prognostic significanc of serum uric acid pe hypertension-2011

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Gianni Bellomo, Sandro Venanzi, Paolo Saronio, Claudio Verdura and Pier Luca NarducciPrognostic Significance of Serum Uric Acid in Women With Gestational Hypertension

Print ISSN: 0194-911X. Online ISSN: 1524-4563Copyright 2011 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Hypertensiondoi: 10.1161/HYPERTENSIONAHA.111.1772122011;58:704-708; originally published online August 29, 2011; Hypertension.

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Pregnancy/Preeclampsia

Prognostic Significance of Serum Uric Acid in Women WithGestational Hypertension

Gianni Bellomo, Sandro Venanzi, Paolo Saronio, Claudio Verdura, Pier Luca Narducci

See Editorial Commentary, pp 548549

Abstract Aim of our study was to ascertain, prospectively, whether serum uric acid is a suitable predictor of preeclampsiaand/or the delivery of small-for-gestational-age infants in women with gestational hypertension. We screened 206primiparas, with a singleton pregnancy, referred for recent onset of hypertension. At presentation, we measured serumuric acid, creatinine, blood glucose, hemoglobin and platelet level, and 24-hour proteinuria, as well as office and 24-hourblood pressures. We followed the women until 1 month after delivery and recorded pregnancy outcome. After logisticregression analysis, uric acid resulted a significant predictor of preeclampsia, with an unadjusted odds ratio of 9.1 (95%CI: 4.8 to 17.4; P 0.001); after adjustment for age, gestation week, hemoglobin and platelet levels, serum creatinine,office and 24-hour average systolic and diastolic blood pressures, it was 7.1 (95% CI: 3.2 to 15.7; P 0.001). Regardingthe association between maternal serum uric acid and the chance of giving birth to a small-for-gestational-age infant,the unadjusted odds ratio was 1.7 (95% CI: 1.4 to 2.2; P 0.001), and it was 1.6 (95% CI: 1.1 to 2.4; P 0.02) afteradjustment. Receiver operating characteristic analysis showed that serum uric acid, at a 309- mol/L cutoff, predictedthe development of preeclampsia (area under the curve: 0.955), with 87.7% sensitivity and 93.3% specificity, and thedelivery of small-for-gestational-age infants (area under the curve: 0.784) with 83.7% sensitivity and 71.7% specificity.In conclusion, the results of our study show that serum uric acid is a reliable predictor of preeclampsia in women referredfor gestational hypertension. ( Hypertension . 2011;58:704-708.)

Key Words: uric acid preeclampsia gestational hypertension blood pressure small for gestation age

H ypertensive disorders complicate 2% to 10% of allpregnancies. 1,2 Among these, preeclampsia remains oneof the largest single causes of maternal and fetal mortality andmorbidity, whereas uncomplicated gestational hypertensioncarries a far better prognosis. Clinical prediction of pre-eclampsia may facilitate initiation of timely management toavert mortality and morbidity in the mother and infant. Raisedserum uric acid (UA) is one of the characteristic findings inpreeclampsia. In clinical practice, serum UA determination isconsidered to be a part of the workup in women withpreeclampsia to monitor disease severity and aid managementof these women. The association between raised serum UAand preeclamptic pregnancies was first reported almost acentury ago. 3 Reduced UA clearance secondary to reduced

glomerular filtration rate, increased reabsorption, and de-creased secretion may be at the origin of elevated serumlevels in women with preeclampsia. 4,5 Several studies havereported a positive correlation between elevated maternalserum UA and adverse maternal and fetal outcomes. 610 Anumber of studies 1115 have evaluated several tests andparameters, including UA, during the first or second trimester

of pregnancy, as potential predictors of preeclampsia, withmixed results, and generally with unsatisfactory sensitivity

and/or specificity. In this study, we have chosen to restrict ouranalysis to pregnant women referred to our unit for suspectedhypertension to evaluate the prognostic value of serum UAfor the subsequent development of preeclampsia and forgiving birth to a small-for-gestational-age (SGA) infant, thusallowing us to identify the subgroup of hypertensive womenat greater risk, necessitating of closer monitoring andsurveillance.

