nature publishing group

original contributions

Association of Uric Acid With Progression to Preeclampsia and Development of Adverse Conditions in Gestational Hypertensive Pregnancies
Yuquan Wu1, Xu Xiong2, William D. Fraser1 and Zhong-Cheng Luo1
Background Preeclampsia is a serious pregnancy complication. Gestational hypertension is a common first clinical presentation of preeclampsia. Little is known about which clinical risk factors are associated with the progression from gestational hypertension to preeclampsia. Methods In a retrospective cohort study of 249 singleton pregnant women with an initial presentation of gestational hypertension in an obstetric hospital, we assessed which routinely available clinical risk factors are associated with the progression to preeclampsia and the development of adverse maternal or infant conditions. results The mean serum uric acid level at the initial presentation of gestational hypertension was significantly higher comparing patients who later progressed to preeclampsia to those who did not (5.06 vs. 4.59 mg/dl, P < 0.01). Lower gestational age and higher serum uric acid level at the initial presentation of gestational hypertension and subsequent need for antihypertensive drug treatment for blood pressure (BP) control were associated with significantly increased risks of progression to preeclampsia, and development of adverse maternal or infant conditions. One standard deviation (s.d.) increase in serum uric acid level was associated with 2.3-fold increased odds of progression to preeclampsia (adjusted odds ratio (aORs) 2.33 (95% confidence interval (CI) 1.453.74)), and 1.5-fold increased odds of developing clinically significant adverse maternal or infant conditions (aOR 1.49 (1.032.17)) irrespective of the progression to preeclampsia. conclusions Higher serum uric acid levels at the initial presentation of gestational hypertension may indicate heightened risk of progression to preeclampsia and development of adverse maternal/infant conditions. Keywords: adverse conditions; blood pressure; gestational hypertension; hypertension; preeclampsia; progression; uric acid
American Journal of Hypertension, advance online publication 1 March 2012. doi:10.1038/ajh.2012.18

Preeclampsia, defined as gestational hypertension (de novo hypertension occurring after 20 weeks of gestation) with proteinuria, is a major cause of severe maternal and neonatal morbidities.1 Hypertension is a common first clinical presentation of preeclampsia,2,3 appearing before the onset of proteinuria in many cases. It is a common clinical practice to consider each gestational hypertensive patient as an emerging preeclamptic case.3 Little is known about why certain women with an initial presentation of gestational hypertension progress to preeclampsia while others do not. Clinical management of gestational hypertensive pregnancies could be facilitated if we can identify important routinely available clinical risk factors for the progression from gestational
1Department of Obstetrics and Gynecology, CHU Sainte-justine, University of Montreal, Montreal, Quebec, Canada; 2Department of Epidemiology, Tulane University, New Orleans, Louisiana, USA. Correspondence: Zhong-Cheng Luo (zc_luo@yahoo.com)

Received 13 September 2011; first decision 20 October 2011; accepted 23 January 2012. 2012 American Journal of Hypertension, Ltd.

hypertension to preeclampsia and adverse maternal or infant conditions. There have been only a few studies on the risk factors of progression to preeclampsia among patients with an initial presentation of gestational hypertension.35 The findings have been limited and inconsistent, except that earlier onset of gestational hypertension has been consistently associated with greater risk of progression to preeclampsia. Bellomo and colleagues recently reported in a single hospital-based cohort that serum level of uric acid, a clinical biomarker routinely tested upon the diagnosis of gestational hypertension, may predict the progression to preeclampsia.4 This raises an intriguing possibility of a routinely available clinical biomarker as a risk marker of progression to preeclampsia. However, it remains unknown whether this finding can be replicated in an independent study; nor is it known whether uric acid is associated with the development of various clinically significant adverse maternal/infant conditions among gestational hypertensive patients. This study sought to assess serum uric acid and other routinely available clinical risk factors in the progression to preeclampsia and the development of clinically
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original contributions
significant adverse maternal/infant conditions following the onset of gestational hypertension.
Methods

