Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391403Contents lists available at ScienceDirect

Best Practice & Research ClinicalObstetrics and Gynaecology

journal homepage: www.elsevier .com/locate /bpobgyn1

Epidemiology of pre-eclampsia and the other hypertensivedisorders of pregnancy

Jennifer A. Hutcheon, PhD, Post-Doctoral Fellowa,*,Sarka Lisonkova, MD, PhD, Post-Doctoral Fellowa,K.S. Joseph, MD, PhD, Professor a,b

aDepartment of Obstetrics and Gynaecology, University of British Columbia, 4500 Oak Street, Vancouver, V6H 2N1, Canadab School of Population and Public Health, University of British Columbia, Vancouver, CanadaKeywords:pregnancyhypertensionpre-eclampsiaepidemiologymortalitymorbiditynatural history* Corresponding author. Tel.: 1 604 875 2000xE-mail address: jhutcheon@cfri.ca (J.A. Hutcheo

1521-6934/$ see front matter 2011 Elsevier Ltdoi:10.1016/j.bpobgyn.2011.01.006Hypertensive disorders of pregnancy include chronic hyperten-sion, gestational hypertension, pre-eclampsia and chronic hyper-tension with superimposed pre-eclampsia. Pre-eclampsiacomplicates about 3% of pregnancies, and all hypertensive disor-ders affect about five to 10% of pregnancies. Secular increases inchronic hypertension, gestational hypertension and pre-eclampsiahave occurred as a result of changes in maternal characteristics(such as maternal age and pre-pregnancy weight), whereasdeclines in eclampsia have followed widespread antenatal careand use of prophylactic treatments (such as magnesium sulphate).Determinants of pre-eclampsia rates include a bewildering array ofrisk and protective factors, including familial factors, spermexposure, maternal smoking, pre-existing medical conditions(such as hypertension, diabetes mellitus and anti-phospholipidsyndrome), and miscellaneous ones such as plurality, oldermaternal age and obesity. Hypertensive disorders are associatedwith higher rates of maternal, fetal and infant mortality, andsevere morbidity, especially in cases of severe pre-eclampsia,eclampsia and haemolysis, elevated liver enzymes and low plate-lets syndrome.

2011 Elsevier Ltd. All rights reserved.4800; Fax: 1 604 875 2987.n).

d. All rights reserved.

mailto:jhutcheon@cfri.cawww.sciencedirect.com/science/journal/15216934http://www.elsevier.com/locate/bpobgynhttp://dx.doi.org/10.1016/j.bpobgyn.2011.01.006http://dx.doi.org/10.1016/j.bpobgyn.2011.01.006

J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391403392Introduction

Hypertensive disorders of pregnancy constitute an enigmatic and clinically challenging group ofpregnancy complications that are responsible for a substantial burden of illness in both industrialisedand less industrialised countries. This review outlines the disease definitions, global burden ofdisease, natural history, and unresolved epidemiologic questions of the hypertensive disorders ofpregnancy.

Definitions and classification of hypertensive disorders of pregnancy

The primary clinical entities that comprise the hypertensive disorders of pregnancy include chronichypertension, gestational hypertension, pre-eclampsia and chronic hypertension with superimposedpre-eclampsia. A major challenge in the study of hypertension in pregnancy has been the developmentof precise definitions for each of these entities, but universal agreement on disease definitions remainselusive.

Chronic hypertension

Chronic (pre-existing) hypertension is defined as a hypertension (systolic blood pressure 140 mmHg or diastolic blood pressure 90 mmHg) that is diagnosed before pregnancy or before 20weeks gestation.1 Hypertension first diagnosed after 20 weeks gestation, and which persists 12 weekspostpartum, is also considered chronic hypertension.

Gestational hypertension

Gestational hypertension is defined as hypertension that develops in pregnancy after 20 weeksgestation and which returns to normal within 12 weeks postpartum.1 The latter part of the definitionmeans that this diagnosis is made retrospectively in the postpartum period.

