PAM Con Punto de Corte 90 Tiene Una Sensibilidad

Ultrasound Obstet Gynecol 2012; 40: 398405Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.11205

Early pregnancy screening for hypertensive disordersin women without a-priori high risk

A. ABDELAZIZ*, M. A. MAHER, T. M. SAYYED, M. F. BAZEED and N. S. MOHAMED*Department of Obstetrics and Gynecology, Faculty of Medicine, Ain-Shams University, Cairo, Egypt; Department of Obstetrics andGynecology, Faculty of Medicine, Menofiya University, Shebin-Elkom, Egypt; Department of Radiology, Faculty of Medicine, MansouraUniversity, Mansoura, Egypt; Department of Biostatistics, High Institute of Public Health, Alexandria University, Alexandria, Egypt

KEYWORDS: high-risk pregnancy; mean arterial blood pressure; pre-eclampsia; pregnancy-induced hypertension; solubleendoglin; uterine artery Doppler

ABSTRACT

Objectives To evaluate the performance of mean arterialpressure, uterine artery pulsatility index and solubleendoglin level alone or in combination in screeningfor hypertensive disorders in pregnant women withouta-priori high risk.

Methods This was a nested casecontrol study ofwomen with singleton pregnancies without a-priorihigh risk who developed pregnancy-induced hypertensivecomplications. Women were enrolled into the study at1114 weeks gestation, when mean arterial pressureand uterine artery pulsatility index were recorded anda blood sample was taken for measurement of solubleendoglin. Women were followed up in the clinic todetect development of any hypertensive disorder. Eachaffected case was matched with two normotensive controlwomen with uncomplicated pregnancies that resulted inphenotypically normal infants. Mean values for eachvariable were compared between cases and controls.Sensitivities, positive predictive values and negativepredictive values at fixed specificity were derived fromreceiveroperating characteristics (ROC) curves.

Results During the study period, 2120 patients wereexamined. Of these, 170 (8.02%) were excluded becausethey were lost to follow-up and in 52 (2.45%) there wasfetal death or miscarriage before 24 weeks gestation.Thus, 1898 cases formed the cohort population. Ofthese, 89 (4.69%) patients developed complications(study group), including 16 (0.84%) cases with earlypre-eclampsia (PE), 60 (3.16%) with late PE and 13(0.68%) with gestational hypertension (GH). There were49 (2.58%) cases of spontaneous preterm delivery before34 weeks. The rest of the cohort population (1760(92.73%) patients, the base cohort) were not affectedby PE or GH. The control group comprised 178 patients.

The best model for the prediction of any of the typesof hypertensive disorders was one that combined meanarterial pressure with soluble endoglin (area under theROC curve (AUC), 0.83). The predictive value of the threecombined markers was highest for screening for early andlate PE (AUC, 0.86 and 0.83, respectively). When eachmarker was considered alone, the highest prediction ofany type of hypertensive disorder was achieved by meanarterial pressure (AUC, 0.73). Sensitivity was lowest fordetection of GH when screening both by individual andby combined markers.

Conclusion First-trimester screening can be useful inpredicting women at high risk of developing hypertensivedisorders of pregnancy but more prospective longitudinalstudies are needed. Copyright 2012 ISUOG. Publishedby John Wiley & Sons, Ltd.

INTRODUCTION

Hypertensive disorders of pregnancy (HDP) are amongthe main public health issues worldwide1. They accountfor an estimated 1015% of maternal deaths globallyand 18% in the USA2. Although the primary etiologyremains elusive, it has been postulated that early-onsetdisease is more likely to be associated with abnormalvillous and vascular morphology, whereas in late-onsetdisease, the placental morphology and histology are notdissimilar to those of controls3. However, there is evidencethat late-onset compared with early-onset disease is morelikely to be related to impaired glucose metabolism4 andto a hyperdynamic-low peripheral resistance maternalcardiovascular profile5, a profile similar to that foundin non-pregnant obese patients with subclinical glucoseintolerance6.

In the UK, the National Institute for Clinical Excellencerecommends that during the first prenatal visit a womans

Correspondence to: Dr M. A. Maher, Department of Obstetrics and Gynecology, Faculty of Medicine, Menofiya University, Shebin-Elkom,Egypt (e-mail: [email protected])

Accepted: 28 May 2012

Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

Early pregnancy screening for hypertensive disorders 399

level of risk for pre-eclampsia (PE) should be evaluated7.The traditional method of screening is by maternal history,which alone would identify only 30% and 20% of casesof early and late PE, respectively8. Poon et al.9 reportedincreased mean arterial pressure (MAP) during the firsttrimester in pregnancies destined to develop PE. Dopplerstudies of the uterine arteries have shown increased pul-satility index (UtA-PI) during both the second trimester10

and the first11. A new marker which has shown promis-ing results in PE detection is soluble endoglin (sEng), a180-kDa homodimeric transmembrane glycoprotein core-ceptor for members of the transforming growth factor(TGF)- superfamily, comprising TGF-1 and TGF-3.Evidence has indicated that sEng contributes to the patho-genesis of PE by regulating the activity of endothelial nitricoxide synthase (eNOS) and, consequently, local vascu-lar tone, by inhibiting TGF-1 binding and signaling inendothelial cells, blocking TGF-1-mediated activation ofeNOS and inhibiting NOS-dependent vasodilation12.