Uric Acid, Progression to Preeclampsia

Study design, setting, and patients. This retrospective cohort study was based on chart reviews of all hypertensive pregnancies with a diagnosis of gestational hypertension without proteinuria at the initial presentation, using medical records from the 1st trimester of pregnancy to 6 weeks postpartum among women who received perinatal care and delivered a singleton infant at Sainte-Justine Hospital (about 3,500 births/year), Montreal, between March 2001 and June 2003. We excluded patients with chronic hypertension, renal disease [diagnosis of or treatment for kidney disease, proteinuria (2+ or higher in urine protein dipstick test) or abnormally high-serum creatinine level (>1.5 mg/l) during the 1st trimester of pregnancy], acute or chronic hepatitis, or primary preeclampsia (rather than progression from gestational hypertension to preeclampsia). The study was approved by the Sainte-Justine Hospital Research Ethics Board; informed consent was waived. A sample size of 250 was expected to have a power of 98% to detect a 0.5 standard deviation (s.d.) or greater difference in continuous variables, and a power of 72% to detect an odds ratio of 2.0 or stronger association for dichotomous risk factors (assumptions: error = 5%, 50% patients progressed to preeclampsia, 25% patients exposed for dichotomous risk factors). A total of 249 patients with an initial presentation of gestational hypertension constituted the final study cohort. Definitions of gestational hypertension and preeclampsia. Gestational hypertension was defined as de novo hypertension (systolic blood pressure (BP) 140 mm Hg and/or diastolic BP 90 mm Hg in two measurements at least 4 h apart) occurring after 20 weeks of gestation without proteinuria or with proteinuria of no greater than trace levels.6 The diagnosis was confirmed in at least one clinical follow-up visit in all study patients. Preeclampsia was defined as gestational hypertension with proteinuria (300 mg in a 24-h urine collection, or 1+ on dipstick urinalysis in two samples taken 6 h apart).6 To avoid misclassification bias, women for whom the recorded diagnosis of preeclampsia was within 1 week (6 days) following the diagnosis of gestational hypertension were considered as primary preeclamptic patients (rather than progression from gestational hypertension to preeclampsia) and excluded, because there could be a delay in obtaining the urine protein test results. This might have excluded some gestational hypertensive patients who rapidly progressed to preeclampsia, but the majority of such patients were more likely primary preeclampsia. Outcomes. The primary outcome was progression to preeclampsia (n = 158). The secondary outcome was a composite indicator of the development of one or more clinically significant adverse maternal or infant conditions (n = 89): (i) hemolytic anemia or hematocrit <24%; (ii) elevated liver
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enzyme levels (aspartate aminotransferase or alanine aminotransferase >70 U/l); (iii) thrombocytopenia (platelet count <100 109/ ml); (iv) severe nausea and vomiting, visual disturbances, chest pain, or shortness of breath; (v) severe proteinuria (protein secretion 3 g/day in 24-h urine collection, applicable to preeclamptic patients only); (vi) oliguria (<500 ml/ day); (vii) pulmonary edema; (viii) eclampsia (seizures); (ix) abruptio placenta; (x) intrauterine growth restriction (birth weight for gestational age <3rd percentile according to the Canadian sex- and gestational age-specific fetal growth standards);7 (xi) low 5-min Apgar score (3);8 (xii) perinatal death (fetal death 20 weeks or neonatal death within 7 days). We did not analyze each specific adverse outcome separately due to small numbers. Diagnostic and clinical management practices. In SainteJustine Hospital during the study reference period, urine protein tests were routinely