Pre-eclampsia

Pre-eclampsia is a systemic syndrome that is typically characterised by new-onset hypertensionand proteinuria in pregnancy (with proteinuria defined as the urinary excretion of 300 mg of proteinin 24 h).1 Pre-eclampsia is characterised by poor placental perfusion and a systemic disease processthat can involve multiple organ systems.2,3 Recent guidelines of the Society of Obstetric Medicine ofAustralia and New Zealand4 recommend that a diagnosis of pre-eclampsia bemadewhen hypertensionarises after 20 weeks gestation and is accompanied by any one of the following complications: renal,haematological, hepatic or neurologic involvement, pulmonary oedema, fetal growth restriction orplacental abruption. One diagnostic criterion, namely fetal growth restriction, seems problematicbecause, by definition, it eliminates all fetal growth restriction among women with gestationalhypertension.

Atypical pre-eclampsia may occur as hypertension associated with systemic symptoms, abnormalhaematological tests or elevated liver enzymes but without proteinuria.1 Similarly, pre-eclampsia canoccur without hypertension when gestational proteinuria is associated with the systemic manifesta-tions.5 Other atypical forms of pre-eclampsia include cases that occur before 20 weeks gestation(usually associated with gestational trophoblast disease) and those that manifest more than 48 h afterdelivery.5

Chronic hypertension with superimposed pre-eclampsia

Chronic hypertension with superimposed pre-eclampsia is diagnosed when a woman with chronichypertension develops new-onset proteinuria, thrombocytopoaenia or any of the other systemicfeatures of the pre-eclampsia syndrome.1

J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391403 393Eclampsia

Neurologic involvement in the form of generalised tonicclonic convulsions in women with pre-eclampsia is termed eclampsia, if the seizures cannot be attributed to any other cause (such as epilepsy,cerebral infection, tumour or ruptured aneurysm).1

Haemolysis, elevated liver enzymes and low platelets syndrome

Haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome is a severe form of pre-eclampsia. The manifestations of this syndrome (i.e. haaemolysis, elevated liver enzymes and a lowplatelet count)1 are presumed to indicate hepatocellular injury. Such injury can include unrupturedhepatic and subcapsular haematomatas.

Older terms and concepts

Labels such as pregnancy-induced hypertension and pregnancy-associated hypertension, previ-ously used to describe the syndrome of hypertension in pregnancy with or without proteinuria andoedema, have been replaced by the more specific entities described above. Hyperuricaemia isa common feature of pre-eclampsia but is not generally considered to be diagnostic.4 The diagnosis ofhypertension based on a relative increase criterion (i.e. a 30 mmHg increase in systolic pressure ora 15 mmHg increase in diastolic pressure compared with previous levels) has been abandoned infavour of the absolute normative blood pressure cut-off of 140/90 mmHg.1

Disease severity

Numerous different classifications for disease severity in pre-eclampsia have been proposed. Criteriahave been based on the severity of hypertension (e.g. a systolic pressure 160mmHg, diastolic pressure110mmHgonat least twooccasions 6 hapart,6 or both), timingof delivery (e.g. delivery

J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391403394pregnancies in the USA.17,18 Reports from other industrialised countries have also yielded estimatesbetween 3 and 5%, including prospective studies fromWellington, NewZealand (3.3%)19 and studies basedon the Swedish, Danish and Norwegian Medical Birth Registers (3.0%, 4.5%, and 3.0%, respectively).7,14,20

Higher estimates have been reported in some studies, with an incidence of 8.4% reported from Wash-ington State21 and rates of 8.7% (mild pre-eclampsia) and 1.7% (severe pre-eclampsia) reported fromNovaScotia.6 These variations likely reflect both differences in maternal characteristics between populations(such as the age distribution) and diagnosis. For instance, the Nova Scotia study6 defined mild pre-eclampsiaon thebasisof elevatedbloodpressurealone (i.e. it includedcaseswithandwithoutproteinuria).

