Early Predictors of Gestational Hypertension

8/11/2019 Early Predictors of Gestational Hypertension

1/6Copyright Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited.

Early predictors of gestational hypertension in alow-risk cohort. Results of a pilot study

Nieves Martell-Clarosa,Fiona Blanco-Kellyb, Mara Abad-Cardiela, Mara J. Torrejonb,Beatriz Alvarez-Alvareza, Manuel E. Fuentesc, Dolores Ortegab, Manuel Arroyob, andMiguel A. Herraizd

Objective:To determine if the clinical or biochemicalmarkers used in pregnancy can be applied as earlypredictors of gestational hypertension.

Design: Prospective cohort study. Population: 315pregnant women referred from the Prenatal Diagnosis Unit

between weeks 1013 of pregnancy and followed up tothe childbirth.

Methods: Biomarkers were measured in serum specimensin the first and second trimester of pregnancy. Bloodpressure (BP) was measured in the first, second and thirdtrimester.

Results:The cumulative incidence of gestationalhypertension was 6.01%. In the first trimester gestationalhypertension predictors were uric acid greater than3.15 mg/dl (P0.01), BMI greater than 24kg/m2

(P0.003) SBP at least 120 mmHg (P0.02) and DBP atleast 71 mmHg (P0.007). After applied multivariateanalysis just uric acid and SBP were statistically significant.

Conclusion: In our cohort of healthy pregnant womenuric acid above 3.15 mg/dl and SBP at least 120mmHg areconsistent predictors of gestational hypertension in the firsttrimester. The most important implication of our study isthe possibility to identify in the first trimester women atrisk to develop gestational hypertension using availablemarkers.

Keywords:biochemical biomarkers, blood pressure,Cystatin-C, gestational hypertension, uric acid

Abbreviations:MoM, multiple of the median; PAPP-A,pregnancy-associated plasma protein A; PE, pre-eclampsia;-HCG, free-b human chorionic gonadothrophin

INTRODUCTION

Gestational hypertension and pre-eclampsia aremultisystem and pregnancy-specific disorders.The incidence is 210% of the pregnancies

depending on the population studied and contribute sub-stantially to perinatal morbidity and mortality of bothmother and fetus [12]. Their origin is still unknown, butit is accepted that it is caused by the presence of theplacentae[3]. Hypertension is a common first clinical pres-entation of pre-eclampsia, appearing before the onset ofproteinuria in many cases[4].

Clinicians have traditionally relied on maternal riskfactors to determine which women are at risk, but thereare not biomarkers with high sensitivity and specificity forpre-eclampsia; the problem being that many women havethese factors and do not develop gestational hypertension/pre-eclampsia [57]. Signs and symptoms usually appear

late in pregnancy, even though the pathological mechan-isms begin between the 8th and 18th week of pregnancy.Since early prediction of gestational hypertension and

pre-eclampsia would allow close surveillance and preven-tive strategies, many tests have been assessed until now.However, no single test so far has met the clinical standardsfor a predictive test and it is not clear whether routineassessment of a range of haematological or biochemicalparameters in pregnant women would make it possible topredict development of gestational hypertension[8].

Gestational hypertension has been recognised as a riskfactor for pre-eclampsia, its early detection and treatmentwould allow a decrease in the incidence of pre-eclampsia.Furthermore, hyperuricaemia in women with gestationalhypertension without proteinuria has been associated withadverse fetal outcomes including small for gestational ageinfant (SGA) and preterm birth [9]. Few studies havefocused their objectives in looking for specifically gesta-tional hypertension predictors. We designed a prospectivestudy, which looks for markers of gestational hypertensionin healthy pregnant women.

