Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391–403

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage: www.elsevier.com/locate/bpobgyn

Epidemiology of pre-eclampsia and the other hypertensive

disorders of pregnancy
Jennifer A. Hutcheon, PhD, Post-Doctoral Fellow a, *,
Sarka Lisonkova, MD, PhD, Post-Doctoral Fellow a,
K.S. Joseph, MD, PhD, Professor a, b
a
Department of Obstetrics and Gynaecology, University of British Columbia, 4500 Oak Street, Vancouver, V6H 2N1, Canada
b
School of Population and Public Health, University of British Columbia, Vancouver, Canada

Keywords:
Hypertensive disorders of pregnancy include chronic hyperten-
pregnancy sion, gestational hypertension, pre-eclampsia and chronic hyper-
hypertension tension with superimposed pre-eclampsia. Pre-eclampsia
pre-eclampsia complicates about 3% of pregnancies, and all hypertensive disor-
epidemiology ders affect about five to 10% of pregnancies. Secular increases in
mortality chronic hypertension, gestational hypertension and pre-eclampsia
morbidity have occurred as a result of changes in maternal characteristics
natural history
(such as maternal age and pre-pregnancy weight), whereas
declines in eclampsia have followed widespread antenatal care
and use of prophylactic treatments (such as magnesium sulphate).
Determinants of pre-eclampsia rates include a bewildering array of
risk and protective factors, including familial factors, sperm
exposure, maternal smoking, pre-existing medical conditions
(such as hypertension, diabetes mellitus and anti-phospholipid
syndrome), and miscellaneous ones such as plurality, older
maternal age and obesity. Hypertensive disorders are associated
with higher rates of maternal, fetal and infant mortality, and
severe morbidity, especially in cases of severe pre-eclampsia,
eclampsia and haemolysis, elevated liver enzymes and low plate-
lets syndrome.
Ó 2011 Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: þ1 604 875 2000x4800; Fax: þ1 604 875 2987.
E-mail address: jhutcheon@cfri.ca (J.A. Hutcheon).

1521-6934/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bpobgyn.2011.01.006
392 J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391–403

Introduction

Hypertensive disorders of pregnancy constitute an enigmatic and clinically challenging group of

pregnancy complications that are responsible for a substantial burden of illness in both industrialised
and less industrialised countries. This review outlines the disease definitions, global burden of
disease, natural history, and unresolved epidemiologic questions of the hypertensive disorders of
pregnancy.

Definitions and classification of hypertensive disorders of pregnancy

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

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 20
weeks gestation.1 Hypertension first diagnosed after 20 weeks gestation, and which persists 12 weeks
postpartum, is also considered chronic hypertension.

Gestational hypertension

Gestational hypertension is defined as hypertension that develops in pregnancy after 20 weeks

gestation and which returns to normal within 12 weeks postpartum.1 The latter part of the definition
means 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 hypertension

and proteinuria in pregnancy (with proteinuria defined as the urinary excretion of 300 mg of protein
in 24 h).1 Pre-eclampsia is characterised by poor placental perfusion and a systemic disease process
that can involve multiple organ systems.2,3 Recent guidelines of the Society of Obstetric Medicine of
Australia and New Zealand4 recommend that a diagnosis of pre-eclampsia be made when hypertension
arises 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 or
placental abruption. One diagnostic criterion, namely fetal growth restriction, seems problematic
because, by definition, it eliminates all fetal growth restriction among women with gestational
hypertension.
Atypical pre-eclampsia may occur as hypertension associated with systemic symptoms, abnormal
haematological tests or elevated liver enzymes but without proteinuria.1 Similarly, pre-eclampsia can
occur 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 after
delivery.5

Chronic hypertension with superimposed pre-eclampsia

Chronic hypertension with superimposed pre-eclampsia is diagnosed when a woman with chronic
hypertension develops new-onset proteinuria, thrombocytopoaenia or any of the other systemic
features of the pre-eclampsia syndrome.1
 J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391–403 393

