Hypertensive disorders of pregnancy include chronic hypertension, gestational hypertension, pre-eclampsia and chronic hypertension with superimposed pre-eclampsia. Pre-eclampsia 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 (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 platelets syndrome.
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. 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. 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). Pre-eclampsia is characterised by poor placental perfusion and a systemic disease process that can involve multiple organ systems. Recent guidelines of the Society of Obstetric Medicine of Australia and New Zealand 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. Similarly, pre-eclampsia can occur without hypertension when gestational proteinuria is associated with the systemic manifestations. 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.
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.
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).
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) 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’, previously 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. 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.
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, or both), timing of delivery (e.g. delivery <34 weeks ), and pregnancy outcome (e.g. pre-eclampsia complicated by fetal death, preterm birth or eclampsia ). Other criteria used to identify severe pre-eclampsia include proteinuria of 5 g or higher in a 24-h urine specimen or 3+ 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, thrombocytopoaenia, fetal growth restriction and gestational age at onset of pre-eclampsia <34 weeks. However, most of the components in criteria for disease severity do not predict adverse maternal or perinatal outcomes. The recent development of a clinical prediction model for risk of adverse maternal outcomes among women with pre-eclampsia may prove useful in revising definitions of disease severity.
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. 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. 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). Pre-eclampsia is characterised by poor placental perfusion and a systemic disease process that can involve multiple organ systems. Recent guidelines of the Society of Obstetric Medicine of Australia and New Zealand 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. Similarly, pre-eclampsia can occur without hypertension when gestational proteinuria is associated with the systemic manifestations. 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.
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.
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).
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) 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’, previously 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. 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.
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, or both), timing of delivery (e.g. delivery <34 weeks ), and pregnancy outcome (e.g. pre-eclampsia complicated by fetal death, preterm birth or eclampsia ). Other criteria used to identify severe pre-eclampsia include proteinuria of 5 g or higher in a 24-h urine specimen or 3+ 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, thrombocytopoaenia, fetal growth restriction and gestational age at onset of pre-eclampsia <34 weeks. However, most of the components in criteria for disease severity do not predict adverse maternal or perinatal outcomes. The recent development of a clinical prediction model for risk of adverse maternal outcomes among women with pre-eclampsia may prove useful in revising definitions of disease severity.
Global burden of illness
Hypertensive disorders of pregnancy complicate roughly 5–10% of pregnancies. A World Health Organization review identified hypertension as the single leading cause of maternal mortality in industrialised countries, accounting for 16% of deaths. In Africa and Asia, hypertensive disorders accounted for 9% of maternal deaths, whereas, in Latin America and the Caribbean, the figure was over 25%. 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 standardisation of diagnostic criteria in population databases. Pre-eclampsia complicates about 3% of pregnancies in the USA. Reports from other industrialised countries have also yielded estimates between 3 and 5%, including prospective studies from Wellington, New Zealand (3.3%) and studies based on the Swedish, Danish and Norwegian Medical Birth Registers (3.0%, 4.5%, and 3.0%, respectively). Higher estimates have been reported in some studies, with an incidence of 8.4% reported from Washington State and rates of 8.7% (mild pre-eclampsia) and 1.7% (severe pre-eclampsia) reported from Nova Scotia. These variations likely reflect both differences in maternal characteristics between populations (such as the age distribution) and diagnosis. For instance, the Nova Scotia study 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. Norwegian data also showed increasing rates, from 3.7% between 1988 and 1992 to 4.4% between 1998 and 2002. Pre-eclampsia rates are subject to seasonal and regional variation. In northern regions, pre-eclampsia is more common in winter births whereas, in Zimbabwe, incidence has been associated with precipitation patterns. In Finland, women in Northern regions have a two-fold higher risk of pre-eclampsia compared with women in Southern regions.
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. Men who fathered a pregnancy with pre-eclampsia are more likely to father another pregnancy complicated by pre-eclampsia in other women.