conducted in gestational hypertensive patients at the time of initial diagnosis and subsequent follow-ups (usually weekly). Gestational hypertensive patients with diastolic BP 95 mm Hg or systolic BP 150 systolic were routinely treated with antihypertensive medications with a target to lower systolic BP 140 mm Hg and diastolic BP 90 mm Hg. Mild hypertensive patients (diastolic BP 9094 mm Hg, systolic BP 140149) were usually not treated but closely monitored for potentially worsening conditions. Expectant management was routinely employed in the care of gestational hypertensive patients without other adverse conditions that could threaten the safety of the mother or baby, especially in pregnancies before term (<37 weeks). Elective delivery was frequently employed in gestational hypertensive pregnancies complicated by additional adverse maternal or infant conditions that the physician-in-charge deemed to be a significant safety threat to the mother or baby. In term (37 weeks) gestational hypertensive pregnancies without other adverse conditions, elective delivery was discretionarily employed, dependent on if the physician-in-charge deemed there was a significant risk to develop preeclampsia or other adverse conditions. Covariables. The following clinical and routine laboratory test data were available at the initial presentation of gestational hypertension: gestational age, maternal age, gravidity, parity, height and prepregnancy weight (and hence prepregnancy body mass index), smoking and alcohol use, histories of miscarriage (spontaneous abortion), gestational hypertension and preeclampsia, hemoglobin (g/dl), hematocrit (%), platelet count (109/ml), serum aspartate aminotransferase, alanine aminotransferase, creatinine, lactate dehydrogenase, and uric acid levels. Gestational age was based on the date of last menstrual period, and verified by first-trimester (>90%) or early 2nd trimester ultrasound where available. If the difference in gestational age estimates between the two methods was 7 days at the 1st trimester, or 2 weeks at early 2nd trimester, the ultrasound-based estimate was used to avoid potentially erroneous last menstrual period-based dating.9
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original contributions
the initial presentation of gestational hypertension were significantly higher comparing patients who later progressed to preeclampsia vs. those who did not (mean s.d.: 5.06 0.78 vs. 4.59 1.01 mg/dl, P < 0.01), whereas the levels of other routinely available lab test biomarkers were very similar. A total of 89 subjects developed adverse maternal or infant conditions, including 12 cases of the HELLP syndrome (hemolytic anemia, elevated liver enzymes and low platelet count), 2 cases of eclampsia, 2 perinatal deaths, and 20 cases of intrauterine growth restriction. Adverse maternal or infant conditions occurred far more frequently in preeclamptic vs. gestational hypertensive only pregnancies (51.9% vs. 7.7%, P < 0.01). All case of HELLP, eclampsia, and perinatal deaths occurred in preeclamptic pregnancies. Antihypertensive drug treatment was much more frequent in preeclamptic vs. gestational hypertensive only patients (P < 0.01). Among the routinely available clinical and lab test variables, only gestational age and serum uric acid level at the onset of gestational hypertension and subsequent antihypertensive drug treatment for BP control were significantly associated with the progression to preeclampsia, and the development of adverse maternal/infant conditions in logistic regression models adjusting for potential confounders (Table 2). Each s.d. increase in serum uric acid level at the onset of gestational hypertension was associated with 2.3-fold higher odds of progression to preeclampsia (aOR 2.33 (95% CI 1.453.74)), while each week delay in the onset of gestational hypertension was associated with about 50% reduction in the odds of progression