preeclampsia review lancet 2010 steegers e

7/28/2019 Preeclampsia Review Lancet 2010 Steegers E

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www.thelancet.com Vol 376 August 21, 2010 631

Lancet 2010; 376: 63144

Published Online

July 1, 2010

DOI:10.1016/S0140-

6736(10)60279-6

Department of Obstetrics and

Gynaecology, Division of

Obstetrics and Prenatal

Medicine, Erasmus MC,

University Medical Centre

Rotterdam, Rotterdam,

Netherlands

(Prof E A P Steegers MD,

J J Duvekot MD); Departmentof Obstetrics and Gynaecology,

University of British Columbia,

Vancouver, BC, Canada

(P von Dadelszen MBChB); and


Gynaecology, Catholic

University of Leuven,

University Hospital

Gasthuisberg, Leuven, Belgium

(Prof R Pijnenborg PhD)

Correspondence to:

Prof Eric A P Steegers,


Gynaecology, Division of

Obstetrics and Prenatal

Medicine, Erasmus MC,

University Medical Centre

Rotterdam, 3000 CB Rotterdam,

Netherlands

[email protected]

Pre-eclampsia

Eric A P Steegers, Peter von Dadelszen, Johannes J Duvekot, Robert Pijnenborg

Pre-eclampsia remains a leading cause of maternal and perinatal mortality and morbidity. It is a pregnancy-specificdisease characterised by de-novo development of concurrent hypertension and proteinuria, sometimes progressinginto a multiorgan cluster of varying clinical features. Poor early placentation is especially associated with early onsetdisease. Predisposing cardiovascular or metabolic risks for endothelial dysfunction, as part of an exaggerated systemicinflammatory response, might dominate in the origins of late onset pre-eclampsia. Because the multifactorialpathogenesis of different pre-eclampsia phenotypes has not been fully elucidated, prevention and prediction are stillnot possible, and symptomatic clinical management should be mainly directed to prevent maternal morbidity (eg,eclampsia) and mortality. Expectant management of women with early onset disease to improve perinatal outcomeshould not preclude timely deliverythe only definitive cure. Pre-eclampsia foretells raised rates of cardiovascularand metabolic disease in later life, which could be reason for subsequent lifestyle education and intervention.

IntroductionComplicating 28% of pregnancies, pre-eclampsia,along with the other hypertensive disorders ofpregnancy, is a major contributor to maternal mortalityworldwide.1,2 In Latin America and the Caribbean,hypertensive disorders are responsible for almost 26%of maternal deaths, whereas in Africa and Asia theycontribute to 9% of deaths. Although maternal mortalityis much lower in high-income countries than indeveloping countries, 16% of maternal deaths can beassigned to hypertensive disorders.1 The incidence ofpre-eclampsia has risen in the USA.3,4 This findingmight be related to an increased prevalence of

predisposing disorders, such as chronic hypertension,diabetes, and obesity.3Some ethnic groups (eg,African-American and Filipino women5,6) and low socioeconomicstatus are associated with a heightened risk. 7Furthermore, severe pre-eclampsia is a major cause ofsevere maternal morbidity (eg, stroke and liver rupture)and adverse perinatal outcomes, such as prematurityand intrauterine growth restriction.2 Although thegeneralised seizures of eclampsia complicate 23 casesper 10 000 births in Europe, eclampsia is 1030 timesmore common in developing countries than in high-income countries.2

Other hypertensive disorders in pregnancy are pre-existing hypertension and gestational hypertension.

Pre-eclampsia is generally defined as new hypertension(diastolic blood pressure of 90 mm Hg) and substantialproteinuria (300 mg in 24 h) at or after 20 weeksgestation.8 However, how best to define the maternalsyndrome of pre-eclampsia, and how to differentiatemild from severe disease is being debated.912 Table 1shows recent classification frameworks, evolving fromprevious work of the American College of Obstetriciansand Gynecologists13 and the International Society for theStudy of Hypertension in Pregnancy.14 The maindifferences between the classification systems are:(1) inclusion or exclusion of complicated non-proteinuricgestational hypertension as pre-eclampsia;(2) differentiation between clinical and researchdefinitions in the Australasian guideline; (3) use of

early-onset pre-eclampsia as a severity criterion inCanada (


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632 www.thelancet.com Vol 376 August 21, 2010

RCOG severe pre-eclampsia

(2006)9

SOMANZ (2008)10 SOGC (2008)11 ASH (2008)12

Pre-existing or chronic

hypertension (blood pressure

140/90 mm Hg before

0 weeks gestation)

NA Chronic hypertension: essential;

secondary; white coat; with or

without superimposed

pre-eclampsia

Pre-existing hypertension:

with or without comorbid

conditions; with or without

superimposed pre-eclampsia

Chronic hypertension of any

cause: with or without


Gestational hypertension

(blood pressure

140/90 mm Hg after

19 weeks (+6 days)

gestation

NA Gestational hypertension

without significant proteinuria

returning to normal within 1

weeks post partum

Gestational hypertension:

with or without comorbid

conditions; with or without


Gestational hypertension:

transient hypertension; blood

pressure returning to normal

within 6 weeks post partum;

late post partum

hypertension, with blood

pressure rise developing

weeks to 6 months post

partum and normalised by

1 year post partum

Pre-eclampsia (clinical

definition)

Gestational hypertension

(pregnancy-inducedhypertension) and significant

proteinuria (>03 g/4 h)

Gestational hypertension plus

one or more of the following:dipstick proteinuria confirmed by

either random Pr:Cr ratio 30

mg/mmol or 03 g/4 h; serum or

plasma creatinine >90 mol/L;

oliguria; thrombocytopenia;

haemolysis; disseminated

intravascular coagulation; raised

serum transaminases; severe

epigastric or right upper quadrant

pain; eclampsia; hypereflexia

with sustained clonus; severe

headache; persistent visual

disturbances; stroke; pulmonary

oedema; fetal growth restriction;

placental abruption

Pre-existing hypertension and

resistant hypertension, newproteinuria, or adverse

condition (see severity

criteria below)

Gestational hypertension and

proteinuria (random Pr:Cr

ratio 30 mg/mmol or 03

g/4 h), or adverse condition

Gestational hypertension or

chronic hypertension andproteinuria (dipstick 1+,

random Pr:Cr ratio

30 mg/mmol or 03 g/4 h)

Pre-eclampsia (research

definition)

Not defined De novo hypertension

>0 weeks gestation, returning

to normal post partum with

properly documented proteinuria

Not defined Not defined

Severe hypertension 170/110 mm Hg 170/110 mm Hg 160/110 mm Hg 160/110 mm Hg

Heavy proteinuria 1 g/L Not defined 35 g per day 3 g per day

Severity criteria

Gestational age at onset Not included Not defined


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Disturbances at this stage could increase risk of pre-

eclampsia, and might explain its higher incidence inwomen with unexplained subfertility or recurrentmiscarriage.21,22 Decidua-associated vascular changes alsoarise in the inner (junctional zone) myometrium,followed by trophoblast invasion with associatedremodelling.23 Interaction of trophoblastic HLA-C,HLA-E, and HLA-G with uterine natural killer cells ordendritic cells, or both, is thought to be important inregulation of invasion,2426 and some combinations ofHLA-C and killer cell immunoglobulin-like receptorisoforms predispose to pre-eclampsia.27

Intervillous flow seems to start 78 weeks of gestationby the appearance of connecting channels between spiralarteries and lacunae in the wall of the implanted

blastocyst.28 Early trophoblast plugging might protect theembryo against high oxygen concentrations. Researchers29have postulated that premature loss of these plugs couldresult in early miscarriage, or, dependent on timing, pre-eclampsia. Gradually plugs are resolved by intravascularmigration of the trophoblast. Intervillous flow is thoughtto start in lateral regions,29 whereas trophoblast invasionand associated deplugging of spiral artery outlets startsin the centre and spreads to the periphery. Peripheralonset of intervillous flow should result in high localoxidative stress, leading to villous regression and

formation of the chorion leave. Insuffi cient lateral spread

of endovascular plugging could therefore result inextensive chorionic regression and a small placenta,29contributing to intrauterine growth restriction, early-onset pre-eclampsia, or both.

