Rev Port Cardiol. 2012;31(6):425---432

Revista Portuguesa de

CardiologiaPortuguese Journal of Cardiology

www.revportcardiol.org

REVIEW ARTICLE

Hyper nt state of the art

Srgio B

Centro Hos

Received 14Available on

KEYWOPregnanchypertenPre-eclaPredictioPathophAntihypetherapy

PALAVRHipertengestacioPr-eclaPredicoFisiopatoTeraputanti-hipe

Please cidoi:10.1016

CorrespoE-mail a

2174-2049/$

Document downloaded from http://www.elsevier.pt, day 02/02/2015. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.arra , Maria do Carmo Cachulo, Rui Providncia, Antnio Leito-Marques

pitalar de Coimbra, Coimbra, Portugal

April 2011; accepted 25 January 2012line 17 May 2012

RDSy-inducedsion;mpsia;n;ysiology;rtensive

Abstract Hypertension complicates 6---8% of pregnancies and includes the following four con-ditions: hypertension preceding pregnancy or documented before the 20th week of gestation;pre-eclampsia (PE)/eclampsia; chronic hypertension with superimposed pre-eclampsia; andgestational hypertension. The latter is dened as a signicant rise in blood pressure afterthe 20th week of pregnancy in previously normotensive women, to over 140/90mmHg. Whenblood pressure remains above 160/110mmHg, it is considered severe. PE is dened as thepresence of proteinuria (300mg/24 hours) in pregnant women with hypertension. The hyper-tensive syndromes of pregnancy are among the leading causes of maternal and fetal morbidityand mortality and anti-hypertensive treatment is part of the therapeutic arsenal used to pre-vent serious complications. Although the role of utero-placental insufciency due to decientmigration of trophoblasts to the spiral arteries is universally accepted, the pathophysiology ofPE remains largely unknown and is the subject of debate. No effective ways of predicting orpreventing PE have been found, which highlights the need for further research in this eld. Thisreview aims primarily to evaluate recent advances in our understanding of the pathophysiologyof gestational hypertension and especially PE, and new ways of predicting PE. Additionally, wepresent a brief review on the diagnosis, prevention and treatment of PE. 2011 Sociedade Portuguesa de Cardiologia. Published by Elsevier Espaa, S.L. All rightsreserved.

AS-CHAVEsonal;mpsia;;logia;icartensora

Hipertenso Arterial na Grvida: o actual estado da arte

Resumo A Hipertenso Arterial (HTA) na gravidez complica 6 a 8% das gestaces e inclui 4principais formas de apresentaco: HTA crnica, que antecede a gravidez ou documentadaantes das 20 semanas de gestaco, pr-eclampsia (PE)/eclampsia, HTA crnica com PE sobre-posta e HTA gestacional. A HTA gestacional dene-se como uma elevaco signicativa da pressoarterial aps as 20 semanas de gestaco em gestantes previamente normotensas, atingindo val-ores superiores a 140/90mmHg. Quando os valores de presso arterial se mantm acima de160/110mmHg de forma sustentada, considerada grave. A pr-eclampsia (PE) dene-se pelapresenca de proteinria (300mg/24 horas) em gestante com HTA. As sndromes hipertensivas

te this article as: Barra, S. Hipertenso Arterial na Grvida: o actual estado da arte. Rev Port Cardiol 2012./j.repc.2012.04.006nding author.ddress: sergioncbarra@gmail.com (S. Barra).

see front matter 2011 Sociedade Portuguesa de Cardiologia. Published by Elsevier Espaa, S.L. All rights reserved.tension in pregnancy: The curre

426 S. Barra et al.

da gravidez encontram-se entre as principais causas de morbimortalidade materno-fetal, sendoque a teraputica anti-hipertensora faz parte do arsenal teraputico utilizado na prevencodas suas graves complicaces. Apesar do papel da insucincia tero-placentria por de-ciente migraco dos trofoblastos para as artrias espiraladas ser universalmente aceite, asiopatologia da PE permanece ainda parcialmente uma incgnita e rene alguma controvrsia.