Pre-eclampsia rates have increased in the USA, with age-adjusted rates rising from 2.4% between1987 and 1988 to 2.9% of deliveries between 2003 and 2004.17 Norwegian data also showed increasingrates, from 3.7% between 1988 and 1992 to 4.4% between 1998 and 2002.20 Pre-eclampsia rates aresubject to seasonal and regional variation. In northern regions, pre-eclampsia is more common inwinter births21,22 whereas, in Zimbabwe, incidence has been associated with precipitation patterns.23

In Finland, women in Northern regions have a two-fold higher risk of pre-eclampsia compared withwomen in Southern regions.24

Risk factorsRisk factors for pre-eclampsia represent a bewildering array of causative antecedents that reflect

the diseases complexity. They can be loosely categorised into broad groups.

Familial factors. A family history of pre-eclampsia increases the risk of pre-eclampsia substantially andwomenwhosemothers have pre-eclampsia aremore likely to have pre-eclampsia.25 Menwho fathereda pregnancy with pre-eclampsia are more likely to father another pregnancy complicated by pre-eclampsia in other women.26

Primipaternity and sperm exposure. Nulliparous women have a three-fold higher risk of pre-eclampsiacompared with multiparous women.27 The primipaternity hypothesis28 suggests that risks of pre-eclampsia are increased among women who have limited exposure to their partners sperm. Evidencein favour of this hypothesis includes the lower risk of pre-eclampsia among multiparous women,among women who have had a previous pregnancy loss, and following prolonged pre-pregnancy co-habitation; and the higher risk of pre-eclampsia observed among women who use barrier contra-ception and those who change partners. An increased birth interval is the alternative explanationoffered for the latter phenomenon,29 although the evidence for this has been disputed.30 Furthersupport for the primipaternity hypothesis comes from studies involving infertile couples. Women notpreviously exposed to their partners sperm (e.g. women conceiving following intracytoplasmic sperminjection for azoospermia, with sperm obtained sugically) have a three-fold higher risk of pre-eclampsia compared with women previously exposed to their partners sperm (e.g. women conceivingafter in-vitro fertilization or intracytoplasmic sperm injection, with sperm obtained from ejaculate).31

Pre-existing medical conditions. Women with pre-existing hypertension32 or diabetes mellitus33 are ata substantially higher risk of pre-eclampsia. Women with anti-phospholipid syndrome,34 the otherthrombophilias,35 autoimmune disease,36 kidney disease,37 and infertility38 are also at higher risk.

Smoking. Numerous studies have shown that smoking reduces pre-eclampsia occurrence by about 50%in a dose-dependent manner.39 The association is not seen with snuff. Women who smoke in earlypregnancy and quit do not have a reduced risk, whereas thosewho start smoking in late pregnancy andthose who smoke throughout pregnancy are protected.40 This suggests that, although generallydeletrious in terms of pregnancy outcomes, the combustion products of tobacco have a protectiveeffect in late pregnancy.

Miscellaneous factors. Pre-eclampsia in a previous pregnancy is a strong predictor of pre-eclampsia ina subsequent pregnancy, especially given an early gestational age at first delivery.41 Some studies havefailed to replicate this finding, however.8 Older maternal age,27 obesity27,32 and multiple pregnancy32

J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391403 395also increase the risk of pre-eclampsia. Other reported risk factors for pre-eclampsia include infec-tions42 and residence at high altitude.43

Maternal effects

Pre-eclampsia and eclampsia were responsible for 0.85 (95% CI 0.54 to 1.35) maternal deaths per100,000 maternities between 2003 and 2005 in the UK.44 Similarly, hypertensive disorders of preg-nancy were responsible for 0.60 (95% CI 0.34 to 1.03) maternal deaths per 100,000 live births in Canadabetween 1999 and 2004.45 Such deaths constitute about 1415% of maternal deaths in these twocountries. Data from the UK show a steady downward temporal trend in maternal deaths from pre-eclampsia and eclampsia.44 Nevertheless, declines have been relatively modest in the UK and Canada.