We focus our study in classical biomarkers previouslyassociated with pre-eclampsia risk as a higher level ofcystacin-C[10], an abnormal lipid profile[11,12]or its shifttowards a dyslipidemic profile [13], the proinflammatorymarker C-reactive protein (CRP)[1416], and the presenceof obesity and overweight. We explore also other

Journal of Hypertension 2013, 31:23802385aHypertension Unit. Hospital Clnico San Carlos, bDepartment of Clinical Chemistry,cDepartment of Epidemiology and Preventive Medicine and dDepartment of Gyne-cology and Obstetrics, Hospital Clnico San Carlos. Instituto de Investigacion Sanitariadel Hospital Clnico San Carlos (IdISSC), Madrid, Spain

Correspondence to Nieves Martell-Claros, Hypertension Unit. Hospital Cl nico SanCarlos. Instituto de Investigacion Sanitaria del Hospital Clnico San Carlos (IdISSC),C/Prof. Martn Lagos s/n. 28040 Madrid, Spain. Tel: +34629112113/34913303395;fax: +34913303280; e-mail:[email protected],[email protected]

Received30 January 2013 Revised 1 July 2013 Accepted16 July 2013

J Hypertens 31:23802385 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.

DOI:10.1097/HJH.0b013e32836523f6

2380 www.jhypertension.com Volume 31 Number 12 December 2013

Original Article
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biomarkers of pre-eclampsia, such as pregnancy-associatedplasma protein A (PAPP-A) and free-b human chorionicgonadothrophin (b-HCG)[1720].

We also studied uric acid levels because in pregnancythey have been proposed not only as a biomarker but alsoto have a pathogenic role in the development of pre-eclampsia in chronic hypertension settings [21,22].

The aim of the present study was to identify early

prognostic factors of gestational hypertension, and theblood pressure (BP) levels evolution along pregnancy.

METHODS

Population sample studiedWe designed a prospective study. We enrolled a total of 315pregnant women referred from the Prenatal Diagnosis Unitof Hospital Clnico San Carlos in Madrid between weeks 10and 13 of pregnancy. Participants were included the day ofthe first trimester chromosomopathies screening (offered toall pregnant women in Spanish national health system).They were informed about the aim of the study and

provided written informed consent. Exclusion criteria were:multiple gestation, chronic hypertension, previous cardio-vascular events, and creatinine more than 1.3 mg/dl, hypo-thyroidism, autoimmune diseases, diabetes mellitus,morbid obesity, previous gestational diabetes, treatmentwith methotrexate or antiepileptic drugs, previous gesta-tional hypertension or pre-eclampsia and maternal age over40 years.

During follow-up women were excluded if any of thefollowing conditions appeared: chromosomopathies, fetalmajor morphological alterations, positive result in the 100goral glucose tolerance test (ADA recommendations) [23],spontaneous abortion, intrauterine growth restriction(IUGR), intrauterine fetal death, or noncomplete obstetricfollow-up of the pregnancy.

The protocol was approved by the ethical committee ofthe Hospital Clnico San Carlos, Madrid, Spain. The pro-cedures followed were in accordance with institutionalguidelines.

MeasurementsWe measured BP, height, and weight in the first (weeks10th13th), second (weeks 20th22nd) and in the thirdtrimester (weeks 30th 32nd). BP was measured with asemiautomatic device with the women in a sitting position,with the arm at the level of the heart, based on the averageof at least two measurements taken using the same arm[24].

The follow-up protocol consisted of obtaining eachtrimester, on the same day as the obstetric routine echog-raphy, a blood sampling after an overnight fast to measuredlipid profile (total cholesterol, HDL-cholesterol, triglycer-ides); uric acid, creatinine, cystatin-C, uCRP. 24-h urinecollection was recovered to quantify proteinuria. ThePAPP-A and free-bHCG were measured only in the firsttrimester. The measurement of urine proteins was per-formed using the pyrogallol red methodology.

Gestational hypertension was defined as SBP at least140 mmHg and/or DBP at least 90 mmHg in at least twooccasions with more than 6-h time interval, after the 20thweek of pregnancy. Pre-eclampsia was considered as

gestational hypertension and proteinuria (protein in urine300 mg/24 h). The study was approved by our HospitalEthics Committee.

Statistical analysisQualitative variables were summarized by their frequencydistribution as well as quantitative variables by their meanand SD. The continuous nonnormally distributed variables

were summarized by the median and interquartile range(IQR: P25P75). For PAPP-A and free-bHCG was employedas multiple of the median (MoM).

In the case of qualitative variables the comparisonbetween the gestational hypertension and non-gestationalhypertension groups was calculated byx2 test, or by Fisherexact test in case more than 25% of the expected valueswere less than 5. For quantitative variables the Studentst-test or nonparametric median test (where appropriate)was used to compare between the two groups.