Overlaying trophoblast invasion and spiral arteryremodelling steps on Jauniauxs placental oxygencurve30 shows that decidua-associated remodelling indecidua and junctional zone myometrium developsduring the steep rise in placental oxygen (1012 weeks),whereas at 10 weeks some decidual arteries are alreadyfilled with endovascular trophoblast over their entirelength.31 Placental flow defects can be detected as earlyas 12 weeks in women who subsequently develop pre-eclampsia.32 Deep invasion of the myometrial arterial

segments comes after the steep rise in placental oxygenfrom 15 weeks onwards, and can therefore be triggeredby increased flow.31 Thus, impaired invasion ofmyometrial spiral arteries in pre-eclampsia might resultfrom, rather than cause, maternal flow defects. Asmyometrial spiral arteries have a more pronouncedmuscular coat and elastica than do the correspondingdecidual vessels, failed remodelling at this level leadsto reduced uteroplacental arterial flow and episodesof irregular placental perfusion. Such hypoxia orreoxygenation episodes in some cases generate reactive

Figure: Possible pathophysiological processes in pre-eclampsia

AV=anchoring villus. COE=coelomic cavity. CY=cytotrophoblast. DB=decidua basalis. DC=decidua capsularis. DP=decidua parietalis. EN=endothelium. ET=extravillous trophoblast. FB=fetal blood vessel.

FV=floating villus. GL=gland. IS=intervillous space. JZ=junctional zone myometrium. MB=maternal blood, leaving the intervillous space with various components such as antiangiogenic factors.

MV=maternal vein. SA=spiral artery. SM=smooth muscle. ST=stroma. SY=syncytiotrophoblast. TM=tunica media. UC=uterine cavity. sFlt-1=soluble form of the vascular endothelial growth factorreceptor. Centre panel of figure adapted from Karumanchi et al,18 with permission from Elsevier.

Two pathophysiological stagesEarly pregnancy

Stage 1

Stage 2

Poor endometrium and inner (junctional zone)

myometrium preparation

Impaired trophoblast invasion of myometrial arteries

Poor spiral artery adaptation

Ischaemia-reperfusion

Placental oxidative and endoplasmic reticulum stress

Enhanced maternal intravascular systemicinflammatory response

Generalised endothelial dysfunction and leucocyte,complement, and clotting activation

Decreased intravascular volume and increasedvascular reactivity

Release components from the intervillous space intothe systemic matemal circulation (sFlt-1 and othermediators)

DP

DCDB

UC

Placental intervillous space

MB

IS

ETSA

EN

SM TM

SM

JZ

ET

SY

MV

GL

COE

FB

FV

CY

ST AV


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oxygen species,33 leading to placental oxidative stressand placental dysfunction, with endoplasmic reticulumstress and impaired protein synthesis.34 We believe thatthe unidentified causes of the first (placental) stage ofpre-eclampsia35 might include excessive or atypicalmaternal immune response to trophoblasts,36 and eitherimpaired decidualisation or failure of proper uterinepreconditioning.37 Thus, pre-eclampsia is a disease offailed interaction between two genetically differentorganisms. As such, Haigs maternal-fetal conflicthypothesis could be relevant.38

The second stage (figure) of systemic maternal disease isassociated with an exaggerated endothelial activation and ageneralised hyperinflammatory state compared withnormal pregnancy.39 Episodes of placental hypoxia orreperfusion result in oxidative stress, subsequent apoptoticand necrotic disruption of syncytial architecture,40 and

release of various components from the intervillous spaceinto the maternal circulation, stimulating productionof inflammatory cytokines.41 The circulating bioactivetrophoblast debris includes syncytiotrophoblast membranemicroparticles 41 and an excess of syncytiotrophoblast-derived antiangiogenic factors, such as soluble endoglinand the soluble form of the vascular endothelial growthfactor (VEGF) receptor (sFlt-1).18 Increased production ofanti-angiogenic factors by trophoblasts was also recentlyshown in molar pregnancy, a disorder known to pre-dispose women to pre-eclampsia.42,43 The excessive systemicinflammatory response of pre-eclampsia44 results inendothelial dysfunction and associated increased vascularreactivity, preceding onset of symptomatic clinical disease.45Loss of endothelial integrity contributes to derangements

of sodium-volume homoeostasis and reversal of many

cardiovascular changes (eg, increased cardiac output andintravascular volume) accompanying normal pregnancy.Thus, pre-eclampsia is a low-output, high-resistancestate with paradoxically decreased aldosterone andrenin activity.46

Linking mechanisms between stages 1 and 2 can bedifferent for several phenotypes of pre-eclampsia,including haemolysis, elevated liver enzymes, and lowplatelet count (HELLP) syndrome,47 and sometimesvaries between individuals. Whether pre-eclampsia willbe of early (often complicated by intrauterine growthrestriction) or late onset can be dependent on whetherthe placenta in stage 1 becomes phenotypically smallbecause of a greater angiogenic imbalance.48 Poor

placentation should not be regarded as the cause of pre-eclampsia, because not all of such pregnancies havepoor outcomes, but instead as a powerful predisposingfactor.39 In the presence of a placenta with an appropriatesize for gestational age, predisposing cardiovascularand metabolic syndrome-like disorders might also beable to set off a cascade of placental and systemicinflammation and oxidative stress, resulting in lateonset pre-eclampsia (also called maternal pre-eclampsia).49 This view is substantiated by findings ofnormal villous morphology in late-onset pre-eclampsia,by contrast with early-onset pre-eclampsia,50 althoughno such data seem to exist for the placental bed.

Although interactions between maternal genetic andconstitutional factors with environmental factorscontribute to the second stage, such factors are nowthought to have an effect on the first stage of thedisease.49 Decreased antioxidant and phase I and phaseII biotransformation activities in the maternal bloodand decidual and placental tissue probably contributeto an increased risk of pre-eclampsia.51 The protectiveeffect of smoking against pre-eclampsia52 couldresult from beneficial carbon monoxide effects ontrophoblast invasion and spiral artery remodelling,increased stage 1 placental blood flow, and decreasedstage 2 inflammatory responses.53 Decreased placentalrelease of sFlt-1 is possibly associated with this

protective effect.54

ScreeningTable 2 shows factors that can easily be measured at thefirst prenatal appointment and that increase the likelihoodof pre-eclampsia in any pregnancy.8,55 In risk assessmentsdone after 20 weeks gestation, attention should be paidto the possible onset of pre-eclampsia by identification ofany of the following signs and symptoms: newhypertension, new proteinuria, symptoms of headache,visual disturbance, epigastric pain, vomiting, reducedfetal movements, and an infant that is small forgestational age.56 Such risk assessment before and after20 weeks can be used in the community to offer referralfor specialist input.

Unadjusted relative risks (95% CI)

Nulliparity 91 (18661)

Multiparous women

Pre-eclampsia in any previous pregnancy 719 (585883)

10 years or more since last baby born Increased*

Age 40 years or older

Nulliparous women 168 (139)

Multiparous women 196 (13487)

Body-mass index of 35 kg/m2 or higher 155 (18188)

Family history of pre-eclampsia (mother or sister) 90 (170493)

Diastolic blood pressure of 80 mm Hg at booking Increased*

Proteinuria at booking appointment (+on dipstick testing, on

more than one occasion or quantified at 300 mg/4 h)

Increased*

Multiple pregnancy 93 (0441)

Underlying medical disordersPre-existing hypertension Increased*

Pre-existing renal disease Increased*

Pre-existing diabetes 356 (54499)

Presence of antiphospholipid antibodies 97 (434175)

*Risk for pre-eclampsia increased, but by how much is unknown.