Eclampsia

Neurologic involvement in the form of generalised tonic–clonic 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 low
platelet count)1 are presumed to indicate hepatocellular injury. Such injury can include unruptured
hepatic 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 and
oedema, have been replaced by the more specific entities described above. Hyperuricaemia is
a common feature of pre-eclampsia but is not generally considered to be diagnostic.4 The diagnosis of
hypertension based on a relative increase criterion (i.e. a 30 mmHg increase in systolic pressure or
a 15 mmHg increase in diastolic pressure compared with previous levels) has been abandoned in
favour 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. Criteria
have been based on the severity of hypertension (e.g. a systolic pressure 160 mmHg, diastolic pressure
110 mmHg on at least two occasions 6 h apart,6 or both), timing of delivery (e.g. delivery <34 weeks7), and
pregnancy outcome (e.g. pre-eclampsia complicated by fetal death, preterm birth or eclampsia8). Other
criteria used to identify severe pre-eclampsia include proteinuria of 5 g or higher in a 24-h urine specimen or
3þ or greater on two random urine samples, oliguria of <500 ml in 24 h, cerebral or visual disturbances,
pulmonary oedema or cyanosis, epigastric or right upper-quadrant pain, impaired liver function, throm-
bocytopoaenia, fetal growth restriction and gestational age at onset of pre-eclampsia <34 weeks.9,10
However, most of the components in criteria for disease severity do not predict adverse maternal or
perinatal outcomes.11 The recent development of a clinical prediction model for risk of adverse maternal
outcomes among women with pre-eclampsia12 may prove useful in revising definitions of disease severity.

Global burden of illness

Hypertensive disorders of pregnancy complicate roughly 5–10% of pregnancies.13 A World Health

Organization review identified hypertension as the single leading cause of maternal mortality in
industrialised countries, accounting for 16% of deaths.14 In Africa and Asia, hypertensive disorders
accounted for 9% of maternal deaths, whereas, in Latin America and the Caribbean, the figure was over
25%.14 Hypertensive disorders of pregnancy are annually responsible for about 25,000 maternal deaths
in Africa, 22,000 maternal deaths in Asia, 3,800 maternal deaths in Latin America and the Caribbean
and 150 maternal deaths in industrialised countries.

Natural history

Pre-eclampsia

Incidence and temporal trends

Accurate estimates of the incidence of pre-eclampsia are difficult to obtain because of a lack of stand-
ardisation of diagnostic criteria in population databases.15,16 Pre-eclampsia complicates about 3% of
394 J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391–403

pregnancies in the USA.17,18 Reports from other industrialised countries have also yielded estimates
between 3 and 5%, including prospective studies from Wellington, New Zealand (3.3%)19 and studies based
on 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 from Nova
Scotia.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-
eclampsia on the basis of elevated blood pressure alone (i.e. it included cases with and without proteinuria).
Pre-eclampsia rates have increased in the USA, with age-adjusted rates rising from 2.4% between
1987 and 1988 to 2.9% of deliveries between 2003 and 2004.17 Norwegian data also showed increasing
rates, from 3.7% between 1988 and 1992 to 4.4% between 1998 and 2002.20 Pre-eclampsia rates are
subject to seasonal and regional variation. In northern regions, pre-eclampsia is more common in
winter 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 with
women in Southern regions.24

Risk factors
Risk factors for pre-eclampsia represent a bewildering array of causative antecedents that reflect
the disease’s complexity. They can be loosely categorised into broad groups.