to preeclampsia (aOR 0.50 (0.400.63)). Each s.d. increase in serum uric acid level was associated with about 1.5-fold higher odds of developing adverse maternal/infant conditions (aOR 1.49 (1.032.17)), while each week delay in the onset of gestational hypertension was associated with a 14% reduction in the odds of developing adverse maternal/infant conditions (aOR 0.86 (0.790.93)). Adverse maternal/infant conditions occurred far more frequently in patients with antihypertensive treatment vs. expectant management (63% vs. 15%, P < 0.01). After the adjustments, antihypertensive drug treatment was associated with about 4.3-fold higher odds of preeclampsia, and 3.8-fold higher odds of adverse maternal/infant conditions (all P < 0.01). Similar associations were observed if the analyses were restricted to patients with an early onset of hypertension (36 weeks); for example, each s.d. increase in uric acid was associated with 2.5-fold higher odds of progression to preeclampsia (aOR 2.46 (1.324.56), P < 0.01). Receiver-operator characteristic curve showed relatively poor sensitivity and specificity performance (area under the curve= 0.66) of serum uric acid level at the initial presentation of gestational hypertension for predicting the progression to preeclampsia (Figure 1). The best cut-off revealed from the curve was 4.7 mg/dl, with sensitivity = 73%, specificity = 58%, positive predictive value = 75%, negative predictive value = 56%. The receiver-operator characteristic characteristics improved (area under the curve = 0.75) but remained unsatisfactory if the analyses were restricted to patients with an early onset of hypertension (36 weeks): the best cut-off remained
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Statistical analysis. To examine the differences in clinical characteristics, we used analysis of variance, Wilcoxon rank and 2-tests, as appropriate to the data. Logistic regression models were used to estimate the crude and adjusted odds ratios (aORs) with 95% confidence intervals (CI) of the progression to preeclampsia, and the development of adverse maternal or infant outcomes. Parsimonious final regression models were fitted by retaining important known factors associated with preeclampsia (primiparity, maternal age 35 years, maternal obesity, smoking, and history of preeclampsia) and other identified significant risk factors at P < 0.05. For routine lab test biomarkers, we assessed the effect size per 1 s.d. increase. Except for uric acid, the mean and s.d. for the whole cohort without adjusting for gestational age were used in calculating the s.d. scores of observed serum biomarkers since their levels were uncorrelated to gestational age (all P > 0.2). It is known that serum uric acid levels rise from mid-gestation to term in normal pregnancy.10 We thus used the hospitals internally derived gestational age specific serum uric acid reference values based on longitudinal serum uric acid data in 102 normotensive pregnancies (mean s.d. were 3.24 0.96 mg/dl at 2024 weeks, 3.65 0.98 mg/dl at 2531 weeks, 4.30 0.94 mg/dl at 3236 weeks, and 4.69 1.06 mg/dl at 37 weeks, respectively; 1 mg/dl = 59.48 mol/l) to calculate serum uric acid level s.d. scores. The serum uric acid reference values are comparable to those reported by Lind and colleagues (for example, mean s.d.: 3.30 0.96 mg/dl at 24 weeks, 4.52 1.11 mg/dl at 38 weeks).10 Receiver-operator characteristic curves were plotted to evaluate the clinical utility of significant clinical biomarkers in predicting the progression to preeclampsia. The clinically determined diagnosis of preeclampsia was the gold standard. The area under the curve, sensitivity, specificity, positive and negative predictive values were calculated. All data analyses were performed using Statistical Analysis System (SAS), version 9.0 (SAS Institute, Cary, NC). Two sided P values <0.05 were considered statistically significant.
results