The risks of serious complications such as acute renal failure and pulmonary oedema are 10 to 30-fold higher among women with severe pre-eclampsia or eclampsia,17 and pre-eclampsia has beenidentified as the leading reason for intensive care unit admissions in the puerperal period.46 Womenwith pre-eclampsia have a 70% higher risk of placental abruption (RR 1.7, 95% CI 1.5-2.0),47 with riskincreasing with increasing disease severity.48

Effects on fetus and infant

Although stillbirth rates among women with pre-eclampsia have decreased considerably in recentdecades, studies from industrialised countries such as Norway show that women with pre-eclampsiahave a 35% higher risk of stillbirth.49 Studies from less industrialised nations show that pre-eclampsiais associated with a two-fold increased risk of stillbirth (95% CI 1.6-4.1).50

Women with severe pre-eclampsia have an 80-fold increased risk of iatrogenic preterm deliverybefore 33 weeks and a 40-fold increased risk between 33 and 36 weeks.6 These excess risks foriatrogenic early delivery play a large role in the four-fold increase in low birth weight rates observed inthe offspring of women with pre-eclampsia.51 Neonatal mortality is about two-fold higher amonginfants of mothers with pre-eclampsia, and this increased risk has remained relatively constant duringrecent decades.49 Offspring of womenwith pre-eclampsia are also at increased risk of lowApgar scores,febrile seizures, encephalopathy, and neonatal intensive care unit admission.5154 Interestingly, infantsborn at very preterm ages as a result of pre-eclampsia have a reduced risk of cerebral white matterdamage and cerebral palsy compared with infants born very preterm for other reasons.55

The relationship between pre-eclampsia and fetal growth is complex. Compared with infants borntowomenwithout pre-eclampsia, infants born towomenwith pre-eclampsia have a three- to four-foldincreased risk of being small for gestational age (a birthweight

J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391403396were complicated by pre-eclampsia,10 whereas the risk remains at 1% for women with no history ofpre-eclampsia. The risk of recurrence is influenced by gestational age at onset and plurality of the indexpregnancy.41,63

Long-term sequelae

A consistent association has been found between pre-eclampsia and long-term risk of cardiovas-cular and metabolic disease in the mother. Women with pre-eclampsia have a three- to four- foldincreased risk of developing chronic hypertension and an approximately two-fold increased risk ofischaemic heart disease, stroke and venous thromboembolism.64 Studies show that cardiovascular riskfactors such as dyslipidaemia and elevated blood pressure are present years before pregnancy inwomen who subsequently developed pre-eclampsia, suggesting that the pre-eclampsia may bea manifestation of a common disease process.65

Studies have reported both decreased66 and increased67 risks of cancer after pre-eclampsia, witha meta-analysis reporting a null effect.64 The overall increase mortality risk after pre-eclampsia (RR1.49, 95 % CI 1.1-2.1]) is largely driven by increased risk of death due to cardiovascular disease.64

Other hypertensive disorders

Pre-existing (chronic) hypertensionBetween 1 and 4% of women aged 1829 years, and 515% of women aged 3039 years in the USA

(19992004) have chronic hypertension.68 The US Nationwide Inpatient Survey estimated that 1.7% ofpregnancies in 2004 were complicated by pre-existing hypertension, a 50% increase since 1998.17

Increases in obesity and maternal age are likely to be responsible for this temporal increase.Rates of perinatal mortality, preterm delivery, and small gestational age infants are all two- to three-

fold higher in this group of women compared with normotensive women,33,69 whereas rates of seriousmaternal morbidity (i.e. acute renal failure, pulmonary oedema and adult respiratory distresssyndrome) can be nine-fold higher.17 Women with pre-existing hypertension have a three-foldincreased risk of death compared with normotensive women.17 The increased risk is often mediatedthrough the increased risk of developing superimposed pre-eclampsia, which is estimated to be 2025%.33,69,70 Although the risks of adverse outcomes increase significantly with the development ofsuperimposed pre-eclampsia,33,70 women with pre-existing hypertension without pre-eclampsia doremain at increased risk.33