The aim of this study was to evaluate the performanceof MAP, UtA-PI and sEng, alone or in combination,between 11 and 14 weeks of gestation, in screeningfor hypertensive disorders in pregnant women withouta-priori high risk.

SUBJECTS AND METHODS

This was a nested casecontrol study carried out betweenOctober 2009 and December 2010 in women attend-ing the Obstetrics and Gynecology Department, ArmedForces Hospital Southern Region, Kingdom of Saudi Ara-bia, for routine antenatal care. Women of any age andany parity were enrolled consecutively at presentationfor the routine first-trimester scan to avoid any potentialselection bias, provided that they had a gestational age(GA) of 1114 weeks and a singleton pregnancy. GA wasestablished on the basis of menstrual dates and confirmedby first-trimester ultrasound; if there was a difference ofmore than 7 days, then the ultrasound value was used.

Those with a history of hypertensive disorder in a pre-vious pregnancy or a medical disorder that may affect thecourse of pregnancy (e.g. chronic hypertension, chronicrenal disease or autoimmune diseases), obese patients(body mass index > 30 kg/m2) and those with major fetalanomaly were excluded. Since termination of pregnancyis prohibited in Saudi Arabia, screening for aneuploidy(for counseling purposes only) is by nuchal translucencymeasurement and no other biochemical tests are required.

The primary outcome was development of any of thehypertensive disorders in pregnancy (early PE, late PE orgestational hypertension (GH)). Written informed consentwas obtained from each woman after she had received fullwritten information about the nature and risks of the dis-eases as well as the benefits and design of the researchproject. The study was approved by the hospitals researchand ethics committee.

At enrollment, we recorded MAP and UtA-PI and tooka venous blood sample for measurement of sEng. Womenwere then followed up in the clinic every 4 weeks until

week 28, then every 2 weeks until week 36 and thenweekly until delivery, unless complications developed thatnecessitated follow-up at shorter intervals or hospitaladmission.

Measurement of mean arterial pressure (MAP)

In current clinical practice, while use of mercury sphygmo-manometers remains the gold standard for non-invasiveblood pressure (BP) monitoring13, there are concernsregarding both their clinical performance and safety14,15.These problems have been largely overcome by use ofautomated BP devices. We used an automated DinamapPro 1000 V3 (GE Medical Systems, Milwaukee, WI,USA) for BP measurement, a device approved for usein pregnancy16. Internal calibration of the machine wasverified daily, while full calibration according to the Asso-ciation for the Advancement of Medical Instrumentationwas performed every 6 months. After the patient hadrested for 5 min in a seated position, her arms were sup-ported at the level of the heart. With a cuff size appropriatefor the maternal arm circumference, the measurement wasobtained automatically from each arm and the higher ofthe two MAPs was used for the subsequent analysis ofresults17.

Measurement of uterine artery pulsatility index(UtA-PI)

Transabdominal ultrasound was performed using a GEVoluson 730 (GE Medical Systems) machine equippedwith a 3.5-MHz abdominal convex probe. A sagittal sec-tion of the uterus was obtained, and the cervical canaland internal cervical os were identified. The transducerwas gently tilted from side to side and color flow mappingwas used to identify each uterine artery along the side ofthe cervix and uterus at the level of the internal os. Pulsedwave Doppler imaging was used with the sampling gateset at 2 mm to cover the whole vessel and care was takento ensure that the angle of insonation was < 3016. Foreach side, when three similar consecutive waveforms wereobtained, the UtA-PI was measured, and the lower of thetwo PI values was considered during screening.

Blood samples and biochemical analysis

Into tubes containing EDTA (ethylenediaminetetraaceticacid) as an anticoagulant, 5-mL venous blood sampleswere drawn from each patient and these were processedwithin 1 hour. Plasma was separated by centrifugation at4000 g for 10 min and samples were stored immediatelyat 80C until assay of sEng was indicated for bothcases and their controls at the end of the study.Samples were analyzed using commercial enzyme-linkedimmunosorbent assay (ELISA) kits (R & D Systems,Minneapolis, MN, USA). The lower limit of detection(sensitivity) of the assay was 0.08 ng/mL.

Copyright 2012 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2012; 40: 398405.

OSCARResaltado

400 Abdelaziz et al.

Diagnosis of hypertensive complications

In 2000, the National High Blood Pressure Educa-tion Program Working Group on High Blood Pressurein Pregnancy defined four groups of hypertension inpregnancy18: (1) GH: systolic BP 140 or diastolic BP 90 mmHg for first time during pregnancy, no pro-teinuria, BP returns to normal before 12 weeks postpar-tum, and final diagnosis made only postpartum; (2) PE:minimum criteria: BP 140/90 mmHg after 20 weeksgestation, proteinuria 300 mg/24 hours or 1+ dip-stick; increased certainty of PE: BP 160/110 mmHg,proteinuria 2.0 g/24 hours or 2+ dipstick; eclamp-sia: seizures that cannot be attributed to other causesin a woman with PE; (3) chronic hypertension: BP 140/90 mmHg before pregnancy or diagnosed before20 weeks gestation, or hypertension first diagnosed after20 weeks gestation and persistent after 12 weeks post-partum; (4) superimposed PE on chronic hypertension:new-onset proteinuria 300 mg/24 hours in hypertensivewomen but no proteinuria before 20 weeks gestation, orsudden increase in proteinuria or BP in women withhypertension and proteinuria before 20 weeks gestation.