Of the 249 patients with an initial presentation of gestational hypertension, 158 patients (63%) progressed to preeclampsia. Comparing patients who progressed to preeclampsia vs. those who did not, the proportion of obese women was higher, the onset of gestational hypertension was earlier (mean gestational age: 31 vs. 37 weeks, P < 0.01), but systolic and diastolic BP were slightly lower at the onset of gestational hypertension (Table 1). The maximal diastolic BP was 110 mm Hg at the onset of gestational hypertension (four patients, three later became preeclamptic). At the time of diagnosis of preeclampsia, diastolic and systolic BP were 91 10 and 152 16 mm Hg, respectively. Preterm onset of gestational hypertension, history of preeclampsia and Caesarean section were much more frequent comparing patients who progressed to preeclampsia vs. those who did not. There were no significant differences in maternal age, smoking, and alcohol use, and history of miscarriage or gestational hypertension. Serum uric acid levels at
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Uric Acid, Progression to Preeclampsia

table 1 | characteristics of 249 singleton pregnant women with an initial presentation of gestational hypertension (gh) with vs. without the progression to preeclampsia (Pe)
Characteristic Maternal age (years) Age 35 Primiparity Smoking Prepregnancy BMI (kg/m2) BMI 30 History of miscarriage Preeclampsia Gestational hypertension Prenatal visits, total number Visits per month Onset of hypertension Gestational age (weeks) <37 weeks Systolic BP (mm Hg) Diastolic BP (mm Hg) Hemoglobin (g/dl) Hematocrit (%) Platelet (109/ml) Serum AST(U/l) ALT (U/l) LDH (U/l) Creatinine (mg/dl) Uric acid (mg/dl) Duration (weeks) GH onset to PE GH onset to delivery Antihypertensive drug treatment Delivery Caesarean section Labor induction Gestational age (weeks) Birth weight <3rd percentile Adverse maternal or infant conditionsa 88 (35.3) 137 (55.0) 36.4 3.5 20 (8.0) 89 (38.2) 19 (20.9) 53 (58.2) 38.7 1.8 5 (5.0) 7 (7.7) 69 (43.7) 84 (53.2) 35.1 3.6 15 (9.5) 82 (51.9) <0.01 0.44 <0.01 0.26 <0.01 3.0 2.7 2.3 2.5 106 (42.6) 1.1 1.3 5 (5.5) 3.0 2.7 3.0 2.7 101 (63.9) <0.01 <0.01 33.5 4.8 158 (63.5) 146 8 86 9 121.4 11.3 0.36 0.03 214 57 24.1 6.0 17.2 6.0 150.8 23.9 0.67 0.13 4.89 0.90 37.6 2.2 22 (24.2) 147 9 87 8 122 12 0.36 0.03 215 69 23.5 6.4 16.3 5.0 151.9 22.8 0.65 0.13 4.59 1.01 31.1 4.2 146 (92.4) 145 7* 85 9* 121 10 0.36 0.03 213 50 24.5 5.7 17.7 6.4 150.2 24.6 0.67 0.12 5.06 0.78 <0.01 <0.01 0.02 0.04 0.43 0.44 0.82 0.22 0.08 0.58 0.17 <0.01 All subjects (N = 249) 30.3 5.8 59 (23.7) 162 (65.1) 28 (11.2) 25.7 5.8 27 (10.8) 97 (39.0) 26 (10.4) 42 (16.9) 8.4 2 1.0 0.2 GH only (N = 91) 29.7 5.4 18 (19.8) 61 (67.0) 11 (12.1) 23.9 3.7 2 (2.2) 32 (35.2) 5 (5.5) 12 (13.2) 8.5 2 1.0 0.3 GH-PE (N = 158) 30.6 6.0 41 (26.0) 101 (63.9) 17 (10.8) 26.3 6.3 25 (15.8) 65 (41.1) 21 (13.3) 30 (19.0) 8.4 2 1.0 0.2 0.23 0.27 0.62 0.75 0.03 <0.01 0.35 0.053 0.24 0.74 0.12 P*

Data presented are mean s.d. or n (%).Conversion factor: uric acid 1 mg/dl = 59.48 mol/l; creatinine 1 mg/dl = 88.4 mol/l. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; BP, blood pressure; GH-PE, gestational hypertension (GH) with progression to preeclampsia (PE); LDH, lactate dehydrogenase. aThe presence of one or more of the following clinically significant adverse conditions: (i) hemolytic anemia; (ii) elevated liver enzyme levels; (iii) thrombocytopenia; (iv) severe nausea and vomiting, visual disturbances, chest pain, or shortness of breath; (v) severe proteinuria; (vi) oliguria; (vii) pulmonary edema; (viii) eclampsia; (ix) abruptio placenta; (x) intrauterine growth restriction (<3rd percentile); (xi) low 5-min Apgar score (3); (xii) perinatal death. *P value in analysis of variance, Wilcoxon rank and 2-tests (where appropriate) for comparisons of GH only vs. GH-PE subjects.