rmaretcas no su

diolo

Introduc

The hypertcause of mdevelopedThere havevariable pr(PE) andHowever, tcerning anrisk, particthe availabrisk groups

Forty pedo not preweek. This

Hypertetal morbidgrowth rescomplicatision is assnewborns w

Althougetiology iscan be conmaternal---fa possibleHLA systema wider picphoblast ththe inamm

There isbe treatedfor the heantihypertehypertensi

Objectiv

The aim ofon the dia

atmecenn off se

cacdelinlarlts orogrcelldlined feclalampensiiagnl orent.

osi

catid onnd poteinordi

Document downloaded from http://www.elsevier.pt, day 02/02/2015. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.Historicamente, no so conhecidas foda PE, pelo que a investigaco nestaprimariamente avaliar os avancos ciengestacional e, em particular, da PE e dtantemente, apresentamos informactratamento anti-hipertensor na PE. 2011 Sociedade Portuguesa de Cardireitos reservados.

tion

ensive syndromes of pregnancy are the leadingaternal and fetal morbidity and mortality in theworld,1,2 occurring in around 8% of pregnancies.been numerous studies aimed at clarifying the

esentation and systemic nature of pre-eclampsiaother hypertensive disorders of pregnancy.3,4

here is some disagreement in the literature con-tihypertensive treatment in pregnant women atularly the pharmacology, efcacy and safety ofle drugs, the best methods for identifying high-, and prediction and prevention of complications.r cent of pregnant women who develop eclampsiasent hypertension or proteinuria in the previoushighlights the need for preventive measures.5

nsive syndromes are also a cause of perina-ity and mortality, mainly from intrauterinetriction due to utero-placental insufciency andons related to prematurity.6 Even mild hyperten-ociated with greater risk for prematurity andho are small for gestational age.7

h much is known of the pathophysiology of PE, itsstill unclear. Increased blood pressure (BP) in PEsidered a compensatory mechanism for reducedetal blood ow.8 Several studies have suggestedrole for the nitric oxide synthase gene and the

and tremost rcatiocases othe ef

GuiparticucologisCare Pical ExThe Mesearchtermspre-echypertwere dclinicatreatm

Diagn

Classiis basesion aand pr

Acc

in the genesis of PE, which would t within

ture of maternal immune responses to the tro-at lead to defective placentation, activation ofatory cascade and endothelial dysfunction.4

agreement that a hypertensive emergency must, but the best drug to use, and the importancealth of both mother and fetus of maintenancensive therapy and treatment of non-severe

on, are less clear.

e and methods

this review was to summarize current knowledgegnosis, pathophysiology, prediction, prevention

Hypertensimeasured a

The patilevel of

An appro A manua

devices tsure bydevicesonly beeuse shoulow-riskmomanos sucientemente ecazes de predico e prevencoa assume particular importncia. Esta reviso visaos mais recentes nas reas da siopatologia da HTAovas formas de predico desta patologia. Concomi-mria recente acerca do diagnstico, prevenco e

gia. Publicado por Elsevier Espaa, S.L. Todos os

ent of hypertension in pregnancy, focusing on thet studies on pathophysiology, prevention, identi-high-risk groups, and antihypertensive therapy invere hypertension, and analyzing the evidence ony and safety of the available drugs.es on hypertension in pregnancy were reviewed,

y those of the Society of Obstetricians and Gynae-f Canada, the British Columbia Reproductiveam, the National Institute for Health and Clin-ence (UK), and the World Health Organization.e, PubMed and Cochrane Library databanks wereor the most recent evidence, using the searchmpsia, pre-eclampsia, hypertension/pregnancy,sia/prevention, gestational hypertension, andve disorders of pregnancy. The concepts exploredosis, assessment, classication, prediction (usinglaboratory markers), prevention, prognosis and

s and classication

on of the hypertensive syndromes of pregnancythe two main manifestations of PE: hyperten-

roteinuria, and so rigorous measurement of BPuria is of particular importance.