Early PE referred to any case that required deliverybefore 34 weeks gestation, while late PE referred to anycase that required delivery at or after 34 weeks. Thecut-off to define early and late-onset PE was chosenarbitrarily. Each case of PE or GH was matched forGA, pregestational body mass index and duration ofblood sample storage with two controls selected randomlyfrom normotensive pregnant women with uncomplicatedpregnancies that ended in delivery of a phenotypicallynormal infant.

Statistical analysis

The data were tested for normal distribution usingthe KolmogorovSmirnov test. Quantitative data wereexpressed as mean and SD and analysis of variance(ANOVA) with post-hoc Bonferroni corrections formultiple comparisons was utilized to determine thedifferences in means among groups. Qualitative datawere expressed as proportions and comparison ofcategorical variables was done using chi-square orMonte Carlo exact test with Z-test for pair-wisegroup comparisons. Correlations of continuous variableswere assessed by Pearsons correlation coefficient.Initially, three univariable logistic regression analyseswere performed using only MAP, UtA-PI and sEngas the independent variable in each case. A combinedmultiple logistic regression model was constructedusing a stepwise procedure to identify the significantpredictors of HDP. The validity of the model wasassessed by HosmerLemeshow goodness-of-fit test andreceiveroperating characteristics (ROC) curve. The ROCcurves for each model were developed based on thepredicted probabilities for every patient. The optimal cut-off for different predictors was calculated for a 10%false-positive rate (FPR) using the ROC curves. We

compared ROC curves using the algorism described byDeLong. P< 0.05 was considered statistically significant.All data analysis was performed using SPSS version 16(SPSS Inc., Chicago, IL, USA). MedCalc software version9.5.0.0 (MedCalc Software, Mariakerke, Belgium) wasused for comparison of ROC curves.

RESULTS

During the study period we examined prospectively 2120women with singleton pregnancies at 1114 weeks. Ofthese, 170 (8.02%) were excluded because they werelost to follow-up and in 52 (2.45%) there was fetaldeath or miscarriage before 24 weeks gestation. Thus,1898 cases formed the cohort population. Of these, 89patients (4.69% of the cohort population) developedcomplications (the study group), including 16 (0.84%)cases with early PE, 60 (3.16%) cases with late PE and 13(0.68%) cases with GH. There were 49 (2.58%) cases ofspontaneous preterm delivery before 34 weeks. The restof the cohort population (1760 (92.73%) patients, thebase cohort) were not affected by PE or by GH. For eachaffected case, two controls were selected randomly fromthe base cohort (178 patients, the control group).

The baseline characteristics and outcomes of patientsincluded in the final analysis (n= 1849, i.e. the base cohortand the study group) are presented in Table 1. There wereno significant differences between groups regarding theirbaseline characteristics (P> 0.05). Regarding outcomes,the proportion of Cesarean sections was higher (Z< 0.05)in both early and late PE groups than in base cohort,control group and GH groups, with no significantdifference between early and late PE groups. There wasno significant difference in Apgar score between early andlate PE groups (Z= 0.569), while cases of early PE had asignificantly lower Apgar score than did both base-cohortand control group (Z= 0.041 and 0.018, respectively).The number of cases admitted to a neonatal intensivecare unit was significantly higher in the early PE groupthan in both base-cohort and control group (Z= 0.037and 0.047, respectively), but there was no significantdifference between early and late PE groups (Z= 0.643).When GA at delivery and neonatal birth weight werecompared between groups, early and late PE groups weresignificantly different from each other, and both weresignificantly lower compared with the other groups.

With respect to the markers of HDP, there was ahighly significant difference (P< 0.001) between groups(Table 2). Post-hoc testing showed that MAP in cases ofHDP (early and late PE and GH) was significantly higherthan in base-cohort and control-group; moreover, MAPin cases of early PE was significantly higher than in casesof both late PE and GH. UtA-PI was significantly higherin both early and late PE groups than in the other groups,while sEng was significantly higher in the early PE groupthan in the other groups.