Gestational hypertension

Gestational hypertension complicates roughly 23% of pregnancies in the USA.16,17 As with pre-eclampsia and pre-existing hypertension, rates of gestational hypertension have been increasing inrecent decades from 10.7 to 30.6 per 1,000 deliveries reported between 1987 and 2004.16 Womenwithgestational hypertension are at increased risk of developing super-imposed pre-eclampsia and about17% of womenwith gestational hypertension subsequently develop pre-eclampsia.71 Although womenwith gestational hypertension are at increased risk of serious obstetric complications compared withnormotensive women, risks to the mother are considerably less than for the other hypertensivedisorders of pregnancies.17 Maternal risks associated with gestational hypertension are generally lessthan two-fold higher, compared with two- to nine-fold higher risk among women with mild pre-eclampsia or pre-existing hypertension. Severity of hypertension is an important predictor of risks,however, and women with severe gestational hypertension are at higher risk of adverse maternal andperinatal outcomes than women with mild pre-eclampsia.72

Eclampsia

The incidence of eclampsia has been estimated to be 2.7 cases per 10,000 births in 2005 in the UK,73

5.7 per 10,000 deliveries in Canada in 2007,74 5.0 per 10,000 maternities in Denmark, Norway andSweden between 1998 and 2000,75 6.0 per 10,000 deliveries in the Netherlands,76 and 8.2 per 10,000

J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391403 397deliveries in the USA between 1996 and 2004.17 The frequency of eclampsia in less industrialisedcountries is substantially higher and estimates range from 1669 per 10,000 births.77

Unlike the hypertensive disorders of pregnancy in general, rates of eclampsia have declined inindustrialised countries in recent decades. The rate of eclampsia in the UK decreased from 4.9/10,000maternities (95% CI 4.5 to 5.4) in 199278 to 2.7 cases per 10,000 births (95% CI 2.4 to 3.1) in 2005.73 This45% decrease reflects a continued temporal decline over the past century, with reductions of over 90%observed since the 1920s.79 In the USA, the age-adjusted frequency of eclampsia decreased non-significantly from 10.4 per 10,000 deliveries between 1987 and 1995 to 8.2 per 10,000 deliveriesbetween 1996 and 2004.17 Improved access to antenatal care, early delivery of womenwith severe pre-eclampsia, and use of magnesium sulphate80 are believed to be responsible for the reductions.

Risks of serious adverse maternal and perinatal outcomes are high among women with eclampsia.In industrialised countries, the case fatality rate is below 1%, but severe maternal complications (suchas coma, stroke and acute respiratory distress) occur in 1030% of cases.73,77,81 About 58% of preg-nancies complicated by eclampsia result in a perinatal loss.77,81,82

Heterogeneity of pre-eclampsia

Considerable heterogeneity in pregnancy outcomes is evident depending on gestational age atonset of pre-eclampsia. For example, maternal mortality rates are 24 times higher when pre-eclampsiaonset occurs at less than 28 weeks compared with onset at term gestation.83 Infants of mothers withpre-eclampsia at preterm gestation are significantly smaller than their non-pre-eclampsia peers ofsimilar gestation, whereas infants of mothers with pre-eclampsia at term gestation are at increased riskof being either smaller or larger than their non-pre-eclampsia peers.51,58 Womenwith early onset pre-eclampsia (before 34 weeks) have a four-fold increased risk of stillbirth in a subsequent pregnancy,whereas women with late-onset pre-eclampsia have no elevated risk for subsequent stillbirth.84

Finally, women with early onset pre-eclampsia have considerably higher risks of recurrence insubsequent pregnancies than women with a later disease onset.41