Patients and MethodsBetween July 2008 and July 2010, after obtaining their consent, wescreened 206 nulliparous women submitted to our unit for suspectedhypertension during pregnancy. Inclusion criteria were age 18

years, singleton pregnancy beyond the 20th week, blood pressure(BP) 140 mm Hg systolic or 90 mm Hg diastolic, and 24-hourproteinuria 300 mg. Known heart disease, nephropathy, or hyper-tension preceding pregnancy were reasons for exclusion from thestudy.

None of the subjects were treated with antihypertensive drugs onentry. As the patients entered the study, BP was obtained on 2separate occasions, 6 hours apart, in a quiet environment with the

Received May 30, 2011; first decision June 19, 2011; revision accepted August 5, 2011.From the Departments of Nephrology and Obstetrics and Gynecology, San Giovanni Battista Hospital, Foligno, Italy.Correspondence to Gianni Bellomo, Department of Nephrology, San Giovanni Battista Hospital, via Arcamone,1, 06034 Foligno(Pg), Italy. E-mail

[email protected]

2011 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.111.177212

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subject seated. A physician on the hospital staff measured BP with astandard mercury sphygmomanometer. In our institution, all of themercury sphygmomanometers are calibrated every 3 months againstan electronic pressure generator. Diastolic BP was taken at Korotkoff phase 5, which has been shown to correspond more closely withintra-arterial measurement and be less dependent on the examinersskill than Korotkoff phase 4. 16 Three measurements were taken, 5minutes apart, and the average was recorded: the mean of theaverages recorded on the 2 occasions was considered the actual BP.BP values 140 mm Hg systolic or 90 mm Hg diastolic wereconsidered abnormal and used for diagnosis of hypertension. Also,after an overnight fast, blood samples were taken for routine tests,including serum creatinine, UA, blood glucose, and a full blood cellcount, and a 24-hour collection was started for the measurement of proteinuria. First-trimester (determined between the ninth and 12thweeks of gestation) serum UA was taken from the womans clinicalrecord and was measured at the same laboratory at our hospital.

Within 4 days from the first visit, all of the women underwentambulatory BP monitoring. An oscillometric pressurometer(TM2430, A&D Company, Tokyo, Japan) was used to measure24-hour BP. Device accuracy was checked in every session against

a mercury sphygmomanometer, and a difference 5 mm Hg wasreason for exclusion from the study.

BP was recorded at 15-minute intervals both during the day andnight for 25 hours, starting between 9:00 and 11:00 AM. Cuffs of appropriate size were used, always applied to the left arm.

All of the BP recordings from the first hour of monitoring wereremoved from analysis because they might be influenced by an alarm

reaction. All of the readings with a pulse pressure

20 mm Hg, adiastolic BP 140 mm Hg or 40 mm Hg, or a systolic BP250 mm Hg or 60 mm Hg were automatically rejected. The

quality of 24-hour BP monitoring was judged satisfactory when70% of the readings passed the editing criteria and 1 recording

per hour was obtained. Daytime was defined as 7:00 AM to 11:00 PM .All of the women were followed up at our hospital until the end of

pregnancy and regularly 1 month after delivery, unless theirclinical conditions dictated otherwise. The outcome of pregnancywas recorded, and clinical parameters regarding the newborn(weight, Apgar score, and duration of hospital stay) were alsorecorded. Preeclampsia was defined as gestational hypertension andproteinuria 300 mg in a timed 24-hour sample. Transient gesta-tional hypertension was defined as the presence of normal office BP

140 mm Hg systolic and 90 mm Hg diastolic) 4 weeks after

delivery in untreated women who had hypertension without pre-eclampsia during the third trimester of pregnancy. For the purpose of

Table 1. Demographic, Laboratory, Blood Pressure, and Perinatal Parameters of the Subjects Studied

Parameter All

(n 163)Gestational

Hypertension (n 90)Preeclampsia

(n 73)