Table 2: Risk markers for pre-eclampsia at antenatal booking according to the PRE-eclampsia Community

Guidelines (PRECOG8)


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Next to history taking, physical examination including

measurement of blood pressure and assessment forpresence of proteinuria, are the cornerstones ofscreening in antenatal care. Blood pressure should bemeasured as for non-pregnancy, with the woman at rest,sitting upright, with the arm supported, and thesphygmomanometer cuff at the level of the patientsheart.11 Korotkoff sound V (disappearance of turbulence)should be used to define diastolic blood pressure andvalues recorded to the nearest 2 mm Hg. Thigh cuffs(1836 cm) should be used for women with an armcircumference of 41 cm or more.56 Of the automated bloodpressure measuring devices on the market, only theMicrolife 3BTO-A and Microlife WatchBP Home57 havemet the British Hypertension Societys criteria for

accuracy. Mean arterial blood pressure might be a betterpredictor for pre-eclampsia than is systolic or diastolicblood pressure or an increase in blood pressure.58Although dipstick testing for screening of proteinuria isprone to issues of intraobserver and interobservervariability and limited sensitivity and specificity,59 it isreadily available, widely used,and might be the only testavailable in low-income and middle-income countries.Although 24 h urine collection is still used to confirm andquantify a substantial amount of proteinuria,56 thismethod seems vulnerable to issues of overcollection,undercollection, and large coeffi cients of variationbetween tests in the same women.60 The spot urinaryprotein-to-creatinine ratio, often used as a screeningmethod,56 is less cumbersome than is 24 h urine collection,andis suggested to be an equivalently accurate measureof clinically significant proteinuria in pregnancy.61 Still tobe established, however, is whether this ratio remainsconstant throughout a 24 h period.62

PredictionEarly prediction of pre-eclampsia would allow for closesurveillance and preventive strategies. Many tests havebeen assessed for their relation to placental perfusion,vascular resistance, and placental products, includingtests for Downs serum screening analytes and hormones,renal and endothelial dysfunction, oxidative stress, and

fetal-derived products. Of 27 tests reviewed by Meads andcolleagues,63 only a few reached specificities above 90%.These were body-mass index of 34 kg/m or higher,-fetoprotein, and bilateral uterine artery Dopplernotching. Sensitivity of higher than 60% was achievedonly by uterine artery Doppler resistance index andcombinations of indices. Kallikreinuria (sensitivity >80%and specificity >90%) and cellular and total fibronectin(specificity >90%) seem worthy of further investigation.No single test, however, met the clinical standards for apredictive testa conclusion also drawn by authors ofanother systematic review.64

Because any single biomarker is unlikely to be effectivein prediction of the onset of a disorder as heterogeneousas pre-eclampsia, researchers65 have suggested that

combinations of tests such as ultrasound assessment of

uterine artery Doppler waveforms, placental thicknessand homogeneity, and serum markers raise theeffectiveness of history and physical-based screening.Logistic regression analysis combining information onuterine artery pulsatility index, mean arterial pressure,serum pregnancy-associated plasma protein-A, serum-free placental growth factor, body-mass index, andpresence of nulliparity or previous pre-eclampsia showedpromising high sensitivity and specificity in prediction ofearly pre-eclampsia.66 Similarly, ratios of antiangiogenicand proangiogenic factors (eg, ratio of sFlt-1 to placentalgrowth factor)67,68 might have better discriminatory powerthan do other methods.69 However, whether or not thesetests will also be useful across the range of placenta-related

complications remains unknown.

Clinical presentationMaternal organ systems that are susceptible to excessiveinflammation and endothelial damage are the CNS,lungs, liver, kidneys, systemic vasculature, coagulation,and the heartthe placenta and fetus are also at risk. Themore organ systems that are affected, the more maternaland perinatal complications arise. Clinicians should takecaution not to undervalue clinical signs and symptoms in(severe) pre-eclampsia (table 1) because they can be non-specific (eg, nausea and vomiting). Caregivers shouldalways remember that pre-eclampsia can potentiallyfulminate, and therefore they should not be given a falsesense of security because mild disease has beendesignated. Some risks pertain to development of theHELLP syndrome of microangiopathic haemolysis andplatelet consumption, and hepatocellular damage fromperiportal or focal parenchymal necrosis. Patientsfrequently (4090%) have epigastric or right upperquadrant pain.70 These clinical symptoms, along withheadache, visual changes, and nausea or vomiting seemto be more predictive than are laboratory parameters foradverse maternal outcomes.71

HELLP syndrome complicates 1020% of cases ofsevere pre-eclampsia, and develops mostly preterm(50%). In 20% of women, however, it presents in late

gestation, or in 30% post partum.72 HELLP withouthypertension or proteinuria is reported in 1020% ofcases. Direct complications of HELLP syndrome areabruptio placentae (920%), disseminated intravascularcoagulation (556%) and acute renal failure (736%).Less frequent complications are eclampsia (49%),pulmonary oedema (310%), and subcapsular liverhaematoma (less than 2%).72 Estimates of complicationrates can be quite high because they are derived mainlyfrom tertiary care centres. Overall, significant maternalmorbidity is encountered in about 15% of women withsevere pre-eclampsia,73 including retinal detachmentand cerebrovascular bleeding, and complications relatedto HELLP syndrome, but with lowered frequencies. Thebrain is at risk because of impaired cerebral


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autoregulation due to endothelial damage together withdecreased sympathetic innervation in the posteriorcerebral circulation, and a lessened ability for neurogenicresponse to increase blood pressure. Cortical blindnessand some cases of eclampsia could evolve from the acutecerebral illness, posterior reversible leukoencephalo-pathy syndrome (PRES).74

Eclampsia, complicating 12% of severe pre-eclampsia,75 is defined as the occurrence of tonic-clonicseizures in a pregnant or recently delivered woman thatcannot be attributed to other causes. Although diffi cultto predict, in 79% of cases promonitory signs andsymptoms are present during the week before the firsteclamptic seizure: headache (56%), visual disturbances(23%), epigastric pain (17%), hypertension (48%),

proteinuria (46%), and concurrent hypertension andproteinuria (38%).76 Hypertension and proteinuria canlast for several weeks post partum.77 Pre-eclampsia canalso deteriorate or present de novo after delivery,occasionally evolving into severe forms that are similarto eclampsia.78 Women with symptoms and signs of pre-eclampsia might have other maternal diseases,79 andtherefore differential diagnoses should be consideredand excluded (panel 1). Perinatal concerns in womenwith pre-eclampsia relate to risks of placental abruption(06%), intrauterine growth restriction (518%), andperinatal mortality (09%), dependent on severity andgestational onset of disease.80

ManagementFor women with pre-eclampsia, dependent on severity,review at day assessment units or admission to hospital isindicated according to local guidelines.56 Table 3 and panel2 show our suggested management paradigms according to

gestational age at presentation. Although we recognise thatthere is no universally accepted standard of care, which isdependent on local facilities, we believe that risk reductionfor women with pre-eclampsia needs a series of strategiesnamely standardised assessment and surveillance,avoidance and management of severe systolic and diastolichypertension, prevention and treatment of seizures ofeclampsia, and avoidance of use of aggressive rehydrationin women admitted with severe pre-eclampsia. Althoughdebate exists about routine use of some individual tests,standardised assessment and surveillance of all vulnerableorgan systems in women with pre-eclampsia has beenassociated with reduced adverse maternal outcomes,86andproposals for blood tests have been developed.56 Tests foruric acid is one of the controversial tests that has been

Panel 1: Differential diagnoses in severe pre-eclampsia by

organ system

Vasculature

Phaeochromocytoma

Hyperaldosteronism

Cushings disease

Thyrotoxicosis

Aorta coarctation

Renal system

Lupus nephritis

Acute and chronic glomerulonephritis

Interstitial nephritis

Pyelonephritis

Liver

Acute fatty liver of pregnancy

Pregnancy cholestasis

Hyperemesis gravidarum

Cholecystitis

Cholangitis

Viral hepatitis

Acute pancreatitis

Gastritis

Gastric ulcer

Haemostasis

Benign thrombocytopenia of pregnancy

Thrombotic thrombocytopenic purpura

Haemolytic uraemic syndrome

Idiopathic thrombocytopenic purpura

Antiphospholipid syndrome

Folate deficiency

Systemic lupus erythematosus

Septic or haemorrhagic shock

Respiratory system

Pneumonia

Pulmonary embolus

(Catastrophic) antiphospholipid syndrome

(Continues in next column)

(Continued from previous column)

Cardiovascular system

Peripartum cardiomyopathy

Myocardial infarction or ischaemia

Brain

Cerebral systemic lupus erythematosus

Epilepsy

Brain tumour

Cerebrovascular accident

Hypertensive encephalopathy

Metabolic disease

Eyes

Retinal arterial or venous thrombosis

Retinal ischaemia

Retinal detachment

Persistent spasm of retinal vessels

Central serous retinopathy

Uveal melanoma

Choroidal osteoma


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suggested. Although researchers have suggested that uricacid is as important as proteinuria for identification of fetalrisk in women with gestational hypertension,93 it is a poorpredictor of maternal and fetal complications in womenwith pre-eclampsia.94In a review,62 researchers concludedthat the amount of proteinuria is not a good marker ofseverity of pre-eclampsia, and that this measure should notguide management.

