Chapter 55 Pre-eclampsia and eclampsia
Pre-eclampsia is a syndrome specific to pregnancy. It has no definitive biomarkers and is diagnosed clinically by new onset of hypertension and proteinuria after 20 weeks’ gestation (Table 55.1). Oedema and hyperreflexia typically also occur. Diagnostic criteria have varied among countries and over time, although in recent years international working groups have worked towards consensus.1,2 There is overlap among pre-eclampsia, pre-existing hypertension, pre-eclampsia superimposed on pre-existing hypertension and non-proteinuric gestational hypertension. Eclampsia describes the occurrence in a pre-eclamptic woman of seizures not attributable to other causes.
Table 55.1 Basic diagnostic criteria for pre-eclampsia
| Hypertension | Systolic arterial pressure > 140 mmHg or |
| Diastolic arterial pressure* > 90 mmHg | |
| and | |
| Proteinuria | ≥ 300 mg protein in a 24-hour collection |
A rise in blood pressure above baseline and oedema are now not usually included.
A positive dipstick test for proteinuria should be confirmed by 24-hour urine collection.
Pre-eclampsia complicates 2–7% of pregnancies in developed countries and is a leading cause of maternal deaths.2,3 Associated maternal mortality is 1.5 per 100 000 live births in the USA.4 The incidence of eclampsia is 0.04–0.1% in the USA and UK,5 with maternal mortality in the UK of 1.8% and fetal/neonatal mortality of around 7%.6 Incidence and mortality for both pre-eclampsia and eclampsia are much higher in developing countries.5
Factors associated with increased maternal risk include:
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
| Blood pressure | Systolic arterial pressure > 160 mmHg |
| Diastolic arterial pressure > 110 mmHg | |
| Renal | Proteinuria ≥ 2 g/24 h |
| Oliguria < 500 ml/24 h | |
| Serum creatinine > 0.09 mmol/l | |
| Hepatic | Epigastric or right-upper-quadrant pain |
| Elevated bilirubin and/or transaminases | |
| Neurological | Persistent headaches |
| Visual disturbances | |
| Convulsions (eclampsia) | |
| Haematological | Thrombocytopenia |
| Deranged coagulation tests | |
| Haemolysis | |
| Cardiac/respiratory | Pulmonary oedema |
| Cyanosis |
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
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
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
| Drug | Dosage guide |
|---|---|
| Hydralazine | Bolus |
| 5 mg IV followed by 5–10 mg every 20 min to maximum of 40 mg | |
| Labetalol | Bolus |
| 20–40 mg IV every 10–15 min to a maximum of 220 mg | |
| Infusion | |
| 1–2 mg/min, reducing to 0.5 mg/min or less after blood pressure is controlled | |
| Nifedipine | Orally |
| 10 mg, repeated after 30 min as required |
IV, intravenously.
LABETALOL
Labetalol is a non-selective β-adrenergic receptor blocker with some α1-blocking effect. When given intravenously, it rapidly reduces blood pressure without decreasing uteroplacental blood flow,25 and does not cause reflex tachycardia, headache or nausea. Although labetalol crosses the placenta, neonatal bradycardia and hypoglycaemia are rarely seen. Duration of action is variable. It should not be given to patients with asthma or myocardial dysfunction.
NIFEDIPINE
Nifedipine is a calcium-channel blocker that directly relaxes arterial smooth muscle. In pre-eclamptic patients with severe hypertension it causes a steady decrease in blood pressure and systemic vascular resistance within 30 minutes with a concomitant increase in maternal cardiac index and heart rate.26 Nifedipine is recommended to be given orally. It is also effective sublingually or chewed but this may be associated with sudden hypotension and fetal compromise. Hypotension and potentiation of neuromuscular block have been reported in patients receiving magnesium sulphate. Nifedipine causes relaxation of uterine muscle which may increase the risk of postpartum haemorrhage. Mild side-effects include headache, flushing, and nausea.
OTHER AGENTS
Sodium nitroprusside (initial dose 0.25 μg/kg per min, maximum dose 5 μg/kg per min) can be used to reduce blood pressure rapidly in a hypertensive emergency3 but care should be taken in patients with depleted intravascular volume and duration should be limited to < 4 hours to avoid fetal cyanide poisoning.3Nitroglycerine infusion (initial dose 5 μg/min, maximum dose 100 μg/min) may be useful in cases complicated by pulmonary oedema. Methyldopa is often used for mild cases but its slow onset time makes it unsuitable for acute treatment. Diazoxide, ketanserin, nimodipine and magnesium are not recommended as first-line agents.24Beta-blockers other than labetalol may cause decreased uteroplacental perfusion, fetal bradycardia and decreased fetal tolerance to hypoxia. Angiotensin-converting enzyme inhibitors and angiotensin antagonists should not be used before delivery because of adverse fetal effects.1,3Diuretics should be avoided since pre-eclamptic patients have reduced plasma volume.