P Preeclampsiavs GestationalHypertension

Demographic and laboratory parameters

Age, y 30.4 4.1 31.7 5.2 28.8 4.6 0.001

Gestation wk at inclusion 34.4 3.0 34.5 2.9 34.2 2.9 0.3BMI, kg/m2 24.3 2.9 24.6 3.0 24.0 2.7 0.22

Hemoglobin, g/L 114 13 112 13 118 11 0.002

Platelets, 1000/mm 3 195 55 216 51 170 48 0.001

Glycemia, mmol/L 4.4 0.7 4.4 0.7 4.3 0.6 0.21

Creatinine, mol/L 69.9 15.7 63.3 7.8 78.1 18.9 0.001

UA, mol/L 297 101 232 48 393 77 0.001

First-trimester UA, mol/L 196 18 202 19 190 23 0.18

Proteinuria, mg/24 h 104 76 88 46 122 84 0.001

Perinatal parameters

Gestation wk at delivery 38.7 2.3 39.6 0.9 37.6 2.9 0.001

Neonatal birth weight, g 3060 740 3397 447 2645 819

0.001SGA, % 27.6 9.0 47.9 0.001

Placental weight, g 613 139 668 90 542 158 0.001

Apgar score, 1 min (% 10) 28.8 23.3 35.6 0.09

Cesarean section, % 39.0 32.0 48.0 0.03

Length of hospital stay, newborn, d 10.7 13.8 5.7 3.1 16.6 14.5 0.001

Length of hospital stay, mother, d 6.6 3.3 5.4 1.9 8.8 3.9 0.001

Blood pressure parameters

Clinic systolic BP, mm Hg 146 10.4 143.9 8.4 149.0 11.7 0.002

Clinic diastolic BP, mm Hg 94.6 6.7 91.5 6.6 96.1 6.2 0.001

ABPM, systolic BP, 24-h average, mm Hg 123.8 13.7 118.2 12.3 130.7 12.2 0.001

ABPM, systolic BP, daytime average, mm Hg 126.9 14.1 122.2 13.5 132.7 12.5 0.001

ABPM, systolic BP, nighttime average, mm Hg 117.9 15.4 110.8 12.9 126.6 13.7 0.001

ABPM, diastolic BP, 24-h average, mm Hg 73.8 9.8 68.7 7.6 80.0 8.9 0.001

ABPM, diastolic BP, daytime average, mm Hg 76.3 10.1 71.3 8.2 82.4 8.7 0.001

ABPM, diastolic BP, nighttime average, mm Hg 69.1 10.7 63.7 8.4 75.7 10.3 0.001

BMI indicates body mass index; UA, uric acid; BP, blood pressure; ABPM, ambulatory blood pressure measurement; SGA, small forgestational age.

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the present study, SGA infants were defined as those weighing lessthan the 10th centile, based on nationwide derived centile charts forsingleton births. 17

All of the results are expressed as mean SD, unless otherwiseindicated. Comparisons between groups were performed using theunpaired Student t test for continuous variables and the Fisher exacttest for proportions. Strength of association of UA with the outcomes(development of preeclampsia and SGA) was assessed by binarylogistic regression, unadjusted first, and after adjustment for age,gestation week, serum creatinine, hemoglobin and platelet levels,and both office and ambulatory BPs; association of serum UA andother variables with birth weight centiles was evaluated by a multiplelinear regression model. Predictive accuracy of laboratory and BP

parameters was assessed by calculating the areas under the receiveroperating characteristic curves, which were compared according tothe method of Hanley and McNeil 18 ; optimal cutoff values werechosen as the point on the receiver operating characteristic curve,closest to the top left corner. P values 0.05 were considered assignificant. All of the calculations were performed using the SPSS15.0 (SPSS Inc, Chicago, IL), and Medcalc 9.1 (Mariakerke,Belgium) software.

The study was approved by the hospital ethics committee. Becausethe study parameters were noninvasive and obtained as part of aroutine clinical management, the committee did not require signedinformed consent; however, verbal informed consent was obtained inall of the cases.

ResultsOverall, 163 women completed the study; among those whodid not, 20 were excluded because they did not meet the BPcriteria on entry, 3 because of proteinuria 300 mg/24 hours,7 because of incomplete clinical data, and 11 because of insufficient quality of the ambulatory BP monitoring record-ings, and 2 withdrew their consent.