ng to the guidelines of the Canadian and British

on Societies, BP in a pregnant woman should bes follows:

ent should be seated at 45 with the arm at thethe chest;priate-sized cuff should be used;l sphygmomanometer should be used. Automatedend to underestimate systolic and diastolic pres-5---15mmHg in pregnancy. The suitability of suchfor women with suspected or conrmed PE hasn tested in a small number of models and theirld be limited to assessment of BP variation inpatients.9,10 In high-risk cases a mercury sphyg-meter is indicated;

Hypertension in pregnancy: The current state of the art 427

Phase 5 Korotkoff sounds should be used to indicate dias-tolic BP11;

Ambulatory BP monitoring in normotensive or mildlyhypertensive pregnant women has not been assessed inrandomized clinical trials, and its value in terms of mater-nal and fetal outcomes is unknown.12

Gestational hypertension is dened as systolicBP 140mmHg and/or diastolic BP 90mmHg on atleast two occasions after the 20th week of pregnancy ina previously normotensive woman. The interval betweenBP measurements should be a minimum of 4---6 hours and amaximum of seven days.

Diastolic BP is a better predictor of adverse pregnancyoutcomes than systolic BP; a diastolic BP of 90mmHg is thelevel above which perinatal morbidity is increased in non-proteinuric hypertension.13 Severe hypertension is denedas systolic BP 160mmHg or diastolic BP 110mmHg andmeasurement should be repeated after 15min to conrm thediagnosis. These cutoffs were selected on the basis of evi-dence of a signicantly increased risk of stroke in pregnantwomen with BP above these levels.14

The recommendations for measurement of proteinuriaare as follows:

All pregnant women should be assessed for proteinuria; When the suspicion of pre-eclampsia is low, a urine

test strip may be used. If this gives a negative orinconclusive result, a more reliable test (24-hour urineprotein/creatinine ratio) is recommended if the degreeof suspicion is high.

A diagnosis of proteinuria is suggested by a score of 2+ onthe test strip and conrmed by levels over 0.3 g/dl in 24-hoururine or a ratio of protein (in mg) to creatinine (in mmol) ofover 30 in a urine sample. However, it is important to bearin mind that target-organ damage in PE can occur in theabsence of signicant proteinuria. Of pregnant women whodevelop pre-eclampsia, 20% only present hypertension in theweek before the rst seizure, 10% only present proteinuria,and 10% present neither.15

Table 1 shows the classication of hypertensive disor-ders of pregnancy proposed by the Canadian Hypertension

Table 1 Classication of hypertensive disorders of pregnancy proposed by the Canadian Hypertension Society.

Classication Denition

A --- Pre-existing hypertension Diastolic hypertension that predates pregnancy or is diagnosedbefore 20 weeks gestation. It may be associated withproteinuria

--- Essential ----- Primary--- Secondary ----- Secondary to such conditions as renal disease,

pheochromocytoma and Cushing syndrome

B --- Gestational hypertension Diastolic hypertension develops after 20 weeks gestation1 --- Without proteinuria ----- Protein excretion in 24-hour urine collection is 110mmHg); thrombocytopenia; oliguria; pulmonary edema;elevated liver enzyme levels; severe nausea, frontalheadache, visual disturbances, abdominal pain in right upperquadrant; suspected abruptio placentae; HELLP syndrome;intrauterine growth retardation, oligohydramnios, or absent orreversed umbilical artery end diastolic ow

2 --- Wit xcreonds

a --- Wb --- W nditi

llectig/l)