Familial factors. A family history of pre-eclampsia increases the risk of pre-eclampsia substantially and
women whose mothers have pre-eclampsia are more likely to have pre-eclampsia.25 Men who fathered
a 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-eclampsia
compared with multiparous women.27 The primipaternity hypothesis28 suggests that risks of pre-
eclampsia are increased among women who have limited exposure to their partner’s sperm. Evidence
in 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 explanation
offered for the latter phenomenon,29 although the evidence for this has been disputed.30 Further
support for the primipaternity hypothesis comes from studies involving infertile couples. Women not
previously exposed to their partners sperm (e.g. women conceiving following intracytoplasmic sperm
injection 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 conceiving
after 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 at
a substantially higher risk of pre-eclampsia. Women with anti-phospholipid syndrome,34 the other
thrombophilias,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 early
pregnancy and quit do not have a reduced risk, whereas those who start smoking in late pregnancy and
those who smoke throughout pregnancy are protected.40 This suggests that, although generally
deletrious in terms of pregnancy outcomes, the combustion products of tobacco have a protective
effect in late pregnancy.

Miscellaneous factors. Pre-eclampsia in a previous pregnancy is a strong predictor of pre-eclampsia in

a subsequent pregnancy, especially given an early gestational age at first delivery.41 Some studies have
failed 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) 391–403 395

also 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 per
100,000 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 Canada
between 1999 and 2004.45 Such deaths constitute about 14–15% of maternal deaths in these two
countries. 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 been
identified as the leading reason for intensive care unit admissions in the puerperal period.46 Women
with pre-eclampsia have a 70% higher risk of placental abruption (RR ¼ 1.7, 95% CI 1.5-2.0),47 with risk
increasing with increasing disease severity.48

Effects on fetus and infant

Although stillbirth rates among women with pre-eclampsia have decreased considerably in recent
decades, studies from industrialised countries such as Norway show that women with pre-eclampsia
have a 35% higher risk of stillbirth.49 Studies from less industrialised nations show that pre-eclampsia
is 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 delivery
before 33 weeks and a 40-fold increased risk between 33 and 36 weeks.6 These excess risks for
iatrogenic early delivery play a large role in the four-fold increase in low birth weight rates observed in
the offspring of women with pre-eclampsia.51 Neonatal mortality is about two-fold higher among
infants of mothers with pre-eclampsia, and this increased risk has remained relatively constant during
recent decades.49 Offspring of women with pre-eclampsia are also at increased risk of low Apgar scores,
febrile seizures, encephalopathy, and neonatal intensive care unit admission.5154 Interestingly, infants
born at very preterm ages as a result of pre-eclampsia have a reduced risk of cerebral white matter
damage 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 born
to women without pre-eclampsia, infants born to women with pre-eclampsia have a three- to four-fold
increased risk of being small for gestational age (a birthweight <10th percentile).51,56 However, the risk
of intrauterine growth restriction is much more pronounced at preterm gestation than at term.57 At
preterm gestation, infants born after pre-eclampsia are 10–25% smaller56,58 than their peers of similar
gestational age. In contrast, at term gestation, they are at a significantly increased risk of being either
small for gestational age or large for gestational age, resulting in no difference in average weight or
weight-for-age.51,56,58
In-utero exposure to pre-eclampsia has been associated with long-term health effects for the
offspring. Offspring of pregnancies complicated by pre-eclampsia have higher levels of systolic and
diastolic blood pressure in childhood and adolescence than their peers from uncomplicated preg-
nancies.59 Also, increased risks of hospitalisation due to metabolic disorders, epilepsy and other
complications have been noted.60,61 Long-term follow-up studies have shown increased risks of stroke
and a trend towards increased risk of coronary heart disease at age 60–70 years.62 It is unclear whether
these increased risks reflect a causal effect of in-utero exposure to pre-eclampsia, or shared genetic or
environmental factors.