Seventy-three women (44.7%) developed preeclampsia,and 43 SGA infants (26.4%) were born. One stillbirthoccurred. The average interval between time of study entryand preeclampsia diagnosis was 14.7 5.1 days.

Demographic, laboratory, perinatal, and BP parameters areshown in Table 1. Women who developed preeclampsia

tended to be younger and have higher levels of UA, hemo-globin, and creatinine; lower levels of platelets; a higher

incidence of cesarean section and SGA infants; and bothhigher office and monitored BP.

Table 2 shows the results of logistic regression analysis:the unadjusted odds ratio for UA associated with the devel-opment of preeclampsia was 9.1 (95% CI: 4.8 to 17.4;P 0.001), and after adjustment for age, gestation week,hemoglobin and platelet levels, serum creatinine, officesystolic and diastolic BPs, and 24-hour average systolic anddiastolic BPs, it was 7.1 (95% CI: 3.2 to 15.7; P 0.001).When the association between maternal serum UA and thechance of giving birth to an SGA infant was considered, the

unadjusted odds ratio was lower (1.6; 95% CI: 1.1 to 2.4;P 0.001), and after adjusting for confounders it was 1.6(95% CI: 1.1 to 2.3; P 0.02). In this regression model,first-trimester UA was not significantly associated with eitherpreeclampsia or SGA (Table 2). Table 3 shows the results of multiple linear regression, with birth weight centile as thedependent variable: again, serum UA and monitored diastolicBP 24-hour average were the only variables significantlyassociated with birth weight centile. Hyperuricemic (UA

309 mol/L; n 9) women who did not develop preeclamp-sia had a higher incidence of SGA compared with normouri-cemic women (22.2% versus 4.9%; P 0.05).

Receiver operating characteristic analysis (Table 4)showed that serum UA was an accurate predictor of pre-eclampsia in this population (areas under the receiver oper-ating characteristic curve: 0.955; sensitivity: 87.7%; specific-ity: 93.3%; positive predictive value: 91.4%; negativepredictive value: 9.6%, for a cutoff of 309 mol/L [5.2mg/dL]), as well as serum UA increase from first trimester(areas under the receiver operating characteristic curve:0.961; sensitivity: 90.4%; specificity: 97.8%; positive predic-tive value: 97.1%; negative predictive value: 7.4%, for acutoff of 113 mol/L [1.9 mg/dL]); a combination of theabove criteria (either UA level 309 mol/L or an increase

113 mol/L) yielded a sensitivity of 93.6% and a specific-

ity of 91.8% (positive predictive value: 90.2%: negativepredictive value: 5.2%).

Table 2. Results of Logistic Regression

Parameter

Preeclampsia SGA

Odds Ratio 95% CI P Odds Ratio 95% CI P

UA, per 59.48 mol/L, 1 mg/dL 7.08 3.20 to 15.69 0.001 1.58 1.06 to 2.37 0.02

First-trimester UA, per 59.48 mol/L, 1 mg/dL 1.23 0.85 to 3.07 0.27 1.15 0.32 to 4.19 0.79

Hemoglobin, per 10 g/L 1.57 0.95 to 2.59 0.10 1.24 0.88 to 1.74 0.22Platelets, per 1000/mm 3 0.994 0.98 to 1.10 0.31 1.00 0.99 to 1.01 0.84

Serum creatinine, per 8.84 mol/L, 0.1 mg/dL 1.21 0.56 to 2.61 0.63 0.76 0.56 to 1.04 0.10

Ambulatory 24-h average, systolic BP, per mm Hg 1.01 0.94 to 1.07 0.91 1.02 0.98 to 1.07 0.33

Ambulatory 24-h average, diastolic BP, per mm Hg 1.08 0.99 to 1.18 0.07 1.07 1.00 to 1.14 0.04

Office systolic BP, per mm Hg 1.06 0.97 to 1.15 0.20 0.97 0.93 to 1.02 0.33

Office diastolic BP, per mm Hg 0.99 0.86 to 1.12 0.74 1.07 0.98 to 1.17 0.13

Gestation wk 1.05 0.82 to 1.35 0.68 0.84 0.73 to 0.98 0.02

Age, per y 0.80 0.71 to 0.92 0.006 1.01 0.92 to 1.10 0.47

Dependent variables were preeclampsia and SGA; explanatory variables were as follows: age, gestation wk, serum creatinine, UA (current and first-trimester levels), hemoglobin and platelet levels, office and ambulatory systolic and diastolic BPs. UA indicates uricacid; BP, blood pressure; SGA, small for gestational age.