For women who are remote from term (99% survival; 96% intact

survival

>99% survival; >96% intact

survival

Increase in maternal risks15

(compared with

normotensive pregnancy)

Substantial Substantial Substantial Moderate Minimum

Consider in-utero transfer to

tertiary centre with NICU

Optional; centre should be

competent with midtrimester

termination of pregnancy or

expectant management

Yes, if mother stable for

transfer

Ideally, but perinatal

outcomes might be

unchanged if transfer post

partum

Optional, but centre should

be competent with expectant

management if considered as

management option

Optional; in case of severe

disease

Expectant management8183 No; although in very few

patients at 3 weeks

gestation clinician mightattempt suffi cient pregnancy

prolongation to attain

perinatal survival

Optional; could be considered

in view of possible perinatal

gains

Optional; could be considered

in view of possible perinatal

gains

Optional; could be considered,

but in severe disease balance

towards delivery

No

Betamethasone for fetal lung

maturation84Optional; dependent on

gestational age

Yes Yes No No

Suggested route of delivery Vaginal (misoprostol

induction of labour)85Probable caesarean section,

unless intrauterine fetal death

Vaginal, depending on fetal

and cervical status


and cervical status


and cervical status

NICU=neonatal intensive care unit. *As defined locally (usually between 3 weeks [+0 days] and 4 weeks [+6 days] gestation). Unpublised data from PIERS.86 Chance of living to discharge from a NICU

without major morbidity (grade 3 intraventricular haemorrhage, stage 3 or 4 retinopathy of prematurity, necrotising enterocolitis, and chronic lung disease).

Table 3: Antepartum management options for women with pre-eclampsia by gestational age at diagnosis


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choose the alternative of intermediate-acting nifedipinetablets should recognise the slow onset of action so thatwomen are not over-treated because of an expectationof a rapid blood pressure response.102 Nifedipine andMgSO4 can be used together effectively and safely.

103Antihypertensives for use in women with non-severehypertension, although generally not related toimproved pregnancy outcome except for less severehypertension,90,104 are also shown in panel 2.

Prevention and management of eclampsia seizures isbased on giving MgSO4.

87,88 Women with severe pre-eclampsia should be considered for MgSO

4

prophylaxis.104Findings from randomised controlled trials87,88 support a

regimen of MgSO4given as a 4 g intravenous loading doseduring a 1520 min period, followed by an infusion of1 g/h, with a first or recurrent seizure treated with another24 g intravenous loading dose. This regimen does notneed testing of blood concentrations of MgSO4 becauseclinical effect can be monitored with deep tendon reflexes.Additionally, it adds a wider therapeutic index betweeneffect and toxicity risk than does the historical 2 g/hregimen. Despite a reduced intravascular volume in pre-eclampsia, plasma volume expansion has not proven toprovide any benefit.91

Timing of delivery should be designed to keepperinatal outcomes at an optimum while obviatingmaternal risks. In pre-eclampsia, this timing should bebased on criteria of fetal wellbeing and gains to be madein terms of perinatal outcomes by achievement ofadditional intrauterine time. Fetal wellbeing is assessedby ultrasound (biometry, umbilical artery Doppler,ductus venosus Doppler, and amniotic fluid) andcardiotocography (preferably computerised).105 Antenatalcorticosteroids for fetal lung maturation should be givento all women at risk of delivery at less than 34 weeks ofgestation.84 Previable fetuses can be delivered withmisoprostol induction.85 In early-onset pre-eclampsiaand often concurrent intrauterine growth restrictionand placental pathology, the fetus is unlikely to tolerate

Panel 2: Suggested antepartum management options for

women with pre-eclampsia at any stage of diagnosis*

Optional assessment and surveillance56,86

On admission, on day of delivery, and additional testing as

indicated by changes in clinical state.

Maternal

Blood: haemoglobin, platelet count, creatinine, uric acid, AST

or ALT, further testing if indicated

Fetal

CTG, ultrasound, AFI, umbilical artery Doppler

MgSO4Regimen: MgSO4 4 g IV loading dose over 150 min,

followed by an infusion of 1 g/h; recurrent seizure(s) treated

with additional 4 g IV loading dose(s); clinical monitoring

by measurement of urinary output, respiratory rate, and

tendon reflexes.

Eclampsia prophylaxis87

Yes; for severe pre-eclampsia during initial stabilisation and

peripartum (delivery +4 h)

Eclampsia treatment88

Yes

Antihypertensive therapy (other doses possible)89,90

Severe hypertension (systolic BP 160 mm Hg or diastolic BP

110 mm Hg)

Nifedipine capsule (5 mg orally for first dose, 10 mg orally

subsequently) every 30 min; nifedipine intermediate acting(10 mg orally) every 45 min; labetalol (100 mg orally) every

45 min, maximum 100 mg/day; labetalol (0 mg IV first

dose, repeat 080 mg IV every 30 min, or 1 mg/min,

maximum 300 mg); hydralazine (510 mg IV) every 30 min,

maximum 0 mg

Nifedipine capsules are safe to use contemporaneously

with MgSO4; nifedipine capsules should not be used in

women with known coronary artery disease, aortic

stenosis, or longstanding diabetes (eg, >15 years); after

two consecutive doses of acute therapy (ie, nifedipine,

labetalol, hydralazine), start or increase maintenance

therapy with agents listed below

(Continues in next column)

(Continued from previous column)

Non-severe hypertension (systolic BP


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labour. However, the closer the pregnancy gets to term,

the more reasonable an attempt at induction of labour isfor women with pre-eclampsia who require timely, butnot emergency, delivery.

When women have severe disease, issues of peripartummanagement of thrombocytopenia and HELLP syndromearise.11,72 Although routine prophylactic platelet transfusionsare not recommended, ordering blood products, includingplatelets, should be considered when platelet counts arefewer than 5010 platelets per L, falling rapidly, or whencoagulopathy is present. Platelet transfusion is alwaysindicated before, during, or after either caesarean sectionor vaginal delivery when platelet counts are fewer than2010/L or in case of significant bleeding (eg, ecchymosis,bleeding from gums or wound).70 Preanaesthetic

assessment of a woman with pre-eclampsia is essential,including an airway examination and assessment ofcoagulation status (such as platelet count). There is norole for tests of platelet function.9,11,106 Use of regionalanalgesia or anaesthesia, or both, is not contraindicated inwomen when platelet counts are higher than 7510/L inthe absence of a coagulopathy, falling platelet count, orconcomitant use of either an antiplatelet agent (eg, aspirin)or anticoagulant (eg, heparin).

Regional anaesthesia (epidural, spinal, or combinedspinal-epidural) is appropriate for women taking low-dose aspirin (without either coagulopathy or platelets


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pregnancy outcomes for women with a thrombophilia.125

Therefore, in view of WHO criteria by Wilson andJungner,126 routine screening of women who had pre-eclampsia and treatment when they were positive forthrombophilia does not yet seems justified, unless theintent is to randomly assign women in definitiverandomised controlled trials. Thrombophilia testing,however, should be recommended for those witha personal or family history of thrombosis.127

Pre-eclampsia, especially of early onset, can be followedby symptoms of maternal post-traumatic stress.128,129Timely recognition of those women at risk and referralreduces the duration of treatment necessary.129 Womenwith pre-eclampsia are at increased risk for futurecardiovascular disease. Pooled relative risks for

hypertension, fatal and non-fatal ischaemic heart disease,and fatal and non-fatal stroke are 370 (95% CI270505), 226 (186252), and 181 (145227),respectively, 1014 years after the index pregnancy.130Early-onset disease and other additional concurrentplacental pathology confer cumulative risk.131 Increasedpre-pregnancy serum concentrations of triglycerides,cholesterol, LDL cholesterol, non-HDL cholesterol, andblood pressure are positively associated with risk ofsubsequent pre-eclampsia and could explain, togetherwith abdominal obesity, the link with future cardiovasculardisease.132,133 Identification of such young women possiblyoffers opportunities for strategies to decrease remotecardiovascular risk.130 As the absolute risk for diseasewithin 12 years is low (less than 0515% dependent onpre-eclampsia severity)130 a first focus might be on lifestylemodifications, including smoking cessation, weightreduction, healthy diet, and exercise,134 in individualisedintervention programmes, including use of the internet.Because the risk of developing chronic hypertensioncould be higher than 20%,130 blood pressure should bechecked regularly. Other individual cardiovascular riskfactors should be treated as indicated, but there seems tobe no place for further screening or preventive druginterventions until further evidence is available. Pre-eclampsia has been suggested to predispose to reducedthyroid function in later years.135

PerspectivesAlthough genetic contributions to the risk of pre-eclampsia are recognised by familial clustering of thisdisorder, underlying mechanisms remain uncertain.136Maternal constitutional and environmental risk factorsfor pre-eclampsia could be implicated by interferencewith the epigenetic programming of the gametes,placenta, and fetus.137 Derangements in genomicimprinting in placental tissue, resulting in disturbedpaternal versus maternal gene expression, haveadditionally been suggested to contribute to pre-eclampsia.137,138 Therefore, high priority will be given inthe near future to elucidation of gene-gene and gene-environment interactions and underlying epigenetic

mechanisms139 that are associated with the programming

of trophoblast cells and how they relate to placentalcauses and systemic linkages of different phenotypes ofpre-eclampsia. Such phenotypes include that for HELLPsyndrome and other placental complications such asisolated intrauterine growth restriction. These insightscould direct future specific preconception and earlypregnancy preventive measures to favourably affectplacentation in women at high risk. Such measuresmight also be targeted at decreasing excessiveinflammatory and oxidative stress (eg, by statins ormetformin) or improvement of endothelial health.