Recurrence in subsequent pregnancy

Women with pre-eclampsia have a 7–15% chance of developing pre-eclampsia in a subsequent

pregnancy, compared with a 1% chance for women with no pre-eclampsia in their first pregnancy.7,8
The risk of pre-eclampsia in a third pregnancy increases to 30% if a woman’s first two pregnancies
396 J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391–403

were complicated by pre-eclampsia,10 whereas the risk remains at 1% for women with no history of
pre-eclampsia. The risk of recurrence is influenced by gestational age at onset and plurality of the index
pregnancy.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- fold
increased risk of developing chronic hypertension and an approximately two-fold increased risk of
ischaemic heart disease, stroke and venous thromboembolism.64 Studies show that cardiovascular risk
factors such as dyslipidaemia and elevated blood pressure are present years before pregnancy in
women who subsequently developed pre-eclampsia, suggesting that the pre-eclampsia may be
a manifestation of a common disease process.65
Studies have reported both decreased66 and increased67 risks of cancer after pre-eclampsia, with
a meta-analysis reporting a null effect.64 The overall increase mortality risk after pre-eclampsia (RR
1.49, 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) hypertension

Between 1 and 4% of women aged 18–29 years, and 5–15% of women aged 30–39 years in the USA
(1999–2004) have chronic hypertension.68 The US Nationwide Inpatient Survey estimated that 1.7% of
pregnancies 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 serious
maternal morbidity (i.e. acute renal failure, pulmonary oedema and adult respiratory distress
syndrome) can be nine-fold higher.17 Women with pre-existing hypertension have a three-fold
increased risk of death compared with normotensive women.17 The increased risk is often mediated
through the increased risk of developing superimposed pre-eclampsia, which is estimated to be 20–
25%.33,69,70 Although the risks of adverse outcomes increase significantly with the development of
superimposed pre-eclampsia,33,70 women with pre-existing hypertension without pre-eclampsia do
remain at increased risk.33

Gestational hypertension

Gestational hypertension complicates roughly 2–3% of pregnancies in the USA.16,17 As with pre-
eclampsia and pre-existing hypertension, rates of gestational hypertension have been increasing in
recent decades from 10.7 to 30.6 per 1,000 deliveries reported between 1987 and 2004.16 Women with
gestational hypertension are at increased risk of developing super-imposed pre-eclampsia and about
17% of women with gestational hypertension subsequently develop pre-eclampsia.71 Although women
with gestational hypertension are at increased risk of serious obstetric complications compared with
normotensive women, risks to the mother are considerably less than for the other hypertensive
disorders of pregnancies.17 Maternal risks associated with gestational hypertension are generally less
than 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 and
perinatal 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 and
Sweden 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) 391–403 397

deliveries in the USA between 1996 and 2004.17 The frequency of eclampsia in less industrialised
countries is substantially higher and estimates range from 16–69 per 10,000 births.77
Unlike the hypertensive disorders of pregnancy in general, rates of eclampsia have declined in
industrialised countries in recent decades. The rate of eclampsia in the UK decreased from 4.9/10,000
maternities (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 This
45% 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 deliveries
between 1996 and 2004.17 Improved access to antenatal care, early delivery of women with 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 (such
as coma, stroke and acute respiratory distress) occur in 10–30% of cases.73,77,81 About 5–8% 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 at

onset of pre-eclampsia. For example, maternal mortality rates are 24 times higher when pre-eclampsia
onset occurs at less than 28 weeks compared with onset at term gestation.83 Infants of mothers with
pre-eclampsia at preterm gestation are significantly smaller than their non-pre-eclampsia peers of
similar gestation, whereas infants of mothers with pre-eclampsia at term gestation are at increased risk
of being either smaller or larger than their non-pre-eclampsia peers.51,58 Women with 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 in
subsequent 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 20–22 weeks), whereas women who
subsequently developed pre-eclampsia at or beyond 34 weeks have low vascular resistance at 20–22
weeks.85 The placental lesions characteristic of pregnancies with pre-eclampsia are considerably more
common in women with an earlier disease onset.86
These observations have lead several authors to propose that, like diabetes, several distinct
subtypes of pre-eclampsia exist.87,88 The early, more severe subtype may be associated with underlying
genetic or environmental factors that result in abnormal placentation. In contrast, the later-onset, less
severe subtype may be a consequence of factors such as obesity, diabetes, cardiovascular disorders or
multi-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 (and

birth-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 pregnancy
compared 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 not
unique to hypertensive disorders of pregnancy but are also seen when examining risk factors such as
maternal smoking, race, plurality and parity. For example, low-birth-weight infants of smokers have
better survival compared with the low-birth-weight infants of non-smokers, whereas the opposite is
true at higher birth weights. This general phenomenon is known as the ‘paradox of intersecting
perinatal mortality curves’ and, although various explanations have been proposed (see below), there
is no consensus regarding the underlying cause.91
398 J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391–403