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First-trimester UA was a poor predictor of preeclampsia,and it showed a sensitivity of 80% but unacceptably poorspecificity for SGA prediction (Table 4). Regarding BPparameters (Table 4), monitored BP performed better thanoffice BP and diastolic better than systolic BP for theprediction of both preeclampsia and SGA, although not aswell as UA.

DiscussionIn this sample of women with gestational hypertension, wehave identified UA as a reliable predictor of preeclampsia.Although the literature reporting predictive indicators forpreeclampsia is fairly extensive, evidence on the accuracy of various tests to predict preeclampsia in women with gesta-tional hypertension is sparse and based mostly on retrospec-tive analyses, rather than on cohort studies, such as the one

we are reporting. Recently, several studies, 4,7,9,10,14 mostlyretrospective, have shown an association between first-trimester UA and the later development of preeclampsiaand/or SGA. In our sample of patients (which included onlywomen with suspected gestational hypertension), first-trimester UA was not associated so strongly with adverseoutcomes; actually, although a fairly sensitive marker forSGA (86.0% sensitivity), it lacked specificity. Conversely,when measured at the moment of initial hospital admission, atfirst diagnosis of pregnancy-induced hypertension, UA (andeven better, its increase from first trimester) carries a muchhigher prognostic value, with a strong correlation to adversematernal outcomes, as reported in 2 recent retrospectivestudies. 19,20 However, retrospective, case-control studies areknown to provide more optimistic results regarding thepredictive capability of a model, with respect to cohortstudies, 21 because of the fact that, in case-control studies,controls are generally on the healthy side of the diseasespectrum, whereas cases generally display the most severe

presentation of a given disease. In this respect, we believe ourprospective study lends stronger support for a role of UA asa predictor of preeclampsia and/or SGA.

The debate is still open whether UA is a simple marker of disease or has a causal role in the development of preeclamp-sia and/or retarded fetal growth. Although the cause of hyperuricemia in preeclampsia has not definitively beenelucidated, current evidence suggests that decreased renalclearance is probably the most important mechanism. How-ever, the increase in UA levels is too large to be attributedsolely to the reduction of glomerular filtration rate; thus, theremust also be decreased secretion or increased reabsorption.This phenomenon appears to be analogous to the decrease in

urate clearance produced by the infusion of vasoconstrictors,such as norepinephrine, 22 and to the increase of blood UAlevel and diminution in its clearance observed in glomerulo-nephritis. 23 According to these considerations, UA could bean early marker of preeclampsia. Other than reduced renalclearance, there may occur increased placental production of UA secondary to placental ischemia and increased tropho-

Table 3. Results of Multiple Linear Regression

ParameterB

CoefficientStandardized

P

UA, mol/L 4.28 0.28 0.01

First-trimesterUA, mol/L

1.46 0.02 0.80

Hemoglobin, g/L 2.05 0.10 0.16Platelets, 1000/mm 3 0.02 0.04 0.61

Serum creatinine, mol/L 9.80 0.07 0.52

Ambulatory 24-h average,systolic BP, mm Hg

0.04 0.02 0.84

Ambulatory 24-h average,diastolic BP, mm Hg

0.69 0.26 0.01

Office systolic BP, mm Hg 0.21 0.08 0.33

Gestation wk 0.95 0.11 0.13

Office diastolicBP, mm Hg

0.16 0.04 0.63

Dependent variables was birth weight centile; independent variables were as

follows: age, gestation wk, serum creatinine, UA (current and first-trimesterlevels), hemoglobin and platelet levels, office and ambulatory systolic anddiastolic BPs. UA indicates uric acid; BP, blood pressure.