C --- Pre-ehyperte

ing horseftersion

D --- Uncla sionwasmentn shoithog on

Document downloaded from http://www.elsevier.pt, day 02/02/2015. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.h proteinuria ----- Protein e(corresp

ithout adverse conditionsith adverse conditions ----- Same co

urine colevel < 18

xisting hypertension+ superimposed gestationalnsion with proteinuria

Pre-existfurther w3 g/d ahyperten

ssiable antenatally HypertenpressureReassessconditiowith or wdependintion in 24-hour urine collection is 0.3 g/dto pre-eclampsia)

ons as in B1b; protein excretion >3 g/d in 24-houron, especially with hypoalbuminemia (albumin

ypertension (as dened in A) associated withning of blood pressure and protein excretion20 weeks gestation. Corresponds to chronicwith superimposed pre-eclampsia

with or without systemic manifestations if bloodrst recorded after 20 weeks gestation.is necessary at or after 42 d post partum. The

uld be reclassied as gestational hypertensionut proteinuria or as pre-existing hypertensionwhether the hypertension has resolved

428 S. Barra et al.

Table 2 Hypertensive disorders in pregnancy: Interna-tional Classication of Diseases (ICD) classication.

O10 Pre-existing essential hypertension complicatingpregnancy, childbirth and the puerperium

O11 Ps

O12 Gp

O13 Gw

O14 Gw

O14.1 SO15 EO16 U

Society anStudy of Hy

A simplClassicati

Pathophy

Despite bebidity andthe pathoghave notpast decadutero-placesion of spirand consevillous spalead to winal vasculformationvascular semation ofstress andlial dysfuntarget-orgacorroboratcental ischsuch as t1 receptoantiangiogetion of thof vasoconangiotensindecreasedabnormalitsis, increaendothelioto clarify tnal cardiovpreventive

Stennetgesting thamay increa

barrier, and affect sympathetic tone and the neuronalcontrol mechanisms of BP.18 New data have also been fur-nished by Furuya et al., who suggest that the failure oftrophoblasts to sufciently invade the placental bed onlypartially explains PIH, and that other factors include (i)

apprinafor

or-1GF)of uplace--- pI) anter pon; tnesi-ecla009ingtionensinheseal dophos, aduc

ublelay

therpsia.udytha

y linal u

s wiendo, wculad utomptssibiareeirwit

ciatele d

Document downloaded from http://www.elsevier.pt, day 02/02/2015. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.re-existing hypertensive disorder withuperimposed proteinuriaestational (pregnancy-induced) edema androteinuria without hypertensionestational (pregnancy-induced) hypertensionithout signicant proteinuriaestational (pregnancy-induced) hypertensionith signicant proteinuriaevere pre-eclampsiaclampsianspecied maternal hypertension

d validated by the International Society for thepertension in Pregnancy.ied classication is found in the Internationalon of Diseases (ICD) (Table 2).

siology

ing a major cause of maternal and fetal mor-mortality, the mechanisms responsible for

enesis of pregnancy-induced hypertension (PIH)yet been fully elucidated. Studies during thee suggest that the initiating event is reducedntal perfusion as a result of abnormal inva-al arterioles by the extravillous cytotrophoblastquent reduction of blood ow to the inter-ce. The resulting placental ischemia woulddespread activation/dysfunction of the mater-ar endothelium, which results in enhancedof endothelin and thromboxane, increasednsitivity to angiotensin II, and decreased for-nitric oxide and prostacyclin. The oxidativesystemic vasospasm associated with endothe-ction would lend support to the model ofn damage outlined.16 A study by Gilbert et al.es this theory by providing evidence linking pla-emia/hypoxia and the production of moleculesumor necrosis factor-, angiotensin II type

the inof prosolublerecepttein VEstressfetal---model(stagethe laquesticulogeof pre

A 2assessrestricangiotthat ton fetand trndingand rein solmay pand oeclam

A stgestingdirectlabnormnancieaffectin vitrtal vasreduceing prthe potationPE. Thand PEis assoarterior antibodies, interleukin-6, and a variety ofnic substances, leading to widespread dysfunc-e maternal vascular endothelium, productionstrictors such as endothelin, thromboxane and

II, and reactive oxygen species (ROS), andformation of vasodilators.17 These endothelialies cause hypertension by impairing natriure-sing total peripheral resistance and glomerularsis. The authors stress the need for further studieshe link between placental ischemia and mater-ascular alterations in order to develop effectivetherapies.et al. add further elements to the equation, sug-t cytokines and ROS released by the placentase vascular permeability, cross the blood---brain

perfusion),come is noindex (uterultrasoundnancies wiwho develcome. Thisare associaconcept ofof pregnan