Single logistic regression analysis using each HDPmarker as the only independent variable revealed thatall three markers were significant predictors of HDP



Table 1 Baseline characteristics and outcomes of 1849 women without a-priori high risk screened for hypertensive disorders of pregnancy

Study group (n =89)Test of significance

Characteristic/ Base cohort Control group Early PE Late PE GHoutcome (n =1760) (n =178) (n = 16) (n =60) (n =13) Test statistic* P

Maternal age (years) 26.4 4.5 25.9 4.2 26.4 5.4 25.7 4.9 24.8 2.9 F = 1.4 0.210Maternal BMI (kg/m2) 26.5 2.8 27.3 3.7 27.2 2.8 27.1 3.1 27.2 2.8 F = 2.03 0.072Parity 3.1 1.7 3.3 1.8 2.2 1.7 2.9 1.2 3.3 1.05 F = 1.5 0.179Maternal ethnicity 0.680

Caucasian 1744 (99.1) 176 (98.9) 170 (100) 16 (100) 13 (100)Asian 16 (0.9) 2 (1.1) 0 (0) 0 (0) 0 (0)

GA at enrollment (weeks) 12.2 0.79 12.2 0.79 12.2 0.83 12.1 0.8 12.2 0.8 F = 0.33 0.894Mode of delivery 2 = 2.04 < 0.0001

Vaginal 1620 (92.0) 164 (92.1) 4 (25.0) 29 (48.3) 11 (84.6)Cesarean section 140 (8.0) 14 (7.9) 12 (75.0) 31 (51.7) 2 (15.4)

Apgar score < 7 at 5 min 139 (7.9) 10 (5.6) 4 (25.0) 9 (15) 0 2 = 12.8 0.012Admission to NICU 184 (10.5) 19 (10.7) 5 (31.2) 13 (21.7) 1 (7.7) 2 = 14.4 0.006GA at delivery (weeks) 38.1 1.5 38.2 1.5 33.4 1.9 36.2 1.1 38.9 1.4 F = 63.5 < 0.0001Birth weight (kg) 3.3 0.4 3.1 0.4 1.9 0.3 2.7 0.4 2.9 0.5 F = 45.2 < 0.0001

Data are presented as mean SD or n (%). The control group is a subgroup of the base cohort. *Tests included ANOVA (F), chi-square (2)and Monte Carlo exact test. Significant. BMI, body mass index; GA, gestational age; GH, gestational hypertension; NICU, neonatalintensive care unit; PE, pre-eclampsia.

Table 2 Markers of hypertensive disorders of pregnancy in 1849 women without a-priori high risk

Study group (n =89)ANOVA

Base cohort Control group Early PE Late PE GHMarker (n =1760) (n = 178) (n =16) (n =60) (n =13) F P

MAP (mmHg) 82.2 1.9 82.8 2.3 100.8 3.5 92.7 5.3 92.4 7.8 636.4 < 0.0001*UtA-PI 1.7 0.3 1.7 0.2 2.5 0.3 2.02 0.3 1.8 0.2 47.7 < 0.0001*sEng (ng/mL) 6.6 0.81 7.8 0.87 7.0 1.13 6.9 0.84 11.06 < 0.0001*

Data expressed as mean SD. The control group is a subgroup of the base cohort. *Significant. Not measured in base cohort. GH,gestational hypertension; MAP, mean arterial pressure; PE, pre-eclampsia; sEng, soluble endoglin; UtA-PI, uterine artery pulsatility index.

(P< 0.05) and all had odds ratios (OR) > 1, indicatingthat as the values of these markers increased, the patientwas more likely to develop HDP. MAP, UtA-PI andsEng had ORs of 5.9 (95% CI, 1.622.1), 1.7 (95% CI,1.22.5) and 1.5 (95% CI, 1.41.7), respectively.

Different ROC curves (Figure 1) were constructed todetermine the predictive values of the three markers fordifferent types of HDP. The most predictive model forHDP was one that combined MAP with sEng (AUC,0.83; 95% CI, 0.690.89). The predictive value of thethree combined markers was highest for screening ofearly and late PE (AUC, 0.86 and 0.83, respectively).When each marker was considered alone, the highestprediction for any type of hypertensive disorders wasachieved by MAP (AUC, 0.73; 95% CI, 0.680.80)(Table 3). Pairwise comparison between ROC curves(Figures S1S3) revealed that the difference between theAUCs of MAP and UtA-PI was 0.09 and this differencewas highly significant (95% CI, 0.0710.314, P< 0.001),the difference between the AUCs of MAP and sEngwas 0.16 and this difference was also highly significant(95% CI, 0.1110.284, P< 0.0001), while the differencebetween the AUCs of UtA-PI and sEng (0.07), was notsignificant (95% CI, 0.0330.143, P> 0.05).

Cut-off values of 86 mmHg for MAP, 1.99 for UtA-PIand 7.6 ng/mL for sEng and their combinations yieldeddifferent sensitivities and positive (PPV) and negative(NPV) predictive values for detecting HDP (Table 4).As a single marker, MAP achieved the highest sensitivity,PPV and NPV for screening for any type of HDP (56.8%,79.4% and 80.9%, respectively).

The correlation of markers of HDP with age, BMI,parity, gestational age at delivery and birth weight inboth control group and HDP groups is shown in TablesS1 and S2. In the control group, there was no significantcorrelation (P> 0.05) between the markers of HDP andcharacteristics of patients while in the hypertensive grouponly MAP had a significant indirect weak correlation withboth GA at delivery and birth weight.