A lowered incidence of hypertensive disease in pregnancywas suggested after periconception low-dose aspirintreatment.140 Trophoblast complement inhibitory therapy

with heparin might seem beneficial in some subgroups ofpatients.141 However, to be able to keep spiral arteryremodelling at an optimum with prophylactic treatment,a need for more comparative research to understand theplacental bed remains. Additionally, pharmacologicalapproaches to counteract the anti-angiogenic state in thesecond stage of the disease could be promising. Epigeneticmodification of fetal vascular tissue during a pregnancythat is complicated by pre-eclampsia might also relate tofuture reproductive status and cardiovascular health.137,142Men and women exposed to pre-eclampsia as a fetus,143and women born small for gestational age,144 have anincreased risk of having (or fathering) a future pregnancythat is complicated by pre-eclampsia. These children alsohave a heightened risk of high blood pressure, features ofmetabolic syndrome, and cardiovascular diseases atrelative early age.145,146

In preconception care, development of simple rules forprediction of recurrent early-onset hypertensive diseasein pregnancy is important.147 During pregnancy,proteomics-based identification of clinically usefulpredictive biomarkers might become feasible.148,149Furthermore, development and validation of diseaseseverity criteria that objectively identify women atincremental risk of adverse outcomes need to bedeveloped. Randomised controlled trials are muchneeded to establish recommendations for management

of early-onset severe pre-eclampsia. In the UK,substandard care contributes to 72% of maternal deathsthat are related to hypertensive disease in pregnancy,16and to 96% of those in the Netherlands.96In the Dutchenquiry,96 no instructions about danger signs to womenhad been documented in 80% of cases. Therefore, patienteducation is of major importance. The need for drills andsimulations for obstetric emergencies such as severehypertension and eclampsia, and for audits of pre-eclampsia-related maternal mortality and severemorbidity should be further advocated.

Contributors

EAS designed the structure of the review and coordinated writing of theSeminar. All authors contributed to the literature search, writing of the

Seminar, and addressing of reviewers comments.


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Conflicts of interest

We declare that we have no conflicts of interest.

Acknowledgments

No funding was used for the preparation or submission of this report.We thank the PhD fellows Durk Berks, Meeke Hoedjes, Nienke Bergen,and Evelyne van Uitert for assisting in the literature search;Jolanda Claessens for her secretarial support; and Frits Wilbrink for hiscontribution to the graphics of the figure. Peter von Dadelszen receivesfunding support from WHO, the Canadian Institutes of HealthResearch, the Michael Smith Foundation for Health Research, and theChild and Family Research Institute.

References1 Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PFA.

WHO analysis of causes of maternal death: a systematic review.Lancet2006; 367: 106674.

2 Duley L. The global impact of pre-eclampsia and eclampsia.Semin Perinatol2009; 33: 13037.

3 Berg CJ, Mackay AP, Qin C, Callaghan WM. Overview of maternal

morbidity during hospitalization for labor and delivery in theUnited States: 19931997 and 20012005. Obstet Gynecol2009;113: 107581.

4 Wallis AB, Saftlas AF, Hsia J, Atrash HK. Secular trends in the ratesof preeclampsia, eclampsia, and gestational hypertension, UnitedStates, 19872004. Am J Hypertens 2008; 21: 52126.

5 Caughey AB, Stotland NE, Washington AE, Escobar GJ. Maternalethnicity, paternal ethnicity, and parental ethnic discordance:predictors of preeclampsia. Obstet Gynecol2005; 106: 15661.

6 Rao AK, Cheng YW, Caughey AB. Perinatal complications amongdifferent Asian-American subgroups. Am J Obstet Gynecol2006;194: e3941.

7 Silva LM, Coolman M, Steegers EA, et al. Low socioeconomicstatus is a risk factor for preeclampsia: the Generation R Study.J Hypertens 2008; 26: 120008.

8 Milne F, Redman C, Walker J, et al. The pre-eclampsia communityguideline (PRECOG): how to screen for and detect onset of pre-eclampsia in the community. BMJ2005; 330: 57680.

9 Tuffnell DJ, Shennan AH, Waugh JJS, Walker JJ. The managementof severe pre-eclampsia/eclampsia, guideline number 10(A).London: Royal College of Obstetricians and Gynaecologists, 2006.

10 Lowe SA, Brown MA, Dekker GA, et al, for the Society of ObstetricMedicine of Australia and New Z. Guidelines for the managementof hypertensive disorders of pregnancy 2008.Aust N Z J Obstet Gynaecol2009; 49: 24246.

11 Magee LA, Helewa ME, Moutquin JM, et al. SOGC guidelines;diagnosis, evaluation and management of the hypertensivedisorders of pregnancy.J Obstet Gynaecol Can 2008;30 (suppl): 148.

12 Lindheimer MD, Taler SJ, Cunningham FG. ASH position article:hypertension in pregnancy.J Am Soc Hypertens 2008; 2: 48489.

13 ACOG Committee on Obstetric Practice. ACOG practice bulletin.Diagnosis and management of preeclampsia and eclampsia.Number 33, January 2002. American College of Obstetricians andGynecologists. Int J Gynaecol Obstet2002; 77: 6775.

14 Brown MA, Lindheimer MD, de Swiet M, Van Assche A,Moutquin JM. The classification and diagnosis of the hypertensivedisorders of pregnancy: statement from the International Society forthe Study of Hypertension in Pregnancy (ISSHP).Hypertens Pregnancy2001; 20: IXXIV.

15 MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality frompreeclampsia and eclampsia. Obstet Gynecol2001; 97: 53338.

16 National Institute for Clinical Excellence, Scottish Executive HealthDepartment, Department of Health, Social Services and PublicSafety, Northern Ireland. Saving motherss lives; 20032005. Theseventh report of the confidential enquiries into maternal deaths inthe United Kingdom. London: CEMACH, 2007.

17 Martin JN Jr, Thigpen BD, Moore RC, Rose CH, Cushman J,May W. Stroke and severe preeclampsia and eclampsia: a paradigmshift focusing on systolic blood pressure. Obstet Gynecol2005;105: 24654.

18 Karumanchi SA, Stillman IE, Lindheimer MD. Angiogenesis andpreeclampsia. In: Lindheimer MD, Roberts JM, Cunningham FG,

eds. Chesleys hypertensive disorders in pregnancy. Amsterdam:Academic Press, Elsevier, 2009: 87103.

19 Brosens I, Robertson WB, Dixon HG. The role of spiral arteries inthe pathogenesis of preeclampsia. In: Obstetrics and Gynecology

Annual, ed Wynn RM. New York: Appleton-Century-Crofts, 1972:17791.

20 Pijnenborg R, Vercruysse L, Hanssens M. The uterine spiralarteries in human pregnancy: facts and controversies. Placenta2006; 27: 93958.

21 Pandian Z, Bhattacharya S, Templeton A. Review of unexplainedinfertility and obstetric outcome: a 10 year review. Hum Reprod2001; 16: 259397.

22 Trogstad L, Magnus P, Moffett A, Stoltenberg C. The effect ofrecurrent miscarriage and infertility on the risk of pre-eclampsia.BJOG 2009; 116: 10813.

23 Ng EH, Chan CC, Tang OS, Yeung WS, Ho PC. The role ofendometrial and subendometrial vascularity measured bythree-dimensional power Doppler ultrasound in the prediction ofpregnancy during frozen-thawed embryo transfer cycles.Hum Reprod2006; 21: 161217.

24 Hanna J, Goldman-Wohl D, Hamani Y, et al. Decidual NK cellsregulate key developmental processes at the human fetal-maternalinterface. Nat Med2006; 12: 106574.