This congested thatmechanismexacerbateII in the mopriate secretion into the maternal circulationmmatory substances such as endoglin and them of vascular endothelial growth factor (VEGF)(an endogenous inhibitor of the angiogenic pro-; (ii) direct damage to the endothelium by shearteroplacental blood ow; and (iii) microfocalntal hypoxia of unknown cause.19 The two-stage

oor placentation in the early gestational periodd maternal systemic endothelial dysfunction ineriod (stage II) --- is thus partially called intohe authors suggest that impaired placental vas-s does not in itself explain the clinical spectrummpsia.study in the Journal of Experimental Medicinethe association between intrauterine growthin pregnant women with hypertension andII type 1 receptor autoantibodies suggestedautoantibodies have direct harmful effects

evelopment by inducing apoptosis of placentalblast cells.20 Shah et al. corroborated thesedding that vascular endothelial growth factored placental growth factor (through increasestyrosine kinase-1, an antiangiogenic protein)a role in the development of proteinuriarenal injury-mediated manifestations in pre-

21

by Wang et al. added to the controversy by sug-t the endothelial dysfunction seen in PE is notked to fetal growth restriction associated withmbilical artery ow. Maternal plasma from preg-th umbilical placental vascular disease did notothelial cell expression of nitric oxide synthasehich led the authors to suggest that the placen-r pathology may be the primary event and thateroplacental circulation is secondary.22 This nd-ed further studies. Aardema et al. also raisedlity that other factors besides defective placen-implicated in the pathophysiology of PIH and

study sets out to test the hypothesis that PIHh an early onset and poor pregnancy outcomed with defective placentation (inadequate spiralilatation and subsequent reduced uteroplacentalwhereas PIH and PE with normal pregnancy out-t. They measured the uterine artery pulsatilityoplacental resistance to blood ow) by Dopplerand found that it was signicantly higher in preg-th complicated PE but was normal in womenoped PIH/PE, but had a good pregnancy out-indicates that only cases with poor outcomes

ted with defective placentation and supports theheterogeneous causes of hypertensive disorderscy.23

cept was strongly supported by Cross, who sug-PE can be initiated by at least three independents: pre-existing maternal hypertension that isd by pregnancy, elevated levels of angiotensinaternal circulation by placental over-production

Hypertension in pregnancy: The current state of the art 429

of renin (placental renin-angiotensin system), and primaryplacental pathology, which prevents the placenta fromcontributing to the normal cardiovascular adaptations ofpregnancy. Identication of genetic risk factors will thusonly be possible when the disease has been separated intodifferent sinvolved.24

Geneticmutationsciated with

Predictin

A good tesinvasive, inbe reliablecity. Ideapreventive

The abisymptom oHowever,and the secomplicati

Variousor familysion, olderobesity,25 a(due to facdrome, or pthese riskbe used in

Recentable risk plevels of sdisease orultrasound

A studyand reliabgenic proteproducedmanifestatthat measliquid chrourinary albods. Accorpredictedmanifestat

Variousically estimthe uterinpulsed Dopbe an effreported mperformedpredict intpredictivethese ndican identifbe measurstudies haunable in

40---60% of those who subsequently develop PE and 20% ofthose who develop fetal growth restriction.32 However, whencombined with assessment in the rst trimester of serummarkers associated with the pathophysiology of PE, partic-ularly placental protein 13, placental growth factor, VEGF

lubleof se

piteulat, sommet

trialslogiat PIH, diare vaSpecdurinr PI

w yrospringin aubstm isnceach

.he aulti

withly deat awasen w

E oredal oocc

h aseventifyupgres35 Fu.