The study has a 72% of power in uric acid for differencedetection in the first trimester. The study has a 92% of powerin SBP for the difference detection in the firs trimester.

ANOVA repeated measures analysis was used to studythe change in the levels of SBP and DBP between the twogroups.

Receiver operator characteristics (ROC) analysis wascalculated to assess the utility of the independent variables(biomarkers) to distinguish gestational hypertension andnon-gestational hypertension group in the first trimester;the area under curve (AUC) and its 95% confidence intervals(95% CI) were calculated. For the biomarker variables thatshowed a statistically significant AUC and based on theoptimal discriminatory point with the best combination ofsensitivity and specificity values, the cutoff points of thebiomarker variables were determined and new variableswere generated. Sensitivity, specificity and a 95% CI for thenew variables were determined.

In order to evaluate the role of the different new bio-marker variables in the first trimester in the association withgestational hypertension, a multiple logistic regressionanalysis were performed. The model is based on stepwiseforward algorism with the Pvalue set at 0.05 for enteringand 0.1 for exclusion. All results of the regression modelswere presented using the odds ratio (OR) and its 95% CI.

For all determinations a P value less than 0.05 wasconsidered significant.

Statistical analysis was performed using SPSS V.15 stat-istical package (SPSS, Chicago, Illinois, USA).

RESULTS

We enrolled 315 pregnant women on the same day asobstetric routine echography. Out of them, 10% (n 32)were not included in the statistical analysis (21 did notcomplete the obstetric follow-up, three had intrauterinedeaths, three had a voluntary pregnancy interruption, threewere spontaneous abortions and two presented IUGR). Inthe second and third visit, 8% (25) and 19% (60) of the totalenrolled pregnant women did not undergo blood sampling.

Mean age of our cohort was 30.254.71 years, and BMI23.97 4.3kg/m2. The clinical and biochemical character-istics of the total group are shown in Table 1. The

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cumulative incidence of gestational hypertension (followedor not by pre-eclampsia) was 6.01% (95%, CI: 3.068.90).From the 17 women who developed gestational hyperten-sion, six also developed pre-eclampsia (2.1%).

We divided the sample in two subgroups, those with andwithout gestational hypertension. The univariate analysis ofthe first trimester and gestational hypertension status of themeasured biomarkers, clinical characteristics and BPmeasurements are shown inTable 1.

The gestational hypertension group showed higherlevels of BMI, uric acid, SBP and DBP to be statisticallysignificant.

We also performed univariate analysis in the secondtrimester variables. Only HDL-cholesterol was significantlydifferent (nongestational hypertension: 69.7 13.6; gesta-tional hypertension: 61.8 14.9, P 0.02).

We observed from the first trimester higher BP levels inthose who developed gestational hypertension, statisticallydifferent compared with nongestational hypertension(P3.15 mmol/l andSBP (>120 mmHg), as we showed previously. When boththese variables were combined the prediction valueimproved the specificity (84.2) but reduced the sensitivity(50%); AUC 0.75 (CI: 0.632-0.873) for the two-variablecombination.

DISCUSSION

In our cohort of healthy pregnant women we have ident-ified a cut off level in BP and uric acid during the firsttrimester as predictors of gestational hypertension.

The incidence of gestational hypertension and pre-eclampsia in our prospective study is in concordance withthat previously reported in the general population[25].

Wilson et al. [26] reported in 1980 on 69 pregnantwomen that in normal pregnancy the mean BP decreasesearly in pregnancy, and by mid trimester diastolic levels areoften 10 mmHg lower than postpartum measurements,approaching prepregnancy values near term.. In our cohort(n285), we did not find any changes in BP across preg-nancy in both groups. SBP and DBP levels were steadyhigher in the gestational hypertension group than in thenongestational hypertension. We found in the first trimesterthat SBP at least 120 mmHg increased the risk of develop-ment of gestational hypertension by 3.6-fold. Kennyet al.[27]described the same SBP level in a cohort of pregesta-tional women, as predictor of pre-eclampsia. Moreover,Tranquilliet al.[28]concluded, with results of 24-h ambu-latory BP monitoring registers, that a DBP more than68 mmHg is a predictor of gestational hypertension in thesecond trimester.

