rising serum uric acid concentration in the second half of pregnancy needed careful scrutiny against the background of physiological increase in serum uric acid in later pregnancy.

FACTORS AFFECTING SERUM URIC ACID LEVELS IN PREGNANCY

The following factors can significantly affect the levels of uric acid in pregnancy:

• Racial variation – A prospective study undertaken in New Zealand to measure serum uric acid levels in normal pregnant women of different races reported significantly higher levels in Polynesian, Maori and Cook Island women than European women in the third trimester;¹⁰

• Diet – Uric acid concentrations are influenced by diet containing high protein or fructose content;¹

• Alcohol consumption increases levels of uric acid;

• Conditions with increased cell turnover can increase serum urate levels, e.g. haemolytic anaemias, sickle cell disease, malignancies, organ transplant or cancer treatment;

• Enzymatic defects in purine metabolism;

• Altered renal function;

• Smoking – it has been reported that the higher uric acid concentrations in women who smoke may be secondary to increased production through the xanthine oxidase pathway;¹¹

• Number of fetuses – serum uric acid concentrations are higher in multiple gestations. A study found significantly higher mean uric acid concentrations at term in twin and triplet pregnancies compared with singletons (0.27, 0.30 and 0.22 mmol/L respectively).¹² The authors suggested that for clinical purposes, the upper limit of the uric acid cut-off concentrations at term should be adjusted using mean + 2 standard deviations as follows: 0.309, 0.428 and 0.452 mmol/L for singleton, twin and triplets, respectively. The changes in renal circulation and increased cell turnover have been suggested as the possible mechanisms leading to hyperuricaemia in these women;¹³

• Diurnal variation – a study reported that the mean serum uric acid value between 08:00 and 09:00 hours was higher than that observed between 17:00 and 18:00 hours.¹⁴ It was concluded that when attempting to interpret the serum uric acid concentration, it is important to consider its diurnal rhythms. Daily monitoring of serum uric acid in preeclamptic pregnancies therefore ought to be at a time of day when serum value is least likely to be affected by the diurnal rhythm. The authors recommended sampling after 11:00 hours and establishing appropriate sets of reference intervals for making pertinent comments on laboratory results for uric acid;

• Test assay – variations in the methods for estimating uric acid levels may affect results;

• Antihypertensive therapy – levels of uric acid could be raised due to the use of antihypertensives.¹⁵

With so many variables affecting the levels of serum uric acid, it is easy to realize why measurements of uric acid have produced conflicting results in various different clinical studies.

URIC ACID AND PRE-ECLAMPSIA

What may be the first report of increased uric acid in pre-eclampsia was published back in 1917.¹⁶ Reduced uric acid clearance secondary to reduced GFR, increased tubular re-absorption and decreased secretion have been cited as the main reasons for elevated serum uric acid levels in women with pre-eclampsia.^17–19 Besides these mechanisms, the pathophysiology of pre-eclampsia is associated with increased trophoblastic tissue shedding, endothelial dysfunction and reduced blood flow in the feto-maternal unit and these may also contribute to the hyperuricaemia.

There is evidence for increased generation of uric acid from the ischaemic placenta. With tissue ischaemia there is metabolism of adenosine triphosphate to adenosine and xanthine, in addition to an increase of the enzyme xanthine oxidase within the ischaemic tissue.²⁰ In pre-eclampsia, serum adenosine²¹ and placental xanthine oxidase are increased.²² Xanthine is then converted by xanthine oxidase to uric acid with the generation of oxidants (superoxide anion). Some authors have hypothesized that hyperuricaemia may actually contribute to the development of hypertension and renal disease in pre-eclampsia.²³ It has been suggested that uric acid may contribute to the pathogenesis through attenuation of normal trophoblast invasion and integration into endothelial cell mono layers, leading to defective spiral artery vascular remodelling.²⁴ The hypothesis has been further supported by in vitro culture studies and hyperuricaemic animal models demonstrating several pathogenic effects of uric acid including proinflammatory effects, stimulation of smooth muscle cell proliferation, inhibition of endothelial cell proliferation/migration and promotion of endothelial dysfunction or damage.¹ However, because uric acid is a marker of oxidative stress, tissue injury and renal dysfunction, it is possible that uric acid is merely associated with a more severe form of pre-eclampsia and that the underlying metabolic syndrome, tissue damage, oxidative stress and inflammation may contribute to the increase in uric acid observed in hypertensive pregnancies.²⁵

From the time its association with pre-eclampsia was first described, it was hoped that uric acid would become the marker of choice allowing accurate prediction of onset or severity of pre-eclampsia or its complications, and thus leading to timely intervention such as termination of pregnancy so as to prevent any adverse outcomes. Unfortunately, the initial enthusiasm faded as more and more conflicting data about its usefulness appeared in the literature.