nti

hasthoucomn; npmeildly

eralrioushosp

Document downloaded from http://www.elsevier.pt, day 02/02/2015. This copy is for personal use. Any transmission of this document by any media or format is strictly prohibited.ubtypes according to the etiological mechanisms

study may have an important role in the future;in the angiotensinogen gene are known to be asso-greater predisposition to PIH.19

g pre-eclampsia

t for predicting PE should be simple, rapid, non-expensive and easy to apply. The results shouldand reproducible, with high sensitivity and speci-lly, it should provide an opportunity for earlytherapy.lity to predict PE within a reasonable time fromnset has improved somewhat in the last decade.these improvements have not been signicant,arch continues for the best way to predict thison of pregnancy.risk markers for PE are known, including personalhistory of PIH or PE, pre-existing hyperten-maternal age in the rst pregnancy, maternalnd history of renal disease and/or thrombophiliator V Leiden heterozygosity, antiphospholipid syn-rothrombin gene mutations).26 However, none of

factors has sufcient positive predictive value toisolation.research has raised the possibility that reason-rediction can be achieved by measuring serumubstances involved in the pathogenesis of theby assessing uterine artery ow by Doppler

.by Boulanger et al. stressed the need for rapid

le methods for quantifying levels of antiangio-ins such as soluble tyrosine kinase-1 and endoglinin excess by the placenta before the clinicalions of PE appear.27 Baweja et al. demonstrateduring urinary albumin using high-performancematography gives a signicantly more reliableumin/creatinine ratio than conventional meth-ding to the authors, a ratio of >35.5mg/mmolpre-eclampsia well before the onset of clinicalions.28

studies on uterine artery Doppler imaging, specif-ation of indices of ow resistance (including

e artery pulsatility index) and notching in thepler spectrum, have suggested that this may

ective way of predicting PE.29 Cnossen et al.ore accurate prediction by this technique whenin the second trimester, as well as the ability torauterine growth restriction (although with lessvalue).30 Papageorghiou and Roberts conrmedngs, adding that uterine artery Doppler screeningy women in whom biochemical markers shoulded.31 Despite the enthusiasm with which theseve been met, Doppler uterine artery analysis isisolation to predict PE risk, as it identies only

and socases9%.33

Desof ambing PEby thissmallCardiopredicfulnesspressusleep.ABPMof 6 fo60%.34

A felarge pmeasuendoglgenic sThe aiimbalacan bedrome

In ttion, mas yetrecentrentlymodelin womwith Ppublishmaternof PE)ity witup toof idecomesthat agtaken.shortly

Preve

TherePE, aling itsfunctiodevelowith mers.

Sevof vatal ptyrosine kinase-1, it may predict up to 90% ofvere preeclampsia for a false positive rate of

the lack of randomized trials showing the benetory blood pressure monitoring (ABPM) in predict-e authors recommend serial BP measurement

hod, based on various observational studies and. A study published in Arquivos Brasileiros deconcluded that certain data from ABPM can

, particularly diastolic pressure load during wake-stolic and systolic pressure load during sleep, andriability and maximum diastolic pressure duringically a maximum diastolic arterial pressure ong sleep of 64mmHg presented an odds ratioH with a sensitivity of 80% and a specicity of

ears ago the World Health Organization began aective observational study to assess the value oflevels of two antiangiogenic substances (solublend soluble tyrosine kinase-1) and one angio-ance (placental growth factor) for predicting PE.to discover whether reversing the angiogenicin PE by adding exogenous angiogenic factorsieved in practice, thereby correcting the syn-

bsence of a test that can predict PE in isola-variate models have been developed, althoughlittle success. Notable among them is the modelveloped by von Dadelszen et al. and which is cur-n advanced stage of investigation. The fullPIERSdeveloped in a prospective multicenter studyho were admitted to tertiary obstetric centers

who developed PE after admission and was rstin January 2011. The model predicted adverseutcomes (mortality or other serious complicationsurring within the rst 48 hours after eligibil-high degree of reliability and performed welln days after eligibility, and brings new hopeing women at increased risk of adverse out-to seven days before complications arise, sosive preventive and therapeutic measures can berther details of the model are due to be released

on and treatment

been extensive research into the prevention ofgh current guidelines focus mainly on prevent-plications. Non-severe PIH may have an adaptiveeonatal morbidity is lower, and neurologicalnt is better, in small for gestational age babieshypertensive as opposed to normotensive moth-

studies have assessed the preventive valuetherapies, including inhibition of placen-

hodiesterase-5 to reverse the placental

430 S. Barra et al.

Table 3 Drugs recommended for treatment of severepregnancy-induced hypertension.