By identifying a set of biomarkers we may achieve the

appropriate predictive values to help in daily clinical prac-tice, not having to rely on several conditions with lowprediction value for gestational hypertension.

During uncomplicated pregnancies, uric acid concen-trations decrease by 2530% in early pregnancy but thenincrease throughout pregnancy until the end of it, whenthey approach nonpregnant values[29]. In our cohort, weobserved that uric acid was significantly higher in the firsttrimester in women who developed gestational hyperten-sion, with an increase of 4.02-fold (P0.01) in the risk ofdeveloping gestational hypertension compared with non-gestational hypertension pregnant women. Uric acid levelshigher than 5.2mg/dl [25] or 4.7 mg/dl [4] have been

TABLE 1. Clinical and biochemical characteristics in total group and subgroups. Univariate analysis from1st trimester

Total Non-GH GH

P

(N283) (N266) (N17)

Mean, (SD) Mean, (SD) Mean, (SD)

T. cholesterol (mg/dl) 193.7 (31.2) 193.9 (31.2) 190.53 (31) 0.67

Triglycerides (mg/dl) 94 (73116.8) 94 (74116) 96 (66123) 0.76

HDL-Chol (mg/dl) 66.64 (12.6) 66.8 (12.4) 63.6 (15.5) 0.31

Creatinine (mg/dl) 0.69 (0.08) 0.69 (0.07) 0.75 (0.14) 0.08Cystatin-C (mg/l) 0.52 (0.08) 0.51 (0.08) 0.54 (0.12) 0.34

Uric acid (mg/dl) 3.04 (0.67) 3.01 (0.67) 3.45 (0.62) 0.01

uCRP (mg/dl) 0.30 (0.140.78) 0.30 (0.140.76) 0.48 (0.151.20) 0.41

MoMbHCG 1.07 (0.71.5) 1.1 (0.71.5) 1.1 (0.71.9) 0.80

MoM Papp-A 1.1 (0.81.6) 1.4 (0.81.6) 0.9 (0.81.9) 0.18

BMI 23.97 (4.30) 23.7 (3.94) 28.1 (7.0) 0.02

SBP (mmHg) 115.8 (11.3) 115.2 (11) 125.4 (11) 0.001

DBP (mmHg) 69.2 (8.1) 69 (8) 77.3 (7.4)



NON-GH

GH

135

125.4

121.7

115.2114.6

114.1

126.4

MeanSBP(mmHg)95%

CI

1 t rimester 2 t rimester 3 t rimester

130

125

120

115

110

(a)

NON-GH

GH

85

77.375.9

68.767.4

69.7

78.6

MeanDB

P(mmHg)95%C

I

1 t rimester 2 t rimester 3 tr imester

80

75

70

65

(b)

FIGURE 1 Evolution of SBP in both groups. P24 0.70 (0.550.84) 0.006 64.7 61.2 0.03 2.70 (1.03 7.09)

Uric acid (mg/dl)>3.15 0.69 (0.57 0.82) 0.008 76.5 65.8



described in pregnancies with gestational hypertensionassociated with 2.3-fold higher odds of progression topre-eclampsia[25]. Early detection of gestational hyperten-sion is important in order to reduce the progression to pre-eclampsia, furthermore each week of delay in the onset ofgestational hypertension was associated with about 50%reduction in the odds of progression to pre-eclampsia [4].The relevance of our results is the finding of a thresholdlevel of uric acid in the first trimester as predictor of gesta-tional hypertension. As an external validation, if we appliedour threshold of 3.15 mg/dl in the first trimester to theBellomos gestational hypertension cohort all the womencould be detected before gestational hypertension was

established.Nevertheless, Laughonet al.[30], in her study found norisk of development gestational hypertension with higheruric concentration in the first trimester. But when theauthors compared women who remained normotensiveto those who developed hypertensive disease by the pres-ence or absence of hiperuricemia, the mean first trimesteruric acid concentration was significantly lower in normo-tensive women compared with women who developedthe hiperuricemic forms of gestational hypertension andpre-eclampsia. The elevated uric acid in the first trimestermay represent concentrations before pregnancy, such asfrom metabolic syndrome or prehypertension, reportedincreases in xanthine oxidase, a synthetic enzyme for uricacid, in pre-eclamptic women[30]. Uric acid increased maybe induce by reduced renal clearance, and increased plan-cental production due to placental ischemia and increasedtrophoblast shedding, leading to further purine availability[25].