DISCUSSION

Our study was conducted to identify a suitable screeningprogram for HDP during the first trimester with thepotential to improve pregnancy outcomes and avoid thedevelopment of serious complications.

To the best of our knowledge, this is the firststudy to include women without a-priori high risk for



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Figure 1 Receiveroperating characteristics curves for first-trimester markers (soluble endoglin ( ), uterine artery pulsatilityindex ( ) and mean arterial blood pressure ( )) in the prediction, in pregnant women without a-priori high risk, of: (a) any type ofhypertensive disorder of pregnancy (n= 89); (b) early pre-eclampsia (n= 16); (c) late pre-eclampsia (n= 60); and (d) gestational hypertension(n= 13). The diagonal line is the reference line.

PE (except for primigravidity); most, if not all, trialsinvolving PE have relied on secondary prevention19,although the majority of women who developed PE wereonly diagnosed once they had developed the full-blownmanifestation of the condition.

The simplest diagnostic tool for PE is BP measure-ment20. MAP in our study showed a sensitivity of 71.3%for the prediction of early PE, 56.7% for late PE and30.5% for GH. Three previous studies examined theperformance of MAP alone during the first trimester.Moutquin et al.21, using a MAP cut-off of 90 mmHg,obtained a detection rate for PE of 62%, for a FPR of38%; however, the definition they used for PE was notaccepted by any professional organization (GH definedby either weight gain or a reading of only 1+ of protein

on urine dipstick analysis on one occasion). Miller et al.22

used a cut-off of 92 mmHg, and reported a detection rateof 25% for PE at a 10% FPR. Poon et al.13 used meanmultiples of the median (MoM) of MAP with a FPR of10%, and reported detection rates for PE and GH of37.5% and 32%, respectively.

UtA-PI would be useful during the first trimester mainlyin cases characterized by a high grade of placentalischemia23,24, and less useful in less severe forms. Whenconsidering this marker alone, our study showed asensitivity of 57.3% for early PE, 39.7% for late PEand 20.1% for GH. Other studies have reported variablescreening performance. Gomez et al.23 and Martin et al.25

identified 50% of women who developed PE when usingthe UtA-PI 95th centile as a cut-off. Plasencia et al.11



Table 3 Area under the receiveroperating characteristics curves (AUC), indicating predictive value of various markers of hypertensivedisorders of pregnancy (HDP), alone and in combination, in 89 women without a-priori high risk who developed HDP and control group

AUC (95% CI)

Marker Early PE Late PE GH Any HDP

MAP 0.80 (0.740.90) 0.72 (0.630.81) 0.59 (0.480.72) 0.73 (0.680.80)UtA-PI 0.74 (0.640.86) 0.68 (0.610.77) 0.52 (0.430.65) 0.64 (0.530.75)sEng 0.79 (0.700.91) 0.59 (0.490.63) 0.55 (0.430.66) 0.57 (0.500.66)MAP & UtA-PI 0.83 (0.750.92) 0.79 (0.640.84) 0.67 (0.550.79) 0.79 (0.690.85)MAP & sEng 0.83 (0.770.93) 0.81 (0.730.90) 0.63 (0.570.76) 0.83 (0.690.89)UtA-PI & sEng 0.76 (0.670.81) 0.77 (0.660.89) 0.57 (0.420.67) 0.69 (0.640.80)MAP, UtA-PI & sEng 0.86 (0.800.92) 0.83 (0.740.90) 0.73 (0.640.82) 0.79 (0.710.86)

GH, gestational hypertension; MAP, mean arterial pressure; PE, pre-eclampsia; sEng, soluble endoglin; UtA-PI, uterine artery pulsatilityindex.

Table 4 Sensitivity and positive (PPV) and negative (NPV) predictive values, at fixed false-positive rate of 10%, of markers of hypertensivedisorders of pregnancy (HDP), alone and in combination, in 89 women without a-priori high risk who developed HDP and control group

Marker/HDP typeSensitivity

(% (95% CI))PPV

(% (95% CI))NPV

(% (95% CI))

MAPEarly PE 71.3 (54.481.2) 48.0 (28.368.2) 97.6 (93.799.2)Late PE 56.7 (47.972.1) 23.5 (7.850.2) 94.8 (90.197.5)GH 30.5 (24.245.4) 57.1 (20.288.2) 95.1 (90.697.6)Any HDP 56.8 (45.079.2) 79.4 (67.088.1) 80.9 (74.785.9)

UtA-PIEarly PE 57.3 (41.772.1) 12.5(6.222.9) 94.3 (88.197.5)Late PE 39.7 (24.750.2) 55.8 (40.070.6) 81.5 (75.386.6)GH 20.1 (12.132.2) 13.6 (3.636) 94.1 (89.197.2)Any HDP 39.3 (23.348.3) 64.8 (50.677.0) 74.6 (68.280.2)

sEngEarly PE 65.5 (54.679.9) 35.7 (19.355.9) 96.4 (91.998.5)Late PE 28.3 (20.838.2) 48.6 (31.765.7) 78.8 (72.484.1)GH 23.1 (14.631.5) 14.3 (3.837.5) 94.1 (89.197.0)Any HDP 36.3 (24.151.4) 64.0 (49.176.7) 73.7 (67.379.3)