25 Goldman-Wohl DS, Ariel I, Greenfield C, et al. Lack of humanleukocyte antigen-G expression in extravillous trophoblasts isassociated with pre-eclampsia. Mol Hum Reprod2000;6: 8895.

26 Le Bouteiller P, Pizzato N, Barakonyi A, Solier C. HLA-G, pre-eclampsia, immunity and vascular events.J Reprod Immunol2003;59: 21934.

27 Moffett A, Hiby SE. How Does the maternal immune systemcontribute to the development of pre-eclampsia? Placenta 2007;28 (suppl A): 5156.

28 Burton GJ, Jauniaux E, Watson AL. Maternal arterial connections tothe placental intervillous space during the first trimester of humanpregnancy: the Boyd collection revisited. Am J Obstet Gynecol1999;181: 71824.

29 Burton GJ, Jauniaux E. Placental oxidative stress: from miscarriageto preeclampsia.J Soc Gynecol Investig2004; 11: 34252.

30 Jauniaux E, Watson AL, Hempstock J, Bao YP, Skepper JN,Burton GJ. Onset of maternal arterial blood flow and placentaloxidative stress. A possible factor in human early pregnancy failure.Am J Pathol2000; 157: 211122.

31 Pijnenborg R, Brosens I. Deep trophoblast invasion and spiralartery remodelling. In: Pijnenborg R, Brosens I, Romero R, eds.Placental bed disorders: basic science and its translation toobstetrics. Cambridge: Cambridge University Press 2010: 97107.

32 Plasencia W, Maiz N, Bonino S, Kaihura C, Nicolaides KH.Uterine artery Doppler at 11 + 0 to 13 + 6 weeks in the predictionof pre-eclampsia. Ultrasound Obstet Gynecol2007; 30: 74249.

33 Burton GJ. Oxygen, the Janus gas; its effects on human placentaldevelopment and function.J Anat2009; 215: 2735.

34 Burton GJ, Yung HW, Cindrova-Davies T, Charnock-Jones DS.Placental endoplasmic reticulum stress and oxidative stress inthe pathophysiology of unexplained intrauterine growthrestriction and early onset preeclampsia. Placenta 2009;30 (suppl A): 4348.

35 Redman CW. Current topic: pre-eclampsia and the placenta.Placenta 1991; 12: 30108.

36 Jauniaux E, Poston L, Burton GJ. Placental-related diseases ofpregnancy: Involvement of oxidative stress and implications inhuman evolution. Hum Reprod Update 2006; 12: 74755.

37 Brosens JJ, Parker MG, McIndoe A, Pijnenborg R, Brosens IA.A role for menstruation in preconditioning the uterus forsuccessful pregnancy. Am J Obstet Gynecol2009; 200: 615.

38 Haig D. Altercation of generations: genetic conflicts of pregnancy.Am J Reprod Immunol1996; 35: 22632.

39 Redman CW, Sacks GP, Sargent IL. Preeclampsia: an excessivematernal inflammatory response to pregnancy. Am J Obstet Gynecol1999; 180: 499506.

40 Huppertz B. Placental origins of preeclampsia: challenging thecurrent hypothesis. Hypertension 2008; 51: 97075.

41 Redman CWG, Sargent IL, Roberts JM. Immunology of normalpregnancy and preeclampsia. In: Lindheimer MD, Roberts JM,

Cunningham FG, eds. Chesleys hypertensive disorders inpregnancy. Amsterdam: Academic Press, Elsevier, 2009: 12942.


12/14

Seminar


42 Koga K, Osuga Y, Tajima T, et al. Elevated serum soluble fms-liketyrosine kinase 1 (sFlt1) level in women with hydatidiform mole.

Fertil Steril2009; published online March 6. DOI:10.1016/j.fertnstert.2009.02.015.

43 Kanter D, Lindheimer MD, Wang E, et al. Angiogenic dysfuction inmolar pregnancy. Am J Obstet Gynecol2010; 202: 184. e15

44 Redman CW, Sargent IL. Placental stress and pre-eclampsia:a revised view. Placenta 2009; 30 (suppl A): 3842.

45 Myers J, Mires G, Macleod M, Baker P. In preeclampsia, thecirculating factors capable of altering in vitro endothelial functionprecede clinical disease. Hypertension 2005; 45: 25863.

46 Irani RA, Xia Y. The functional role of the renin-angiotensin systemin pregnancy and preeclampsia. Placenta 2008; 29: 76371.

47 Buimer M, Keijser R, Jebbink JM, et al. Seven placental transcriptscharacterize HELLP-syndrome. Placenta 2008; 29: 44453.

48 Wikstrom AK, Larsson A, Akerud H, Olovsson M. Increasedcirculating levels of the antiangiogenic factor endostatin in early-onsetbut not late-onset preeclampsia. Reprod Sci 2009; 16: 9951000.

49 Roberts JM, Hubel CA. The two stage model of preeclampsia:

variations on the theme. Placenta 2009; 30 (suppl A): 3237.50 Egbor M, Ansari T, Morris N, Green CJ, Sibbons PD. Morphometric

placental villous and vascular abnormalities in early- and late-onsetpre-eclampsia with and without fetal growth restriction. BJOG2006; 113: 58089.

51 Zusterzeel PL, Peters WH, Burton GJ, Visser W, Roelofs HM,Steegers EA. Susceptibility to pre-eclampsia is associated withmultiple genetic polymorphisms in maternal biotransformationenzymes. Gynecol Obstet Invest2007; 63: 20913.

52 Stone CD, Diallo O, Shyken J, Leet T. The combined effect ofmaternal smoking and obesity on the risk of preeclampsia.J Perinat Med2007; 35: 2831.

53 Bainbridge SA, Sidle EH, Smith GN. Direct placental effects ofcigarette smoke protect women from pre-eclampsia: the specificroles of carbon monoxide and antioxidant systems in the placenta.Med Hypotheses 2005; 64: 1727.

54 Jeyabalan A, Powers RW, Durica AR, Harger GF, Roberts JM,Ness RB. Cigarette smoke exposure and angiogenic factors in

pregnancy and preeclampsia. Am J Hypertens 2008; 21: 94347.55 Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal

booking: systematic review of controlled studies. BMJ2005; 330: 565.

56 Milne F, Redman C, Walker J, et al. Assessing the onset of pre-eclampsia in the hospital day unit: summary of the pre-eclampsiaguideline (PRECOG II). BMJ2009; 339: 62628.

57 Chung Y, de Greeff A, Shennan A. Validation and compliance ofa home monitoring device in pregnancy: Microlife WatchBP Home.Hypertens Pregnancy2009: 28: 34859.

58 Cnossen JS, Vollebregt KC, de Vrieze N, et al. Accuracy of meanarterial pressure and blood pressure measurements in predictingpre-eclampsia: systematic review and meta-analysis. BMJ2008;336: 111720.

59 Brown MA, Buddle ML. Inadequacy of dipstick proteinuria inhypertensive pregnancy. Aust N Z J Obstet Gynaecol1995; 35: 36669.

60 Cote AM, Firoz T, Mattman A, Lam EM, von Dadelszen P,Magee LA. The 24-hour urine collection: gold standard or historical

practice? Am J Obstet Gynecol2008; 199: 625.61 Cote AM, Brown MA, Lam E, et al. Diagnostic accuracy of urinaryspot protein:creatinine ratio for proteinuria in hypertensivepregnant women: systematic review. BMJ2008; 336: 100306.

62 Lindheimer MD, Kanter D. Interpreting abnormal proteinuria inpregnancy. The need for a more pathophysiological approach.Obstet Gynecol2010; 115: 36575.

63 Meads CA, Cnossen JS, Meher S, et al. Methods of prediction andprevention of pre-eclampsia: systematic reviews of accuracy andeffectiveness literature with economic modelling.Health Technol Assess 2008; 12: iii-iv, 1270.

64 Conde-Agudelo A, Romero R, Lindheimer MD. Tests to predict pre-eclampsia. In: Lindheimer MD, Roberts JM, Cunningham FG, eds.Chesleys hypertensive disorders in pregnancy. Amsterdam:Academic Press, Elsevier, 2009: 189211.

65 Toal M, Chan C, Fallah S, et al. Usefulness of a placental profile inhigh-risk pregnancies. Am J Obstet Gynecol2007; 196: 363.

66 Poon LCY, Kametas NA, Maiz N, Akolekar R, Nicolaides KH.

First-trimester prediction of hypertensive disorders in pregnancy.Hypertension 2009; 53: 81218.