The 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.92,93

Haig’s hypothesis

The evolutionary theory of maternal–fetal genetic conflict also provides a rationale for higher
neonatal survival among preterm infants born to mothers with hypertension.94 Maternal hypertension
may represent an adaptive process that occurs in response to unmet nutritional and oxygen demands

Fig. 1. Gestational age-specific fetal mortality rates per 1000 total births (A) and gestational age-specific neonatal mortalityrates per
1000 live births (B) among women with and without pregnancy-induced hypertension, USA, 1999–2002 (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) 391–403 399

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.,as
a Z-score]); (B) gestational age-specific stillbirths rates per 1000 fetuses at risk; and (C) gestational age-specific neonatal mortality rates
per 1000 fetuses at risk. Data from the USA, 1999–2002 (National Center for Health Statistics cohort linked birth-infant death files).
400 J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391–403

of the fetus.95 Genotypes that promote infant survival may include genes responsible for fetal ability to
affect 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 of
gestational age and birth weight.96 Viewing gestational age or birth weight in relative rather than
absolute terms resolves the paradox (Fig. 2A). Neonatal mortality rates are higher among infants born
to women with hypertension in pregnancy at all relative birth weights. A similar resolution of the
paradox 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 neonatal
death, also resolves the paradox. As all fetuses in ongoing pregnancies are at risk of being stillborn, this
formulation uses the number of fetuses in ongoing pregnancies at each week of gestation as the
denominator for stillbirth rates (as opposed to conventional calculations which use the number of total
births at each week of gestation).97 A similar formulation is used for neonatal mortality.91,98 Under the
fetuses-at-risk approach, women with hypertension in pregnancy have higher rates of stillbirth and
neonatal 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 hallmarks
of which include poor placental perfusion and systemic involvement, is a heterogeneous disease, with
a 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 of
pregnancies. Secular increases in chronic hypertension, gestational hypertension and pre-eclampsia
have occurred as a result of changes in maternal characteristics (i.e. maternal age and pre-pregnancy
weight), 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 and
protective factors, such as familial factors, sperm exposure, maternal smoking, pre-existing medical
conditions, 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 in
cases 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 preterm
gestation are unexpectedly lower among mothers with hypertensive disorders (compared with peri-
natal mortality rates among mothers without hypertension in pregnancy), whereas the opposite is true
at later gestation.

Practice points

 Pre-eclampsia and the other hypertensive disorders of pregnancy are responsible for
a substantial fraction of the burden of maternal and perinatal morbidity and mortality
worldwide.
 In industrialised countries, rates of pre-eclampsia, gestational hypertension and chronic
hypertension have increased in recent years, whereas rates of eclampsia have decreased
dramatically.
 An early gestational age at onset for pre-eclampsia is associated with a significantly worse
prognosis for mother and infant.
 J.A. Hutcheon et al. / Best Practice & Research Clinical Obstetrics and Gynaecology 25 (2011) 391–403 401

Research agenda

 A standardised disease definition that is consistent with the occurrence of adverse maternal
and perinatal outcomes.
 Improved surveillance of incidence and outcomes of hypertensive disorders of pregnancy in
developing countries.
 A better understanding of the reasons for the heterogeneity in risk factors and outcomes
within pre-eclampsia subtypes.

Conflict of interest

None declared.

Acknowledgements

JAH was supported by post-doctoral fellowship awards from the Canadian Institutes of Health
Research 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 Family
Research Institute, Vancouver, Canada.

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