MAP & UtA-PIEarly PE 75.3 (58.984.5) 50.0 (29.670.4) 97.6 (93.799.2)Late PE 73.3 (64.684.9) 78.6 (55.288.0) 91.2 (85.994.7)GH 47.8 (33.257.4) 33.3 (17.254.0) 97.6 (93.599.2)Any HDP 70.0 (57.881.4) 83.8 (73.091.0) 86.0 (80.190.4)

MAP & sEngEarly PE 81.8 (68.592.1) 43.3 (26.062.3) 98.2 (94.399.5)Late PE 68.3 (56.480.6) 71.2 (57.781.9) 89.9 (84.393.8)GH 40.2 (30.249.8) 37.0 (20.157.5) 97.5 (93.499.2)Any HDP 71.8 (60.380.8) 79.0 (68.387.0) 86.6 (80.691.0)

UtA-PI & sEngEarly PE 81.3 (70.888.6) 76.5 (49.892.2) 98.3 (94.799.6)Late PE 63.7 (46.180.7) 60.3 (47.872.2) 87.4 (81.491.8)GH 35.8 (21.645.8) 33.3 (17.254.0) 97.6 (93.599.2)Any HDP 69.7 (54.981.2) 62.0 (51.771.4) 83.8 (77.288.9)

MAP, UtA-PI & sEngEarly PE 83.8 (68.5100.0) 43.8 (26.862.2) 98.8 (95.199.8)Late PE 80.3 (71.989.0) 72.7 (60.282.2) 93.0 (87.896.2)GH 48.8 (35.063.9) 35.7 (19.355.9) 98.2 (94.399.2)Any HDP 78.8 (66.483.2) 79.5 (69.387.2) 89.4 (83.793.3)

Cut-off value for mean arterial pressure (MAP) = 86 mmHg, cut-off for uterine artery pulsatility index (UtA-PI) = 1.99 and cut-off forsoluble endoglin (sEng) = 7.6 ng/mL. GH, gestational hypertension; MAP, mean arterial pressure; PE, pre-eclampsia; sEng, soluble endoglin;UtA-PI, uterine artery pulsatility index.

reported a detection rate of 82% for early PE comparedwith 31% and 12% for late PE and GH, respectively. Forscreening we selected the lowest PI, this being preferableto the mean or highest PI because impedance to flow in

the uterine artery has been shown to be lower on the sideof implantation26.

Understanding of the role of sEng in the pathophysiol-ogy of PE is based on the following observations: (1) it



inhibits endothelial function in vitro; (2) its administra-tion induces hypertension in vivo; (3) there is increasedendoglin m-RNA expression (three-to-five-fold) in womenwith PE; and (4) there is increased endoglin proteinexpression in placentae from women with PE12. Althoughseveral studies have reported increased sEng in PE27,28,there is still contradictory evidence as to whether thisincrease precedes the clinical onset of the disease and maybe apparent from the first trimester. Baumann et al.29

used sEng alone at 1114 weeks, reporting a significantdifference (P< 0.01) between cases who developed late PEand unaffected controls; they found that using a cut-offof 5 ng/mL yielded a sensitivity and specificity of 63%and 57%, respectively, at a 10% FPR. Foidart et al.30,also at 1114 weeks, used sEng in association with othermarkers and found that the level of sEng was significantlyhigher in cases destined to develop early PE comparedwith cases who developed late PE or unaffected controls,and by using this marker alone at a 10% FPR they wereable to detect 46.7% of cases of early PE. Lim et al.31

examined women at 1419 weeks and reported that sEngcould detect 62% of patients who subsequently devel-oped PE, at a FPR of 10%. On the other hand, someauthors found no role of the marker at this early stageof pregnancy32,33. This variation in findings may reflectdifferences in sample handling, processing and labora-tory procedures, making it difficult to compare diagnosticvalues across different studies34.

In attempts to improve sensitivities, some studieshave considered combinations of markers. Poon et al.9

studied patients at risk for PE using MAP, UtA-PI,pregnancy-associated plasma protein-A and placentalgrowth factor, reporting detection rates of 93.1% forearly PE, 35.7% for late PE and 18.3% for GH. In ourstudy the combination of markers achieved sensitivitiesof 83.8%, 80.3% and 48.8% for early PE, late PE andGH, respectively. Screening by a combination of thesemarkers was particularly effective in identifying womenwho developed PE rather than GH.

The HDP detection rate was higher in our study thanhas been reported previously9,30. This could be explainedby the existence of different risk factors for PE among ourpopulation, such as a higher prevalence of atherogeniclipid profile, lower vitamin C and E diet intake andthe positive consanguinity in most cases, or the extrasurveillance led to more diagnoses.