Table 4. Results of ROC Analysis

Parameter

Preeclampsia SGA

AUC (95% CI)OptimalCutoff

Sensitivity/ Specificity, % AUC (95% CI)

OptimalCutoff

Sensitivity/ Specificity, %

UA, mol/L 0.955 (0.911 to 0.981)* 309 87.7/93.3 0.784 (0.712 to 0.844) 309 83.7/71.7

First-trimester UA ( mol/L) 0.659 (0.580 to 0.691) 196 61.6/61.1 0.527 (0.447 to 0.605) 208 86.0/24.2

DUA, mol/L 0.961 (0.918 to 0.985)* 113 90.4/97.8 0.779 (0.709 to 0.840) 101 86.0/70.8

Hemoglobin, g/L 0.660 (0.582 to 0.732) 113 65.8/62.2 0.606 (0.526 to 0.681) 123 39.5/83.3

Platelets, 1000/mm 3 0.758 (0.685 to 0.822) 196 79.5/65.6 0.692 (0.615 to 0.762) 164 57.5/78.3

Serum creatinine, mol/L 0.842 (0.777 to 0.895) 67 83.6/75.6 0.726 (0.651 to 0.793) 67 86.0/61.7

Ambulatory 24-h average, systolic BP, mm Hg 0.775 (0.704 to 0.837) 121 79.5/66.7 0.696 (0.619 to 0.766) 126 62.8/70.8

Ambulatory 24-h average, diastolic BP, mm Hg 0.832 (0.766 to 0.886) 77 71.2/86.7 0.790 (0.719 to 0.850) 79 69.8/82.5

Office systolic BP, mm Hg 0.615 (0.536 to 0.690) 148 42.5/78.9 0.552 (0.472 to 0.630) 147 48.8/65.0

Office diastolic BP, mm Hg 0.683 (0.606 to 0.724) 93 61.6/65.6 0.716 (0.640 to 0.784) 93 69.8/82.5

AUC indicates area under the curve; BP, blood pressure; UA, uric acid; ROC receiver operating characteristic.

*P 0.001 vs hemoglobin, platelets, creatinine, first-trimester UA, and all BP parameters.P 0.01 vs hemoglobin, first-trimester UA, and office and systolic BPs.

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blast shedding, leading to further purine availability forbreakdown. Fetuses exposed to hypoxia (eg, secondary todecreased placental perfusion) have been shown to haveincreased serum levels of purine metabolites. 24 In preeclamp-sia, therefore, it is conceivable that these metabolites cancross into the maternal circulation to be degraded by maternalxanthine oxidase. These latter mechanisms might explain therelationship between raised UA levels and fetal growthretardation. An active role for UA in the development of preeclampsia has been proposed: studies in animals havesuggested that UA may play a more active part in thedevelopment of hypertension in preeclampsia and perhapslater in life. 25,26 UA has been shown to induce endothelialdysfunction in humans 27,28 and, recently, to be able to inducehuman trophoblast production of interleukin 1 by activatingthe Nod-like receptor Nalp 3, thus stimulating the expressionof inflammasome components. 29

Finally, regarding BP parameters, the findings of our studyshow that ambulatory BP monitoring derived measures are

better predictors of preeclampsia and (to a lesser extent)SGA, with respect to office BP, probably because of the highprevalence of white-coat hypertension in the pregnant popu-lation 30 ; however, only 24-hour average diastolic BP wassignificantly associated with SGA and birth weight centileand showed a borderline significant association withpreeclampsia.

PerspectivesIn conclusion, we believe the findings of our study show that,in women with suspected hypertension in pregnancy, serumUA 309 mol/L can accurately predict the later develop-ment of preeclampsia and, more so, an increment

113 mol/L from first-trimester levels. We provide thresh-old values that might prove useful in clinical practice,although, of course, further studies are necessary.

DisclosuresNone.

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708 Hypertension October 2011


prognostic significanc of serum uric acid pe hypertension-2011

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