at 4.7 mg/ dl, with sensitivity = 73%, specificity = 63%, positive predictive value = 95%, negative predictive value = 29%.
discussion

An important finding is that higher serum uric acid levels may indicate higher risks of progression to preeclampsia and
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development of adverse maternal/infant conditions in patients with an initial presentation of gestational hypertension. There have been many studies on the risk factors (reviewed by Duckitt and Harrington)11 or recurrent risk of preeclampsia (reviewed by Barton and Sibai),12 yet little is known about the risk factors for the progression to preeclampsia among
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table 2 | crude and adjusted odds ratios* of the progression from gestational hypertension (n = 249) to preeclampsia (n = 158), and the development of adverse maternal or infant conditions (n = 89).
Preeclampsia Crude OR (95% CI) Serum uric acid at GH onset, per s.d. increasec GA at GH onset (weeks) Antihypertensive drug treatmentb Primiparous Maternal age >35 years Maternal smoking Obesity (prepregnancy body mass index >30) History of preeclampsia 3.48 (1.51, 3.83)* 0.47 (0.39, 0.57)* 12.7 (4.87, 32.9)* 0.87 (0.51, 1.50) 1.42 (0.76, 2.66) 0.88 (0.39, 1.96) 8.36 (1.93, 36.2)* 2.64 (0.96, 7.25) Adjusteda OR (95% CI) 2.33 (1.45, 3.74)* 0.50 (0.40, 0.63)* 4.27 (1.13, 16.1)* 1.08 (0.35, 3.29) 2.42 (0.78, 7.48) 0.41 (0.10, 1.72) 5.39 (0.73, 39.8) 3.47 (0.56, 21.7) Adverse maternal or infant conditionsd Crude OR (95% CI) 2.44 (1.20, 2.46)* 0.79 (0.73, 0.84)* 9.45 (5.15, 17.2)* 1.18 (0.68, 2.04) 0.99 (0.54, 1.83) 1.40 (0.63, 3.12) 0.89 (0.38, 2.07) 1.14 (0.49, 2.63) Adjusteda OR (95% CI) 1.49 (1.03, 2.17)* 0.86 (0.79, 0.93)* 3.84 (1.84, 8.00)* 1.74 (0.77, 3.96) 1.08 (0.50, 2.30) 1.51 (0.56, 4.09) 0.41 (0.15, 1.18) 2.02 (0.59, 6.86)

CI, confidence interval; GA, gestational age; GH, gestational hypertension; OR, odds ratio. aAdjusting odds ratios from logistic regression models; the covariates included gestational age and serum uric acid level at GH onset, antihypertensive drug treatment, maternal age, parity, smoking, obesity (prepregnancy body mass index 30), and history of preeclampsia. bOnly antihypertensive drug treatment before the diagnosis of preeclampsia was considered in estimating the adjusted odds ratio of progression to preeclampsia. cSerum uric acid level s.d. scores were based on the study hospitals internally derived gestational age-specific serum uric acid reference values in normotensive pregnancies (mean s.d.: 3.24 0.96 mg/dl at 2024 weeks, 3.65 0.98 mg/dl at 2531 weeks, 4.30 0.94 mg/dl at 3236 weeks, and 4.69 1.06 mg/dl at 37 weeks, respectively; 1 mg/dl = 59.48 mol/l). dThe development of one or more clinically significant adverse maternal or infant conditions, see Methods section for definition. *P < 0.05.