Our study has several strengths: (1) it included womenwithout a-priori high risk; (2) screening was performedduring the first trimester; (3) women were examinedprospectively; (4) screening was performed at a well-defined GA; (5) different parameters were measured atthe same time, which can improve detection rate; and(6) strict criteria were used to define PE and GH. Onthe other hand, there were weaknesses, including: (1) thenature of the disease screened. The main limitations ofdifferent approaches to screening for HDP are their lowPPVs, indicating that most screen-positive patients will notin fact develop the disease. (2) The casecontrol natureof the study had the disadvantages that selection bias

could not be excluded and each subject was examinedonly once; better for this type of research would havebeen a longitudinal study. Furthermore, (3) normotensivewomen who had fetal growth restriction were not includedas a separate category and (4) we did not perform acost-effectiveness analysis.

In conclusion, first-trimester screening can be useful inpredicting low-risk women who are destined to developHDP. If these results are confirmed by further prospectivelongitudinal studies, we propose a combined approach toscreen for a womans specific risk for HDP.

REFERENCES

1. Jim B, Sharma S, Kebede T, Acharya A. Hypertension inpregnancy: a comprehensive update. Cardiol Rev 2010; 18:178189.

2. Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF.WHO analysis of causes of maternal death: a systematic review.Lancet 2006; 367: 10661074.

3. Egbor M, Ansari T, Morris N, Green CJ, Sibbons PD. Mor-phometric placental villous and vascular abnormalities in early-and late-onset preeclampsia with and without fetal growthrestriction. BJOG 2006; 113: 580589.

4. DAnna R, Baviera G, Corrado F, Giordano D, De Vivo A,Nicocia G, DiBenedetto A. Adiponectin and insulin resistancein early- and late-onset pre-eclampsia. BJOG 2006; 113:12641269.

5. Bosio PM, McKenna PJ, Conroy R, OHerlihy C. Maternalcentral hemodynamics in hypertensive disorders of pregnancy.Obstet Gynecol 1999; 94: 978984.

6. Collis T, Devereux RB, Roman MJ, de Simone G, Yeh J,Howard BV, Fabsitz RR, Welty TK. Relations of stroke volumeand cardiac output to body composition: the strong heart study.Circulation 2001; 103: 820825.

7. National Collaborating Center for Womens and ChildrensHealth. Commissioned by the National Institute for ClinicalExcellence. Antenatal Care: Routine Care for the HealthyPregnant Woman. Clinical Guideline. October 2003. NationalCollaborating Center for Womens and Childrens Health:London, 2003. Published by the RCOG Press at the RoyalCollege of Obstetricians and Gynaecologists.

8. Yu CK, Smith GC, Papageorghiou AT, Cacho AM, Nico-laides KH. An integrated model for the prediction of preeclamp-sia using maternal factors and uterine artery Doppler velocime-try in unselected low-risk women. Am J Obstet Gynecol 2005;193: 429436.

9. Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH.First-trimester prediction of hypertensive disorders in preg-nancy. Hypertension 2009; 53: 812818.

10. Papageorghiou AT, Yu CK, Cicero S, Bower S, Nicolaides KH.Second-trimester uterine artery Doppler screening in unselectedpopulations: a review. J Matern Fetal Neonatal Med 2002; 12:7888.

11. Plasencia W, Maiz N, Bonino S, Kaihura C, Nicolaides KH.Uterine artery Doppler at 11 + 0 to 13 + 6 weeks in theprediction of pre-eclampsia. Ultrasound Obstet Gynecol 2007;30: 742749.

12. Venkatesha S, Toporsian M, Lam C, Hani J, Mammoto T,Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Still-man IE, Roberts D, DAmore PA, Epstein FH, Sellke FW,Romero R, Sukhatme VP, Letarte M, Karumanchi SA. Solubleendoglin contributes to the pathogenesis of preeclampsia. NatMed 2006; 12: 642649.

13. Poon LC, Kametas NA, Pandeva I, Valencia C, Nicolaides KH.Mean arterial pressure at 11 + 0 to 13 + 6 weeks in theprediction of preeclampsia. Hypertension 2008; 51: 17.



14. Mion D, Pierin AM. How accurate are sphygmomanometers?J Hum Hypertens 1998; 12: 245248.

15. Markandu ND, Whitcher F, Arnold A, Carney C. The mercurysphygmomanometers should be abandoned before it isprescribed. J Hum Hypertens 2000; 14: 3136.

16. Kasdaglis T, Aberdeen G, Turan O, Kopelman J, Atlas R,Jenkins C, Blitzer M, Harman C, Baschat AA. Placental growthfactor in the first trimester: relationship with maternal factorsand placental Doppler studies. Ultrasound Obstet Gynecol2010; 35: 280285.

17. Cnossen JS, Vollebregt KC, de Vrieze N, Riet G, Mol BWJ,Franx A, Khan KS, van der Post JAM. Accuracy of mean arterialpressure and blood pressure measurements in predicting pre-eclampsia: systematic review and meta-analysis. BMJ 2008;336: 11171120.

18. Report of the National High Blood Pressure Education ProgramWorking Group on High Blood Pressure in Pregnancy. Am JObstet Gynecol 2000; 183: S1S22.

19. Khalil A, Cowans NJ, Spencer K, Goichman S, Meiri H, Har-rington K. First-trimester markers for the prediction of pre-eclampsia in women with a-priori high risk. Ultrasound ObstetGynecol 2010; 35: 671679.