Haemodynamic and placental morphology studies also suggest that pre-eclampsia is a heteroge-neous entity. Women who subsequently develop early onset pre-eclampsia have high vascular resis-tance and low cardiac output before disease onset (at 2022 weeks), whereas women whosubsequently developed pre-eclampsia at or beyond 34 weeks have low vascular resistance at 2022weeks.85 The placental lesions characteristic of pregnancies with pre-eclampsia are considerably morecommon in women with an earlier disease onset.86

These observations have lead several authors to propose that, like diabetes, several distinctsubtypes of pre-eclampsia exist.87,88 The early, more severe subtypemay be associatedwith underlyinggenetic or environmental factors that result in abnormal placentation. In contrast, the later-onset, lesssevere subtype may be a consequence of factors such as obesity, diabetes, cardiovascular disorders ormulti-fetal pregnancy.

Modification of the effect of pre-eclampsia on perinatal mortality by gestational age

Intersecting perinatal mortality curves

A paradoxical relationship between hypertension in pregnancy and gestational age-specific (andbirth-weight-specific) perinatal mortality has been reported in several studies.89,90 At term gestation,neonatal mortality rates are higher among infants of women with hypertension in pregnancycompared with infants of women without hypertension. The opposite is true at preterm gestation(Fig. 1). This phenomenon is also observed with stillbirth (Fig. 1). Such paradoxical effects are notunique to hypertensive disorders of pregnancy but are also seen when examining risk factors such asmaternal smoking, race, plurality and parity. For example, low-birth-weight infants of smokers havebetter survival compared with the low-birth-weight infants of non-smokers, whereas the opposite istrue at higher birth weights. This general phenomenon is known as the paradox of intersectingperinatal mortality curves and, although various explanations have been proposed (see below), thereis no consensus regarding the underlying cause.91

J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391403398The stress hypothesis

Increased level of maternal cortisol due to stress factors, such as hypertension, can lead to accel-erated lung maturation92 and a lower risk of respiratory distress syndrome, intraventricular haemor-rhage and neonatal death.92,93Haigs hypothesis

The evolutionary theory of maternalfetal genetic conflict also provides a rationale for higherneonatal survival among preterm infants born to mothers with hypertension.94 Maternal hypertensionmay represent an adaptive process that occurs in response to unmet nutritional and oxygen demandsA

B

Fig. 1. Gestational age-specific fetal mortality rates per 1000 total births (A) and gestational age-specific neonatal mortalityrates per1000 live births (B) among women with and without pregnancy-induced hypertension, USA, 19992002 (National Center for HealthStatistics cohort linked birth-infant death files).

A

B

C

Fig. 2. Fetal and neonatal mortality rates among women with and without gestational hypertension/pre-eclampsia, with (A) birth-weight-specific mortality expressed in relative terms (as the number of standard deviations from the subpopulation mean [i.e.,asa Z-score]); (B) gestational age-specific stillbirths rates per 1000 fetuses at risk; and (C) gestational age-specific neonatalmortality ratesper 1000 fetuses at risk. Data from the USA, 19992002 (National Center for Health Statistics cohort linked birth-infant death files).

J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391403 399

J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391403400of the fetus.95 Genotypes that promote infant survival may include genes responsible for fetal ability toaffect maternal physiology in early gestation leading to hypertension.The relative birth weight hypothesis

The paradox has also been explained as an artefact arising from an incorrect conceptualisation ofgestational age and birth weight.96 Viewing gestational age or birth weight in relative rather thanabsolute terms resolves the paradox (Fig. 2A). Neonatal mortality rates are higher among infants bornto women with hypertension in pregnancy at all relative birth weights. A similar resolution of theparadox is seen when relative gestational age is used.The fetuses-at-risk approach

An alternative formulation of perinatal mortality, using fetuses at risk for stillbirth or neonataldeath, also resolves the paradox. As all fetuses in ongoing pregnancies are at risk of being stillborn, thisformulation uses the number of fetuses in ongoing pregnancies at each week of gestation as thedenominator for stillbirth rates (as opposed to conventional calculations which use the number of totalbirths at each week of gestation).97 A similar formulation is used for neonatal mortality.91,98 Under thefetuses-at-risk approach, women with hypertension in pregnancy have higher rates of stillbirth andneonatal death at all gestational ages compared with normotensive women (Fig. 2B and C).