1
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Figure 1 | Receiver-operator characteristic curve for serum uric acid level at the initial presentation of gestational hypertension in predicting the progression to preeclampsia.

patients with an initial presentation of gestational hypertension. A history of miscarriage was identified as a risk factor in the progression to preeclampsia in an Australian study.3 This association could not be confirmed in our cohort. It should be cautioned that our study was not powered to detect weak to moderate associations with OR <2. Higher 24-h ambulatory monitoring blood pressures were observed before the progression to preeclampsia.5 In contrast, we observed that BP at the onset of gestational hypertension was of little value in predicting progression to preeclampsia. However, later worsening of hypertension, as indicated by antihypertensive drug treatment for BP control, was strongly associated with the progression to preeclampsia and the development of adverse maternal/infant conditions. Caution is warranted in data interpretation on the impact of antihypertensive drug treatment itself; because
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only severe or worsening hypertensive patients needed to be treated (confounding by indication), it is likely misleading to link the treatment per se to adverse outcomes. Our results confirm that early onset of gestational hypertension is associated with an increased risk of progression to preeclampsia.2,5 The lower odds of progression to preeclampsia among patients with later onset of gestational hypertension may be partly due to a shorter duration to delivery. Current practice is in favor of elective delivery in term hypertensive pregnancies to avoid the risk of developing preeclampsia. Maternal obesity and history of preeclampsia were not associated with progression to preeclampsia. Caution is warranted in data interpretation as the numbers of patients with such risk factors were relatively small (hence, wide CIs). Larger cohort studies are required to clarify these associations.
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The associations between higher uric acid levels and preeclampsia,1316 or between higher uric acid levels and poorer perinatal outcomes among preeclamptic patients,17,18 have been well documented. More recently, elevated uric acid levels at as early as the 1st trimester of pregnancy have been associated with the development of preeclampsia.19 Only one recent study has examined the association between uric acid and progression to preeclampsia among patients with an initial presentation of gestational hypertensionBellomo and colleagues reported that each 1 mg/dl increase in serum uric acid level at the onset of gestational hypertension was associated with a large aOR of 7.1 (3.2, 15.7) for the progression to preeclampsia (effective n = 163; 45% progressed to preeclampsia) in a prospective cohort.4 Uric acid levels were not adjusted for gestational age in their analyses. In our larger retrospective cohort (n = 248), we confirmed this positive association, but found a much smaller effect size (aOR = 2.3 per s.d. increase adjusting for gestational age, 1 s.d. was close to 1 mg/dl at various gestational ages). If uric acid levels were not adjusted for gestational age, the effect size was slightly smaller (aOR = 2.1, detailed results not shown). These findings suggest that serum uric acid level may be a risk marker of progression to preeclampsia among patients with an initial presentation of gestational hypertension, even though most serum uric acid levels were within the normal range. We could not confirm the excellent sensitivity (88%) and specificity (93%) of serum uric acid in predicting the progression to preeclampsia reported by Bellomo and colleagues.4 The relatively poor sensitivity and specificity in our cohort suggest limited clinical utility of uric acid alone in predicting the progression to preeclampsia. Larger multicenter prospective studies are required to elucidate the clinical utility of uric acid in predicting the progression to preeclampsia and the development of adverse conditions. Historically, increased serum uric acid levels in preeclampsia have been attributable to reduced excretion of uric acid in the proximal tubules secondary to hypovolemia which may occur early in the development of preeclampsia.20 However, we observed no change in hemoconcentration (as indicated by hematocrit data) in patients who later progressed to preeclampsia. Recent studies suggest more complex roles of uric acid in hypertensive pregnancy.21,22 Roberts and colleagues reported that even in the absence of proteinuria, hyperurincemia in gestational hypertensive patients was associated with adverse birth outcomes (preterm or small-for-gestational-age) relative to normotensive pregnancies.22 Koopmans and colleagues recently linked higher uric acid levels to the development of eclampsia in gestational hypertensive and preeclamptic pregnancies.23 We found that higher uric acid levels were associated with an increased risk of developing adverse maternal/ infant conditions among gestational hypertensive patients. Experimental studies suggest that uric acid may attenuate trophoblast invasion21 and inhabit placental system A amino acid intake.24 Uric acid may be directly involved in the pathogenesis of preeclampsia by promoting inflammation, oxidative stress and endothelial dysfunction.25,26 These bioactivities of uric acid may explain why it seems to be a risk marker for the
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progression to preeclampsia and the development of adverse maternal/infant conditions. Limitations of our study must be acknowledged. The study population in our hospital (a tertiary obstetrics care center) may be over-represented by more severe gestational hypertensive patients. Our study was limited to routinely available clinical and lab test predictors. Future studies may explore the combinations with other important early biomarkers of preeclampsia such as pregnancy-associated plasma protein-A, placental growth factor, soluble fms-like tyrosine kinase 1, and endoglin2729 in predicting the progression to preeclampsia and the development of adverse maternal or infant conditions. Such additional research data may be helpful in developing a potentially useful risk classification tool to assist clinicians in better management of gestational hypertensive patients. In conclusion, higher serum uric acid levels at the initial presentation of gestational hypertension may indicate heightened risk of progression to preeclampsia and development of adverse maternal/ infant conditions.
Acknowledgements: This work was supported by Strategic Training Initiative in Research in Reproductive Health Sciences (STIRRHS), Canadian Institutes of Health Research (CIHR, grant # 81285). Y.W. was supported by a scholarship from CIHR-STIRRHS during data work in the project, W.D.F. partly supported by a CIHR Canada Research Chair in Perinatal Epidemiology, and Z.C.L. by a CIHR New Investigator Award and a Clinical Epidemiology Scholar Award from the Quebec Foundation for Health Research (FRSQ). The study was approved by the Sainte-justine Hospital Research Ethics Board. Informed consent was exempted because the study was based on anonymous retrospective chart reviews. Disclosure: The authors declared no conflict of interest.
1. Roberts JM, Gammill HS. Preeclampsia: recent insights. Hypertension 2005; 46:12431249. 2. Barton JR, Obrien JM, Bergauer NK, Jacques DL, Sibai BM. Mild gestational hypertension remote from term: progression and outcome. Am J Obstet Gynecol 2001; 184:979983. 3. Saudan P, Brown MA, Buddle ML, Jones M. Does gestational hypertension become pre-eclampsia? Br J Obstet Gynaecol 1998; 105:11771184. 4. Bellomo G, Venanzi S, Saronio P, Verdura C, Narducci PL. Prognostic significance of serum uric acid in women with gestational hypertension. Hypertension 2011; 58:704708. 5. Davis GK, Mackenzie C, Brown MA, Homer CS, Holt J, McHugh L, Mangos G. Predicting transformation from gestational hypertension to preeclampsia in clinical practice: a possible role for 24 hour ambulatory blood pressure monitoring. Hypertens Pregnancy 2007; 26:7787. 6. ACOG Committee on Practice Bulletin - Obstetrics. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol 2002; 99:159167. 7. Kramer MS, Platt RW, Wen SW, Joseph KS, Allen A, Abrahamowicz M, Blondel B, Brart G; Fetal/Infant Health Study Group of the Canadian Perinatal Surveillance System. A new and improved population-based Canadian reference for birth weight for gestational age. Pediatrics 2001; 108:E35. 8. Casey BM, McIntire DD, Leveno KJ. The continuing value of the Apgar score for the assessment of newborn infants. N Engl J Med 2001; 344:467471. 9. Dietz PM, England LJ, Callaghan WM, Pearl M, Wier ML, Kharrazi M. A comparison of LMP-based and ultrasound-based estimates of gestational age using linked California livebirth and prenatal screening records. Paediatr Perinat Epidemiol 2007; 21 Suppl 2:6271. 10. Lind T, Godfrey KA, Otun H, Philips PR. Changes in serum uric acid concentrations during normal pregnancy. Br J Obstet Gynaecol 1984; 91:128132. 11. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 2005; 330:565. 12. Barton JR, Sibai BM. Prediction and prevention of recurrent preeclampsia. Obstet Gynecol 2008; 112:359372.
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Uric Acid, Progression to Preeclampsia

original contributions
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