20. Villar J, Say L, Shennan A, Lindheimer M, Duley L, Conde-Agudelo A, Merialdi M. Methodological and technical issuesrelated to the diagnosis, screening, prevention, and treatmentof preeclampsia and eclampsia. Int J Gynecol Obstet 2004; 85:(Suppl 1): S28S41.

21. Moutquin JM, Rainville C, Giroux L, Raynauld P, Amyot G,Bilodeau R, Pelland N. A prospective study of blood pressurein pregnancy: prediction of preeclampsia. Am J Obstet Gynecol1985; 151: 191196.

22. Miller RS, Rudra CB, Williams MA. First-trimester meanarterial pressure and risk of preeclampsia. Am J Hypertens2007; 20: 573578.

23. Gomez O, Martinez JM, Figueras F, Rio DM, Brobio V,Puerto B, Coll O, Cararach V, Vanrell JA. Uterine arteryDoppler at 1114 weeks of gestation to screen for hyperten-sive disorders and associated complications in an unselectedpopulation. Ultrasound Obstet Gynecol 2005; 26: 490494.

24. Romero R, Nien JK, Espinoza J, Todem D, Wenjiang FU,Chung H, Kusanovic JP, Gotsch F, Erez O, Mazaki-Tovi S,Gomez R, Edwin S, Chaiworapongsa T, Levine RJ, Karu-manchi SA. A longitudinal study of angiogenic (placentalgrowth factor) and anti-angiogenic (soluble endoglin and sol-uble vascular endothelial growth factor receptor-1) factors in

normal pregnancy and patients destined to develop preeclamp-sia and deliver a small for gestational age neonate. J MaternFetal Neonatal Med 2008; 21: 923.

25. Martin AM, Bindra R, Curcio P, Cicro S, Nicolaides KH.Screening for preeclampsia and fetal growth restriction byuterine artery Doppler at 1114 weeks of gestation. UltrasoundObstet Gynecol 2001; 18: 583586.

26. Poon LC, Staboulidou I, Maiz N, Plasencia W, Nicolaides KH.Hypertensive disorders in pregnancy: screening by uterine arteryDoppler at 1113 weeks. UltrasoundObstet Gynecol 2009; 34:142148.

27. Jeyabalan A, McGonigal S, Gilmour C, Hubel CA, Rajaku-mar A. Circulating and placental endoglin concentrations inpregnancies complicated by intrauterine growth restriction andpreeclampsia. Placenta 2008; 29: 555563.

28. De Vivo A, Baveria G, Giordano D, Todarello G, Corrado F,DAnna R. Endoglin, PlGF and sflt-1 as markers for predictingpre-eclampsia. Acta Obstet Gynecol Scand 2008; 87: 837842.

29. Baumann MU, Bersinger NA, Mohaupt MG, Raio L, Gerber S,Surbek DV. First-trimester serum levels of soluble endoglinand soluble fms-like tyrosine kinase-1 as first-trimester markersfor late-onset preeclampsia. Am J Obstet Gynecol 2008; 199:266.e16.

30. Foidart JM, Munaut C, Chantraine F, Akolekar R. Maternalplasma soluble endoglin at 1113 weeks gestation in pre-eclampsia. Ultrasound Obstet Gynecol 2010; 35: 680687.

31. Lim JH, Kim SY, Park SY, Lee MH, Yang JH, Kim MY,Chung JH, Lee SW, Ryu HM. Soluble endoglin and transform-ing growth factor-beta1 in women who subsequently developedpreeclampsia. Prenat Diagn 2009; 29: 471476.

32. Erez O, Romero R, Espinoza J, Wenjiang FU, Todem D,Kusanovic JP, Gotsch F, Edwin S, Nien JK, Chaiworapongsa T,Mittal P, Mazaki-Tovi S, Than NG, Gomez R, Hassan SS. Thechanges in concentration of angiogenic and anti-angiogenic fac-tors in maternal plasma between the first and second trimestersin risk assessment for the subsequent development of preeclamp-sia and small-for-gestational age. J Matern Fetal Neonatal Med2008; 21: 279287.

33. Rana S, Lindheimer M, Karumanchi A. Angiogenic proteinsas markers for predicting pre-eclampsia. Expert Rev ObstetGynecol 2007; 2: 6165.

34. Chen YP. Novel angiogenic factors for predicting preeclampsia:sFlt-1, PlGF, and soluble endoglin. The Open Clinic Chemist J2009; 2: 16.

SUPPORTING INFORMATION ON THE INTERNET

The following supporting information may be found in the online version of this article:

Figures S1S3 Scatter plots of correlation between markers of hypertensive disorders of pregnancy:mean arterial pressure (MAP) and soluble endoglin (sEng) (Figure S1), MAP and uterine arterypulsatility index (UtA-PI) (Figure S2) and UtA-PI and sEng (Figure S3).

Tables S1 and S2 Correlation of markers of hypertensive disorders of pregnancy with age, body massindex, parity, gestational age at delivery and birth weight in the control group (Table S1) and thehypertensive group (Table S2).


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