Agent Dosage Comments

Labetalol

Nifedipine

Hydralazin

vasoconstrof PE,36 was a prevegestationaldeterminedantihyperteprimary hybeyond sim

Calciumcalcium incomplicatiC and E),acids and precommen

Antihypcomplicatidence ofmoderate hcally for ththat reducfetal outco

Severetreated intality. Mostwill have Pthe recenturgencies.mended foBP to 160/110mmHg) should beorder to decrease maternal morbidity and mor-

Agen

Meth

Labet

Nifed

reasondihydrslow-receptinhibitticularthe matervent Pdrugsdoses.

Treof debdevelonicanin masmallthat amaterwomen with severe hypertension in pregnancyE, and most of those will have had normal BP inpast. Such marked BP elevations are consideredLabetalol, nifedipine and hydralazine are recom-r the treatment of severe PIH, aiming to reduce/110mmHg. Table 3 lists the main drugs used inand their doses. Sodium nitroprusside should onlya last resort if all other measures have failed to160/110mmHg.nt of non-severe hypertension (BP0---109mmHg) aims to achieve values of0---105mmHg (or 130---139/80---89mmHg inh renal or cardiovascular comorbidities). Initialshould be with methyldopa, labetalol, other

ers such as metoprolol, pindolol or propanololis not recommended since unlike the otherers mentioned, it is associated for unknown

Conclusi

Pregnancy-entity, deson maternantihypertehypertensisevere casRecent advogy of PE hto predictoped, baseand/or anttication oof uterinetion of subcomplicatia 250---500mg orally2---4 times daily(max. 2 g/d)

No need for a loadingdose

100---400mg orally2---3 times daily(max. 1200mg/d)

Typicalcontraindications forbeta-blockers

Intermediate-release capsules:10---20mg orally 2---3times daily (max.180mg/d;slow-releasecapsules: 20---60mgorally once daily(max. 120mg/d)

Rapid-releasecapsules arecontraindicated dueto the risk of fetalhypotension

ith intrauterine growth retardation), or oralidine calcium channel blockers (preferablyintermediate-release nifedipine). Angiotensinblockers and angiotensin-converting enzymeare contraindicated due to their toxicity, par-ephrotoxicity. Thiazide diuretics used aftertrimester are not associated with adverseor fetal outcomes, but neither do they pre-r severe hypertension. Table 4 lists the mainin the treatment of non-severe PIH and their

nt of non-severe hypertension is the subjectbecause of potential harmful effects on fetalnt. Two meta-analyses on this subject found a sig-sociation between treatment-induced decreasesl mean arterial pressure and prematurity andestational age infants,39,40 reinforcing the ideaypertensive therapy in itself does not reduceon

induced hypertension is still a little-understoodpite the enormous impact of its complicationsal and fetal outcomes. There is consensus thatnsive therapy is essential in cases of severe

on, but there is disagreement concerning non-es due to the risk of adverse fetal outcomes.ances in our understanding of the pathophysiol-ave raised expectations that effective methods

the condition and its complications will be devel-d on specic markers of endothelial dysfunctioniangiogenic proteins, the detection and quan-f which, complemented by Doppler assessmentartery ow, will help with timely identica-

groups of pregnant women at risk of developingons. It will then be possible to apply preventive

Hypertension in pregnancy: The current state of the art 431

measures such as low-dose aspirin and calcium supplemen-tation, plan the optimum timing for delivery, potentiallyreverse antiangiogenic status using exogenous angiogenicsubstances, and use antihypertensive therapy appropriately,with greater condence and with less risk for both motherand fetus.

Conicts

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