67 Verlohren S, Galindo A, Schlembach D, et al. An automatedmethod for the determination of the sFlt-1 / PIGF ratio in the

assessment of pre-eclampsia. Am J Obstet Gynecol2010;202: 161.e1161.e11.

68 Sunderji S, Gaziano E, Wothe D, et al. Automated assays forsVEGF R1 and PIGF as an aid in the diagnosis of preterm pre-eclampsia: a porspective clinical study. Am J Obstet Gynecol2010;202: 40.e17.

69 Kusanovic JP, Romero R, Chaiworapongsa T, et al. A prospectivecohort study of the value of maternal plasma concentrations ofangiogenic and anti-angiogenic factors in early pregnancy andmidtrimester in the identification of patients destined to developpre-eclampsia.J Matern Fetal NeonatalMed2009; 22: 102138.

70 Sibai BM. Diagnosis, controversies, and management of thesyndrome of hemolysis, elevated liver enzymes, and low plateletcount. Obstet Gynecol2004; 103: 98191.

71 Cavkaytar S, Ugurlu EN, Karaer A, Tapisiz OL, Danisman N. Areclinical symptoms more predictive than laboratory parameters foradverse maternal outcome in HELLP syndrome?Acta Obstet Gynecol Scand2007; 86: 64851.

72 Haram K, Svendsen E, Abildgaard U. The HELLP syndrome:clinical issues and management. A Review. BMCPregnancy Childbirth 2009; 9: 8.

73 Tuffnell DJ, Jankowicz D, Lindow SW, et al, for the YorkshireObstetric Critical Care G. Outcomes of severe pre-eclampsia/eclampsia in Yorkshire 1999/2003. BJOG 2005; 112: 87580.

74 Zeeman GG. Neurologic complications of pre-eclampsia.Semin Perinatol2009; 33: 16672.

75 Sibai BM. Preeclampsia as a cause of preterm and late preterm(near-term) births. Semin Perinatol2006; 30: 1619.

76 Knight M, Ukoss. Eclampsia in the United Kingdom 2005.BJOG 2007; 114: 107278.

77 Berks D, Steegers EAP, Molas M, Visser W. Resolution ofhypertension and proteinuria after preeclampsia: a 2-year follow-upstudy. Obstet Gynecol2009; 14: 130714.

78 Sibai BM, Stella CL. Diagnosis and management of atypicalpreeclampsia-eclampsia. Am J Obstet Gynecol2009; 200: 481.

79 Sibai BM. Imitators of severe pre-eclampsia. Semin Perinatol2009;33: 196205.

80 Sibai BM. Diagnosis and management of gestational hypertensionand preeclampsia. Obstet Gynecol2003; 102: 18192.

81 Magee LA, Yong PJ, Espinosa V, Cote AM, Chen I, von Dadelszen P.Expectant management of severe preeclampsia remote from term:a structured systematic review. Hypertens Pregnancy2009: 28: 31247.

82 Churchill D, Duley L. Interventionist versus expectant care forsevere pre-eclampsia before term. Cochrane Database Syst Rev2002;3: CD003106.

83 Gaugler-Senden IP, Huijssoon AG, Visser W, Steegers EA,de Groot CJ. Maternal and perinatal outcome of preeclampsia withan onset before 24 weeks gestation. Audit in a tertiary referralcenter. Eur J Obstet Gynecol Reprod Biol2006; 128: 21621.

84 Brownfoot FC, Crowther CA, Middleton P. Different corticosteroidsand regimens for accelerating fetal lung maturation for women atrisk of preterm birth. Cochrane Database Syst Rev2008;4:CD006764.

85 Allen R, OBrien BM. Uses of misoprostol in obstetrics andgynecology. Rev Obstet Gynecol2009; 2: 15968.

86 Menzies J, Magee LA, Li J, et al, for the Preeclampsia IntegratedEstimate of RiSk (PIERS) Study Group. Instituting surveillanceguidelines and adverse outcomes in preeclampsia. Obstet Gynecol2007; 110: 12127.

87 The Eclampsia Trial Collaborative Group. Which anticonvulsant forwomen with eclampsia? Evidence from the Collaborative EclampsiaTrial. Lancet1995; 345: 145563.

88 The Magpie Trial Collaboration Group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate?The Magpie Trial: a randomised placebo-controlled trial. Lancet2002; 359: 187790.

89 Magee LA, Cham C, Waterman EJ, Ohlsson A, von Dadelszen P.Hydralazine for treatment of severe hypertension in pregnancy:meta-analysis. BMJ2003; 327: 95564.

90 Abalos E, Duley L, Steyn DW, Henderson-Smart DJ.

Anihypertensive drug therapy for mild to moderate hypertensionduring pregnancy. Cochrane Database Syst Rev2007; 1: CD002252.


13/14

Seminar


91 Ganzevoort W, Rep A, Bonsel GJ, et al. A randomised controlledtrial comparing two temporising management strategies, one with

and one without plasma volume expansion, for severe and earlyonset pre-eclampsia. BJOG 2005; 112: 135868.

92 Nelson-Piercy C. Thromboprophylaxis during pregnancy, labourand after vaginal delivery. Guideline number 37. London: RoyalCollege of Obstetricians and Gynaecologists, 2004.

93 Roberts JM, Bodnar LM, Lain KY, et al. Uric acid is as important asproteinuria in identifying fetal risk in women with gestationalhypertension. Hypertension 2005; 46: 126369.

94 Thangaratinam S, Ismail KMK, Sharp S, Coomarassamy A,Khan KS. Accuracy of serum acid in predicting complications ofpre-eclampsia: a systematic review. BJOG 2006; 113: 36978.

95 Koopmans CM, Bijlenga D, Groen H, et al. Induction of labourversus expectant monitoring for gestational hypertension or mildpre-eclampsia after 36 weeks gestation (HYPITAT): a multicentre,open-label randomised controlled trial. Lancet2009; 374: 97988.

96 Schutte JM, Schuitemaker NW, van Roosmalen J, Steegers EA,Dutch Maternal Mortality C. Substandard care in maternal mortalitydue to hypertensive disease in pregnancy in the Netherlands.BJOG 2008; 115: 73236.

97 Katz L, de Amorim MM, Figueiroa JN, Pinto e Silva JL.Postpartum dexamethasone for women with hemolysis, elevatedliver enzymes, and low platekets (HELLP) syndrome: a double-blind, placebo-controlled, randomized clinical trial.Am J Obstet Gynecol2008; 198: 283.

98 Matchaba PT, Moodley J. Corticosteroids for HELLP syndrome inpregnancy. Cochrane Database Syst Rev2009; 3:CD002076.

99 Duley L, Henderson-Smart DJ, Meher S. Drugs for treatment ofvery high blood pressure during pregnancyCochrane Database Syst Rev2006; 3: CD001449.

100 Hennessy A, Thornton CE, Makris A, et al. A randomizedcomparison of hydralazine and mini-bolus diazoxide forhypertensive emergencies in pregnancy: the PIVOT trial.Aust N Z J Obstet Gynaecol2007: 47: 27985.

101 Grossman E, Messerli FH, Grodzicki T, Kowey P. Should amoratorium be placed on sublingual nifedipine capsules given for

hypertensive emergencies and pseudoemergencies? JAMA 1996;276: 132831.

102 Magee LA, von Dadelszen P. The management of severehypertension. Semin Perinatol2009; 33: 13842.

103 Magee LA, Miremadi S, Li J, et al. Therapy with both magnesiumsulfate and nifedipine does not increase the risk of seriousmagnesium-related maternal side effects in women withpreeclampsia. Am J Obstet Gynecol2005; 193: 15363.

104 Leveno KJ, Cunningham FG. Management. In: Lindheimer MD,Roberts JM, Cunningham FG, eds. Chesleys hypertensive disordersin pregnancy. Amsterdam: Academic Press, Elsevier, 2009: 389414.

105 Freeman RK. Antepartum testing in patients with hypertensivedisorders in pregnancy. Semin Perinatol2008; 32: 27173.

106 Turner JA. Severe preeclampsia: anesthetic implications of thedisease and its management. Am J Ther2009; 16: 28488.

107 Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia inthe anticoagulated patient: defining the risks (the second ASRAConsensus Conference on Neuraxial Anesthesia and

Anticoagulation). Reg Anesth Pain Med2003; 28: 17297.108 Getahun D, Ananth CV, Oyelese Y, Chavez MR, Kirby RS,

Smulian JC. Primary preeclampsia in the second pregnancy: effectsof changes in prepregnancy body mass index between pregnancies.Obstet Gynecol2007; 110: 131925.