Primipaternity and sperm exposure
Nulliparous women have a three-fold higher risk of pre-eclampsia compared with multiparous women. The primipaternity hypothesis 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 contraception and those who change partners. An increased birth interval is the alternative explanation offered for the latter phenomenon, although the evidence for this has been disputed. 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).
Pre-existing medical conditions
Women with pre-existing hypertension or diabetes mellitus are at a substantially higher risk of pre-eclampsia. Women with anti-phospholipid syndrome, the other thrombophilias, autoimmune disease, kidney disease, and infertility are also at higher risk.
Smoking
Numerous studies have shown that smoking reduces pre-eclampsia occurrence by about 50% in a dose-dependent manner. 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. 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. Some studies have failed to replicate this finding, however. Older maternal age, obesity and multiple pregnancy also increase the risk of pre-eclampsia. Other reported risk factors for pre-eclampsia include infections and residence at high altitude.
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. Similarly, hypertensive disorders of pregnancy 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. 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. 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, and pre-eclampsia has been identified as the leading reason for intensive care unit admissions in the puerperal period. Women with pre-eclampsia have a 70% higher risk of placental abruption (RR = 1.7, 95% CI 1.5-2.0), with risk increasing with increasing disease severity.
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. 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).
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. 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. 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. Offspring of women with pre-eclampsia are also at increased risk of low Apgar scores, febrile seizures, encephalopathy, and neonatal intensive care unit admission. 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.
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). However, the risk of intrauterine growth restriction is much more pronounced at preterm gestation than at term. At preterm gestation, infants born after pre-eclampsia are 10–25% smaller 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.
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 pregnancies. Also, increased risks of hospitalisation due to metabolic disorders, epilepsy and other complications have been noted. 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. 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. The risk of pre-eclampsia in a third pregnancy increases to 30% if a woman’s first two pregnancies were complicated by pre-eclampsia, 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.
Long-term sequelae
A consistent association has been found between pre-eclampsia and long-term risk of cardiovascular 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. 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.
Studies have reported both decreased and increased risks of cancer after pre-eclampsia, with a meta-analysis reporting a null effect. 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.
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. The US Nationwide Inpatient Survey estimated that 1.7% of pregnancies in 2004 were complicated by pre-existing hypertension, a 50% increase since 1998. 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, whereas rates of serious maternal morbidity (i.e. acute renal failure, pulmonary oedema and adult respiratory distress syndrome) can be nine-fold higher. Women with pre-existing hypertension have a three-fold increased risk of death compared with normotensive women. The increased risk is often mediated through the increased risk of developing superimposed pre-eclampsia, which is estimated to be 20–25%. Although the risks of adverse outcomes increase significantly with the development of superimposed pre-eclampsia, women with pre-existing hypertension without pre-eclampsia do remain at increased risk.
Gestational hypertension
Gestational hypertension complicates roughly 2–3% of pregnancies in the USA. 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. 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. 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. 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.
Eclampsia
The incidence of eclampsia has been estimated to be 2.7 cases per 10,000 births in 2005 in the UK, 5.7 per 10,000 deliveries in Canada in 2007, 5.0 per 10,000 maternities in Denmark, Norway and Sweden between 1998 and 2000, 6.0 per 10,000 deliveries in the Netherlands, and 8.2 per 10,000 deliveries in the USA between 1996 and 2004. The frequency of eclampsia in less industrialised countries is substantially higher and estimates range from 16–69 per 10,000 births.
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 1992 to 2.7 cases per 10,000 births (95% CI 2.4 to 3.1) in 2005. This 45% decrease reflects a continued temporal decline over the past century, with reductions of over 90% observed since the 1920s. 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. Improved access to antenatal care, early delivery of women with severe pre-eclampsia, and use of magnesium sulphate 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. About 5–8% of pregnancies complicated by eclampsia result in a perinatal loss.
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