AETIOLOGY

The cause of pre-eclampsia is unknown. As yet, there is no satisfactory single unifying aetiological hypothesis. Although there is a genetic predispostion, the exact mode of inheritance is unclear and there may be multiple phenotypes.⁹ Immunologic factors such as an abnormal maternal response to fetopaternal antigens have been implicated. Pre-eclampsia is more common in primigravidae, multiple gestation, obesity, black race, molar pregnancy, when there is pre-existing hypertension, underlying disease (e.g. autoimmune disease, renal disease, diabetes and thrombophilias) and when there is a previous or family history of pre-eclampsia.¹⁰ A change in partner has been considered a risk factor but this may be partially related to increased risk associated with extended intervals between pregnancies.¹¹

PATHOGENESIS

Pre-eclampsia is a systemic disease that affects most organ systems. Many theories of pathogenesis have been proposed,^12–14 but a common concept is that of a two-stage disease with an initial stage of abnormal placentation followed by a second stage of clinical disease. Initially, there is inadequate endovascular invasion of fetal trophoblast into the spiral arteries with reduced dilatation of uterine spiral arteries and placental hypoxia. This acts as a precipitating factor that leads to a generalised inflammatory response, of which diffuse endothelial dysfunction is a prominent component. The result is an increase in sensitivity to vasoactive substances, a decrease in endothelial synthesis of vasodilator substances such as prostaglandin and nitric oxide, activation of platelet and coagulation and an increase in capillary permeability. This causes widespread vasoconstriction, fluid extravasation, proteinuria, decreased intravascular volume, haemoconcentration and decreased organ perfusion. The link between placental triggering and the systemic response is unknown, but has been theorised to involve oxidative stress and circulating cytotoxic factors. Candidates for the latter include circulating angiogenic factors such as vascular endothelial growth factors, placental growth factor and fms-like tyrosine kinase-1 (sFlt1).^13,14

CLINICAL PRESENTATION

Pre-eclampsia is a syndrome with a spectrum of presentations. Although hypertension is the cardinal sign, some women present with convulsions, abdominal pain or general malaise¹⁵ and some complications may be life-threatening without a marked increase in blood pressure. Features typical of severe disease are listed in Table 55.2. Rarely, cocaine intoxication and phaeochromocytoma may be confused with pre-eclampsia.

Table 55.2 Clinical features suggestive of severe pre-eclampsia

Haemodynamic changes of pre-eclampsia consist of hypertension, increased systemic vascular resistance and decreased intravascular volume. Cardiac output is usually decreased, usually secondary to changes in preload and afterload rather than contractility.¹⁶ Sympathetic activation occurs, and this may account for observations of increased cardiac output in the early stage.¹⁷ Pulmonary oedema may occur because of iatrogenic fluid overload, decreased left ventricular function, increased capillary permeability and narrowing of the colloid osmotic–pulmonary capillary wedge pressure gradient; this is more likely to occur after delivery. Sudden ventricular tachycardia may occur during hypertensive crises.

Neurological complications include eclamptic convulsions, cerebral oedema, raised intracranial pressure and stroke. Intracranial haemorrhage is an important cause of death.³

Renal changes include reduced glomerular filtration rate and renal plasma flow, which are associated with the characteristic lesion of glomeruloendotheliosis. Hyperuricaemia is associated with increased prenatal risk, particularly if serum uric acid concentration rises rapidly.

Haemostatic abnormalities include thrombocytopenia, which may be associated with decreased platelet function. Associated coagulation abnormalities may occur but are unlikely unless the platelet count is < 100 000 × 10⁹/l.^18,19

Hepatic complications include liver oedema, hepatocellular necrosis, periportal and subcapsular haemorrhage, hepatic infarcts and rupture. Patients with HELLP syndrome (see below) are particularly at risk.

The leading causes of maternal death in pre-eclampsia/eclampsia are intracranial haemorrhage, pulmonary oedema and hepatic complications.^3,4 Fetal morbidity results from placental insufficiency, prematurity and abruptio placentae.

MANAGEMENT

The treatment of pre-eclampsia is delivery of the placenta and fetus. Before delivery, and during the immediate postpartum period, management is supportive and focused on control of blood pressure, prevention of seizures, maintenance of placental perfusion and prevention of complications. If complications are avoided, the disease normally resolves completely after delivery. Transfer of the mother to a tertiary centre before delivery should be considered if a level III neonatal unit is not available (see Chapter 1). Pregnant and postnatal women may have special requirements which not all staff are experienced with.²⁰ Admission into an ICU before delivery may be appropriate in severe cases, or when the labour ward lacks the expertise or equipment for intensive monitoring. Because prematurity is a major cause of neonatal morbidity, expectant management to prolong pregnancy has been described in patients < 34 weeks’ gestation.²¹ This requires careful balancing of the maternal and perinatal risks. After delivery, severe cases should preferably be managed in an ICU for 24–72 hours.

GENERAL MEASURES

Before delivery, patients should be kept in the lateral or semilateral position and the fetal heart rate should be monitored. Regular oral or intravenous histamine H₂ antagonists will decrease gastric acidity and volume. Prophylactic dexamethasone or betamethasone should be considered for fetal lung maturity if gestation is less than 34 weeks and early delivery is anticipated. Routine monitoring should include frequent clinical assessment, blood pressure, electrocardiogram (ECG) and fluid balance. Pulse oximetry aids the detection of incipient pulmonary oedema.²² Central venous pressure (CVP) monitoring, preferably via an antecubital vein, and/or pulmonary artery catheterisation may assist in fluid balance (see below). Full blood count, coagulation screen, electrolytes, uric acid, renal function, liver function and urinalysis should be performed serially to monitor disease progression.

ANTIHYPERTENSIVE THERAPY

The aim of antihypertensive therapy is to prevent maternal complications (intracerebral haemorrhage, cardiac failure and abruptio placentae) while maintaining placental blood flow. It is important to appreciate that hypertension is a marker and not a causal factor in pre-eclampsia. Therefore, although controlling hypertension reduces the risk of complications, it does not ameliorate the underlying pathological process. Acute treatment is indicated when blood pressure is greater than 160 mmHg systolic or 105–110 mmHg diastolic. Reduction of systolic pressure is particularly important for the prevention of stroke.²³ Initially, systolic blood pressure should only be reduced by about 20–30 mmHg and diastolic pressure by 10–15 mmHg while monitoring the fetus.¹ Concomitant plasma expansion reduces the risk of sudden hypotension when vasodilators are used.¹ Recommended antihypertensive drugs for acute treatment are summarised in Table 55.3 and described below.^1,2 The most commonly used drugs are hydralazine, labetalol and nifedipine; insufficient data are currently available to prove which of these is superior.²⁴

Table 55.3 Main drugs used for acute management of hypertension in pre-eclampsia