109 Mostello D, Kallogjeri D, Tungsiripat R, Leet T. Recurrence ofpreeclampsia: effects of gestational age at delivery of the firstpregnancy, body mass index, paternity, and interval between births.Am J Obstet Gynecol2008; 199: 55.

110 Maggard MA, Yermilov I, Li Z, et al. Pregnancy and fertility followingbariatric surgery: a systematic review.JAMA 2008; 300: 228696.

111 Duley L, Meher S, Abalos E. Management of pre-eclampsia. BMJ2006; 332: 4638.

112 Barton JR, Sibai BM. Prediction and prevention of recurrentpreeclampsia. Obstet Gynecol2008; 112: 35972.

113 Trumbo PR, Ellwood KC. Supplemental calcium and risk reductionof hypertension, pregnancy-induced hypertension, and

preeclampsia: an evidence-based review by the US Food and DrugAdministration. Nutr Rev2007; 65: 7887.

114 Askie LM, Duley L, Henderson-Smart DJ, Stewart LA, on behalf ofthe PARIS Collaborative Group. Antiplatelet agents for prevention

of pre-eclampsia: a meta-analysis of individual patient data. Lancet2007; 369: 179198.

115 Rogers JM. Tobacco and pregnancy. Reprod Toxicol2009; 28: 15260.

116 Pabinger I. Thrombophilia and its impact on pregnancy.Thromb Res 2009; 123 (suppl 3): 1621.

117 Sikkema JM, Franx A, Bruinse HW, van der Wijk NG, de Valk HW,Nikkels PG. Placental pathology in early onset pre-eclampsia andintra-uterine growth restriction in women with and withoutthrombophilia. Placenta 2002; 23: 33742.

118 Robertson L, Wu O, Langhorne P, et al, for the Thrombosis: Riskand Economic Assessment of Thrombophilia Screening Study.Thrombophilia in pregnancy: a systematic review. Br J Haematol2006; 132: 17196.

119 Dizon-Townson D, Miller C, Sibai B, et al, for the National Instituteof Child Health and Human Development Maternal-Fetal MedicineUnits Network. The relationship of the factor V Leiden mutationand pregnancy outcomes for mother and fetus. Obstet Gynecol2005;106: 51724.

120 Kahn SR, Platt R, McNamara H, et al. Inherited thrombophilia andpre-eclampsia within a multicenter cohort: the MontrealPre-eclampsia Study. Am J Obstet Gynecol2009; 200: 151.

121 Kocher O, Cirovic C, Malynn E, et al. Obstetric complications inpatients with hereditary thrombophilia identified using the LCxmicroparticle enzyme immunoassay: a controlled study of5,000 patients. Am J Clin Pathol2007; 127: 6875.

122 Facchinetti F, Marozio L, Frusca T, et al. Maternal thrombophiliaand the risk of recurrence of preeclampsia. Am J Obstet Gynecol2009; 200: 46.

123 van Rijn BB, Hoeks LB, Bots ML, Franx A, Bruinse HW. Outcomesof subsequent pregnancy after first pregnancy with early-onsetpre-eclampsia. Am J Obstet Gynecol2006; 195: 72328.

124 Steegers-Theunissen RP, Van Iersel CA, Peer PG, Nelen WL,Steegers EA. Hyperhomocysteinemia, pregnancy complications,and the timing of investigation. Obstet Gynecol2004; 104: 33643.

125 Walker MC, Ferguson SE, Allen VM. Heparin for pregnant women

with acquired or inherited thrombophilias.Cochrane Database Syst Rev2003; 2:CD003580.

126 Wilson JMG, Jungner G. Principles and practice of screening fordisease. Public health papers, no 34. Geneva: World HealthOrganization, 1969.

127 Silver RM, Warren JE. Preconception counseling for women withthrombophilia. Clin Obstet Gynecol2006; 49: 90619.

128 Rep A, Ganzevoort W, Bonsel GJ, Wolf H, de Vries JI. Psychosocialimpact of early-onset hypertensive disorders and relatedcomplications in pregnancy. Am J Obstet Gynecol2007; 197: 158.

129 Poel YH, Swinkels P, de Vries JI. Psychological treatment of womenwith psychological complaints after pre-eclampsia.J Psychosom Obstet Gynaecol2009; 30: 6572.

130 Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsiaand risk of cardiovascular disease and cancer in later life: systematicreview and meta-analysis. BMJ2007; 335: 974.

131 Newstead J, von Dadelszen P, Magee LA. Preeclampsia and futurecardiovascular risk. Expert Rev Cardiovasc Ther2007; 5: 28394.

132 Magnussen EB, Vatten LJ, Lund-Nilsen TI, Salvesen KA,Davey Smith G, Romundstad PR. Prepregnancy cardiovascular riskfactors as predictors of pre-eclampsia: population based cohortstudy. BMJ2007; 335: 978.

133 Berends AL, de Groot CJ, Sijbrands EJ, et al. Shared constitutionalrisks for maternal vascular-related pregnancy complications andfuture cardiovascular disease. Hypertension 2008; 51: 103441.

134 Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based guidelinesfor cardiovascular disease prevention in women. American HeartAssociation scientific statement. Arterioscler Thromb Vasc Biol2004;24: 2950.

135 Levine RJ, Vatten LJ, Horowitz GL, et al. Pre-eclampsia, solublefms-like tyrosine kinase 1, and the risk of reduced thyroid function:nested case-control and population based study. BMJ2009;339: b4336.

136 Mutze S, Rudnik-Schoneborn S, Zerres K, Rath W. Genes and thepreeclampsia syndrome.J Perinat Med2008; 36: 3858.

137 Nafee TM, Farrell WE, Carroll WD, Fryer AA, Ismail KM.Epigenetic control of fetal gene expression. BJOG 2008; 115: 15868.


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138 Oudejans CB, van Dijk M. Placental gene expression and pre-eclampsia. Placenta 2008; 29 (suppl A): 7882.

139 Arngrimsson R. Epigenetics of hypertension in pregnancy.Nat Genet2005; 37: 46061.

140 Lambers MJ, Groeneveld E, Hoozemans DA, et al. Lower incidenceof hypertensive complications during pregnancy in patients treatedwith low-dose aspirin during in vitro fertilization and earlypregnancy. Hum Reprod2009; 24: 244750.

141 Hossain N, Schatz F, Paidas MJ. Heparin and maternal fetalinterface: Why should it work to prevent pregnancy complications?Thromb Res 2009; 124: 65355.

142 Krause B, Sobrevia L, Casanello P. Epigenetics: new concepts of oldphenomena in vascular physiology. Curr Vasc Pharmacol2009;7: 51320.

143 Wu CS, Nohr EA, Bech BH, Vestergaard M, Catov JM, Olsen J.Health of children born to mothers who had preeclampsia:a population-based cohort study. Am J Obstet Gynecol2009; 201: 269.

144 Zetterstrom K, Lindeberg S, Haglund B, Magnuson A, Hanson U.Being born small for gestational age increases the risk of severe

pre-eclampsia. BJOG 2007; 114: 31924.

145 Oglaend B, Forman MR, Romundstad PR, Nilsen ST, Vatten LJ.Blood pressure in early adolescence in the offspring of preeclamptic

and normotensive pregnancies.J Hypertens 2009; 27: 205154.146 Tenhola S, Rahiala E, Halonen P, Vanninen E, Voutilainen R.

Maternal preeclampsia predicts elevated blood pressure in 12-year-old children: evaluation by ambulatory blood pressure monitoring.Pediatr Res 2006; 59: 32024.

147 Sep SJ, Smits LJ, Prins MH, Spaanderman ME, Peeters LL. Simpleprepregnant prediction rule for recurrent early-onset hypertensivedisease in pregnancy. Reprod Sci 2009; 16: 8087.

148 Blankley RT, Gaskell SJ, Whetton AD, Dive C, Baker PN, Myers JE.A proof-of-principle gel-free proteomics strategy for theidentification of predictive biomarkers for the onset ofpre-eclampsia. BJOG 2009; 116: 147380.

149 de Groot CJ, Guzel C, Steegers-Theunissen RP, et al. Specificpeptides indentified by mass spectrometry in placental tissue frompregnancies complicated by early onset preeclampsia attained bylaser capture dissection. Proteomics Clin Applic2007; 1: 32535.

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