Kidney biomarkers as creatinine or more sensitivemarker for subtle changes of glomerular filtration rate inpregnancy as cystatin C[31]have been used as variables forthe gestational hypertension severity, but not as earlypredictors. Also, we did not find relationship of creatinineor cystatin C levels with the presence of gestational hyper-tension.

Regarding lipid profile, hypertriglyceridemia and total

cholesterol have been positively correlated with the devel-opment of pre-eclampsia[1113]. Nevertheless these cor-relations may be confounded by the presence of diabetesmellitus, obesity, nonfasting sampling or ethnic differences.We did not find association between the levels of trigly-cerides in gestational hypertension compared with non-gestational hypertension pregnant women.

The uCRP did not show discriminative capacity betweengroups in our cohort; neither did it seem to have a role inprediction of gestational hypertension. Also we did not findany association between MoM bHCG and PAPP-A withgestational hypertension. Poon et al. [32] described aspecific algorithm for the calculation of patients specific

risks for early and late pre-eclampsia and gestationalhypertension, based in a combination of factors in thematernal history, the measurement of MAP and uterineartery pulsatility index and maternal serum levels ofplacental growth factor including PAPP-A that only pre-dicted 18% of gestational hypertension. So, this proteindoes not seem to be a specific marker for developmentof gestational hypertension.

Due to the low frequency of gestational hypertension inpregnancy in healthy women, the results of our study areunderpowered and should be replicated/proved in largerstudies.

In conclusion, in our cohort of healthy pregnant womenSBP more than 120mmHg and uric acid above 3.15 mg/dlare consistent predictors of gestational hypertension in thefirst trimester. The most important implication of this studyis the possibility to identify in the first trimester women atrisk to develop gestational hypertension using availablemarkers.

ACKNOWLEDGEMENTS

Conflicts of interestThe authors do not have any conflict of interest.

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TABLE 3. Multivariate analysis

First Trimester P OR (CI 95%)

Uric acid (mg/dl)>3.15 0.017 4.02 (1.213.47)

SBP120 mmHg 0.029 3.6 (1.0712.06)

Adjusted values. P, statistical significance of the discriminative capacity. OR, odds ratio.

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Reviewers Summary Evaluations

Reviewer 1Gestational hypertension is the most common medical com-plication of pregnancy and is associated with increasedmaternal, fetal, and neonatal morbidity and mortality. In acohort of 315 healthy pregnant women, uric acid 3.15mg/dl and systolic BP 120 mmHg in the first trimester werefound to be predictive of gestational hypertension.

The results have to be interpreted with caution as theincidence of gestational hypertension was low, and there-

fore error of small numbers cannot be excluded. The resultsare applicable only to low-risk populations, as females withknown and widely accepted risk factors for developingpreeclampsia were excluded: multiple gestation, chronichypertension, chronic kidney disease, autoimmune dis-ease, diabetes mellitus, morbid obesity, previous gesta-tional hypertension or preeclampsia, and maternal ageover 40.

Reviewer 2The search for predictive markers of gestational hyperten-sion (and preeclampsia) is still a puzzling open question. Todate there is no marker to predict with sufficient certaintythe subsequent development of gestational hypertension innormotensive pregnant women. The research here pre-sented by Martell-Claros and co workers tries to give ananswer to the problem. In a well designed prospectivestudy and with a multivariate analysis the authors identifiedtwo simple markers which were altered by the first trimesterin women who subsequently developed gestational hyper-

tension: increased uric acid and SBP over 120 mmHg. Ifthese results are confirmed in a larger series of women thiswould offer a simple prognostic tool. A limitation of thisnice piece of work is the relatively small series, and thepossibility that a BP over the normal pregnancy rangewould rather be the expression of a general tendency tohypertension rather than to true gestational hypertension,which is a condition due to impaired placentation.

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Early Predictors of Gestational Hypertension