ROLE OF URIC ACID IN CURRENT CLINICAL PRACTICE

In current clinical practice, pre-eclampsia is diagnosed when there is onset or first detection of hypertension after 20 weeks of pregnancy with blood pressure readings of 140/90 mmHg or more on two occasions at least four hours apart and associated with proteinuria of at least 300 mg of protein over 24 hours. A urine dipstick testing for protein 1+ or a protein/creatinine ratio of 0.03 g/mmol appears to be equivalent to 0.3 g/24 hours of proteinuria. Many hospital protocols still consider estimation of serum uric acid level to be a standard part of the investigative work-up in women with suspected or confirmed pre-eclampsia to monitor disease severity and aid in the management of these women. This is despite the fact that hyperuricaemia is neither used as a primary diagnostic criterion for pre-eclampsia nor typically considered a basis for management decisions.

EXISTING EVIDENCE FOR SERUM URIC ACID TESTING IN GESTATIONAL HYPERTENSION/PRE-ECLAMPSIA

Many studies have shown a positive correlation between serum uric acid levels and the clinical severity of gestational hypertension/pre-eclampsia.^26–35 A number of studies have also reported that serum uric acid can predict fetal outcome in women with pre-eclampsia.^36–39 One study reported an increase in small for gestational age fetuses among gestation induced hypertensive women with proteinuric and non-proteinuric hyperuricaemia.⁴⁰ Roberts et al. ²⁸ suggested that hyperuricaemia is as effective as proteinuria in identifying gestational hypertensive pregnancies at increased risk of fetal complications, while other investigators have cited uric acid as a predictor of fetal risk comparable to blood pressure.⁴¹ Gowri et al. reported increased admissions to neonatal unit and caesarean sections in pre-eclamptic women with elevated uric acid.⁴² Yet another study suggested that the uric acid levels in the highest quartile of the normal range during the first 20 weeks of pregnancy were associated with higher risk for the development of gestational diabetes mellitus and mild pre-eclampsia.⁴³

However other studies have reported contrasting results. Calvert et al. ⁴⁴ were unable to demonstrate any relationship between serum uric acid levels and the outcome of the pregnancies studied. Fay et al. ⁴⁵ found that the rise in uric acid levels in patients who developed pre-eclampsia was only significantly higher than in non-hypertensive patients the week prior to delivery. Masse et al. ⁴⁶ in their prospective study of 1366 nulliparous women, in whom uric acid was measured between 15 and 24 weeks gestation and again between 25 and 34 weeks gestation, also found that measurement of serum uric acid levels was not helpful in predicting pre-eclampsia. There are several other reports suggesting that uric acid is not a good predictor of pre-eclampsia or its complications and studies have disputed the association between perinatal morbidity/mortality and higher uric acid levels in patients with pre-eclampsia.^15,47–49

Although some reports demonstrated increased uric acid levels in women with pre-eclampsia prior to the onset of clinical disease,²⁵ Myers et al. did not find a significant difference in uric acid levels at 22 and 26 weeks in their cohort of women. Across all gestations investigated, they found no correlation between plasma uric acid levels and the effect of plasma on in vitro endothelial function.⁵⁰ Lim et al. ⁵¹ reported a significant overlap in uric acid values among the hypertensive women leading to the conclusion that it was not clinically useful in distinguishing pre-eclampsia from gestational hypertension. Paula et al. ⁵² reported that a serum uric acid level equal to or above 0.357 mmol/L in the pregnant hypertensive women was associated with proteinuria and diastolic blood pressure, but not with fetal outcome.