Conclusion

Hypertensive disorders of pregnancy include chronic hypertension, gestational hypertension, pre-eclampsia and chronic hypertension with superimposed pre-eclampsia. Pre-eclampsia, the hallmarksof which include poor placental perfusion and systemic involvement, is a heterogeneous disease, witha distinct and more severe clinical profile when gestation at disease onset is less than 34 weeks. Pre-eclamspia complicates about 3% of pregnancies, and all hypertensive disorders affect about five to 10 ofpregnancies. Secular increases in chronic hypertension, gestational hypertension and pre-eclampsiahave occurred as a result of changes in maternal characteristics (i.e. maternal age and pre-pregnancyweight), whereas declines in eclampsia have followed widespread antenatal care and use of prophy-lactic treatments (i.e. magnesium sulphate). Determinants of pre-eclampsia rates include risk andprotective factors, such as familial factors, sperm exposure, maternal smoking, pre-existing medicalconditions, plurality, older maternal age and obesity. Hypertensive disorders of pregnancy are asso-ciated with higher rates of maternal and fetal and infant mortality, and severe morbidity, especially incases of severe pre-eclampsia, eclampsia and HELLP syndrome. Women with hypertension in preg-nancy show the paradox of intersecting perinatal mortality curves; perinatal mortality rates at pretermgestation are unexpectedly lower among mothers with hypertensive disorders (compared with peri-natal mortality rates amongmothers without hypertension in pregnancy), whereas the opposite is trueat later gestation.Practice points

Pre-eclampsia and the other hypertensive disorders of pregnancy are responsible fora substantial fraction of the burden of maternal and perinatal morbidity and mortalityworldwide.

In industrialised countries, rates of pre-eclampsia, gestational hypertension and chronichypertension have increased in recent years, whereas rates of eclampsia have decreaseddramatically.

An early gestational age at onset for pre-eclampsia is associated with a significantly worseprognosis for mother and infant.

Research agenda

A standardised disease definition that is consistent with the occurrence of adverse maternaland perinatal outcomes.

Improved surveillance of incidence and outcomes of hypertensive disorders of pregnancy indeveloping countries.

A better understanding of the reasons for the heterogeneity in risk factors and outcomeswithin pre-eclampsia subtypes.

J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391403 401Conflict of interest

None declared.

Acknowledgements

JAH was supported by post-doctoral fellowship awards from the Canadian Institutes of HealthResearch and the Michael Smith Foundation for Health Research (MSFHR). SL was supported by a post-doctoral fellowship award from MSFHR. KSJ holds a career scientist award from the Child and FamilyResearch Institute, Vancouver, Canada.

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Epidemiology of pre-eclampsia and the other hypertensive disorders of pregnancy Introduction Definitions and classification of hypertensive disorders of pregnancy Chronic hypertension Gestational hypertension Pre-eclampsia Chronic hypertension with superimposed pre-eclampsia Eclampsia Haemolysis, elevated liver enzymes and low platelets syndrome Older terms and concepts Disease severity

Global burden of illness Natural history Pre-eclampsia Incidence and temporal trends Risk factors Familial factors Primipaternity and sperm exposure Pre-existing medical conditions Smoking Miscellaneous factors

Maternal effects Effects on fetus and infant Recurrence in subsequent pregnancy Long-term sequelae Other hypertensive disorders Pre-existing (chronic) hypertension

Gestational hypertension Eclampsia

Heterogeneity of pre-eclampsia Modification of the effect of pre-eclampsia on perinatal mortality by gestational age Intersecting perinatal mortality curves The stress hypothesis Haig's hypothesis The relative birth weight hypothesis The fetuses-at-risk approach

Conclusion Conflict of interest Acknowledgements References