In 2006 a systematic review of five studies with a total of 572 women, including 44 who developed pre-eclampsia, concluded that there was insufficient evidence to draw firm conclusions about the accuracy of serum uric acid testing in the disorder.⁵³ Another systematic review¹⁷ published in 2006 evaluated the accuracy of serum uric acid in predicting complications of pre-eclampsia. The authors concluded that serum uric acid does not seem to be a clinically useful test to predict maternal or fetal complications in women with pre-eclampsia. There was no strong evidence to justify the use of therapeutic measures like magnesium sulphate or early delivery aimed at reducing maternal and fetal complications based on the levels of uric acid.¹⁷ Koopmans et al. ⁵⁴ subsequently repeated the meta-analysis in 2009 with a bivariate meta-analytic model and a decision analysis to assess the value of serum uric acid in the management of women with pre-eclampsia and suggested that serum uric acid seemed to be a useful test in predicting eclampsia. Based on their decision analysis, in which they combined test accuracy both with the prevalence of disease and with the impact of clinical outcomes, the authors found measurement of serum uric acid to be a useful test to predict maternal complications in the management of women with pre-eclampsia.⁵⁴

Since uric acid as a single marker on its own failed to accurately predict onset of pre-eclampsia, a combination of serum uric acid level, roll-over test result and body mass index was suggested to improve the predictive value of these markers of pre-eclampsia.⁵⁵ Others suggested that the clinical utility of blood pressure measurements, uric acid and creatinine assessments may be improved by the use of gestation specific cut-off values and z scores. However, the positive likelihood ratios associated with the use of z scores were still low, indicating limited clinical utility.⁵⁶

The conflicting results from the above studies and the conclusions of the systematic reviews point to the fact that serum uric acid measurements cannot be used to predict onset of pre-eclampsia or its complications with reliability. Also, hyperuricaemia cannot form the basis for decision to induce labour or start magnesium sulphate therapy if other maternal parameters like clinical symptoms or blood pressure measurements are reassuring.

WHY URIC ACID SHOULD NOT FORM A PART OF ROUTINE INVESTIGATIONS FOR pregnancy-induced hypertension/PRE-ECLAMPSIA

Uric acid levels do not form a part of essential diagnostic criteria for pregnancy-induced hypertension or pre-eclampsia. There is sufficient evidence that uric acid levels do not accurately predict the onset or complications of pre-eclampsia and there are several variables or patient characteristics which can affect these measurements significantly. Most obstetricians do not base management decisions on level of uric acid. It is the severity of clinical signs/symptoms, hypertension, proteinuria and other maternal/fetal parameters that form the basis of management of pre-eclampsia. In addition, if uric acid did influence delivery decisions, this would account for an increased frequency of indicated preterm birth.²⁸ Apart from re-establishing the well known association of hyperuricaemia with pre-eclampsia, what other benefit does repeated routine uric acid testing confer in hypertensive pregnancies?

The cost–benefit analysis of uric acid testing in cases of pre-eclampsia also does not favour the routine testing approach. A study was carried out to investigate the accuracy of predictive tests as well as the effectiveness of preventive interventions for pre-eclampsia and to assess the cost-effectiveness of strategies (test–intervention combinations) to predict and prevent pre-eclampsia. It estimated a cost of £5 for serum uric acid test and approximately £20 for Doppler ultrasonography tests. The authors reported that the best estimate of additional average cost associated with an average case of pre-eclampsia was high at approximately £9000. They reported that none of the tests including uric acid appeared sufficiently accurate to be clinically useful.⁵⁷ Another study found that the costs for the management of a pregnancy with pre-eclampsia after 20 weeks of gestation amounted to an estimated £2726 with standard practice of diagnostic testing for pre-eclampsia.⁵⁸ The results of these studies are particularly important in the present economic scenario. In the UK, pre-eclampsia complicates over 4%⁵⁹ or about 31,000 pregnancies each year.⁶⁰ Even if a conservative estimate of 30,000 pregnancies complicated by pre-eclampsia was considered every year, based on an estimate of £5 cost for the measurement of uric acid approximately 5–6 times in a pregnancy, it would amount to a saving of nearly a million pounds for the National Health Service.

CONCLUSION

It is beyond any doubt that hyperuricaemia is a finding associated with pre-eclampsia. However increased uric acid level is not useful for prediction, diagnosis and/or management of pre-eclampsia. While we welcome uric acid testing for specific indications such as complex cases of superimposed pre-eclampsia on chronic hypertension with underlying renal damage and encourage further research into whether uric acid contributes to the pathogenesis of the pre-eclampsia syndrome, we strongly believe that the current practice of repeated routine uric acid testing for every suspected or diagnosed case of pregnancy induced hypertension or pre-eclampsia must stop.

DECLARATIONS

Guarantor: VST.

Funding: No funding was received for preparation of this manuscript.

Conflicts of interest: None of the authors has any potential conflicts of interests to declare.

Contributorship: VST and HS researched literature. VST wrote the first draft of the manuscript. Both authors reviewed and edited the manuscript and approved the final version of the manuscript.