ANTICONVULSANT THERAPY
Anticonvulsants are used to prevent recurrent convulsions in eclampsia or to prevent initial convulsions in pre-eclampsia. Magnesium sulphate is the drug of choice, although it may not be effective in all cases.27–29
MAGNESIUM SULPHATE
There is universal agreement that patients with eclampsia should receive magnesium sulphate. However, because only a small proportion of patients with pre-eclampsia progress to eclampsia, the effectiveness and risk–benefit and cost–benefit ratios of prophylactic administration in pre-eclampsia are controversial.30–32 The authors’ practice is to start magnesium when there are clinical signs of severe pre-eclampsia, although the concept that eclampsia follows on from severe pre-eclampsia has been questioned.33 The mechanism of action of magnesium for preventing eclamptic seizures is unknown. Although abnormal electroencephalograms are frequent in pre-eclampsia and eclampsia, they are not altered by magnesium sulphate. Part of magnesium’s action has been considered to be reduction of cerebral vasospasm via antagonism of calcium at membrane channels or intracellular sites. However, the cerebral vasodilator nimodipine was shown to be ineffective for preventing seizures.34 Magnesium amplifies release of prostacyclin by vascular endothelium, and this may inhibit platelet aggregation and vasoconstriction. Doppler ultrasonography suggests that magnesium vasodilates smaller-diameter intracranial blood vessels, and some of its effects may be from relieving cerebral ischaemia. Part of the anticonvulsant activity of magnesium may be mediated by blockade or suppression of N-methyl-D-aspartate (NMDA) receptors. Magnesium has tocolytic effects and mild general vasodilator and antihypertensive actions and increases renal and uterine blood flow.
Guidelines for administration of magnesium sulphate are summarised in Table 55.4. An intravenous loading dose followed by an infusion is preferred, although intramuscular administration is an alternative. Magnesium is rapidly excreted by the kidney. The half-life in patients with normal renal function is 4 hours and 90% of the dose is excreted by 24 hours after the infusion.35 When there is renal impairment or oliguria the dose should be reduced and serum concentration should be monitored. Suggested target serum concentration for severe pre-eclampsia is 2–3.5 mmol/l (4–7 mEq/l or 4.8–8.4 mg/dl). Magnesium toxicity is associated with muscle weakness and may lead to respiratory paralysis (> 7.5 mmol/l). Increased conduction time with increased PR and QT intervals and QRS duration can lead to sinoatrial and atrioventricular block (> 7.5 mmol/l) and cardiac arrest in diastole (> 12.5 mmol/l). Toxicity is unlikely when deep tendon reflexes are present (the upper limb should be used during epidural analgesia). Magnesium toxicity can be treated with small intravenous doses of calcium. Other reported adverse effects of magnesium include death from overdose, increased bleeding, slowed cervical dilatation and increased risk of pulmonary oedema. Magnesium crosses the placenta and can cause neonatal flaccidity and respiratory depression.
| Intravenous regimen | Loading dose: 4–6 g over 20 min |
| Maintenance: 1–2 g/h | |
| Intramuscular regimen | 4 g every 4 h |
Renal function and tendon reflexes should be monitored. Reduce dose and monitor serum concentrations in oliguria or renal impairment.
(1 g magnesium sulphate = 98 mg = 4.06 mmol = 8.12 mEq elemental magnesium).
OTHER ANTICONVULSANTS
If repeated seizures occur despite therapeutic levels of magnesium, conventional anticonvulsants can be considered, but it is important to exclude other causes of convulsions. Although phenytoin is inferior to magnesium for preventing eclamptic seizures,36 it may be considered when there is renal failure. An initial intravenous loading dose of 10 mg/kg is followed 2 hours later by 5 mg/kg. Doses are diluted in normal saline and given no faster than 50 mg/min. Electrocardiogram and arterial pressure should be monitored. Maintenance doses of 200 mg orally or intravenously are started 12 hours after the second bolus and given 8-hourly. Similarly, intravenous infusion of diazepam has been used (40 mg diazepam in 500 ml normal saline titrated to keep patients sedated but rousable).37
ECLAMPSIA
Eclampsia may occur without marked preceding hypertension or without proteinuria,33 and up to one-third of cases occur postpartum, often more than 48 hours after delivery.38 Priorities in the management of eclamptic seizures are airway protection, oxygenation, and termination and prevention of seizures. Delivery of the fetus should be considered after maternal stabilisation. Patients should be placed in the left lateral position and given oxygen. Magnesium should be given if not already started. Approximately 10% of eclamptic patients will have a recurrent seizure despite receiving magnesium.39 Prolonged seizures can be terminated by diazepam 5–10 mg intravenously. If seizures are refractory, thiopental and suxamethonium should be given and the airway secured. Recurrent convulsions or prolonged unconsciousness may indicate additional cerebral pathology (e.g. cerebral oedema, intracerebral haemorrhage, venous thrombosis) and a computed tomographic (CT) scan should be done. Intensive neurological management, aimed at controlling intracranial pressure and optimising cerebral perfusion, has significantly reduced mortality in unconscious eclamptic patients.40
FLUID BALANCE
Fluid management in pre-eclampsia is controversial. Pre-eclamptic patients usually have reduced circulating intravascular volume and oliguria is common in patients with pre-eclampsia. Therefore, fluid loading with crystalloid or colloid solution has been advocated. However, the effectiveness of this is uncertain and, because of the risk of pulmonary oedema, this practice can be questioned.41 A suggested fluid regimen is to start maintenance crystalloid at 75–125 ml/h intravenously, aiming for urine output > 0.5 ml/kg per hour, averaged over 3–4 hours. When there is oliguria or other signs of poor perfusion, repeated fluid challenge with 250–500 ml crystalloid or 100–200 ml colloid may be given, while monitoring with a pulse oximeter and examining for fluid overload. Urinary sodium < 20 mmol/l, osmolality > 500 mosmol/kg or fractional excretion of sodium of < 1 supports a prerenal cause for oliguria. Renal failure in pre-eclampsia is uncommon. Some patients with persistent oliguria and a rising serum creatinine concentration may require a period of continuous renal replacement therapy but the majority of cases recover. However, the risk of irreversible renal damage is greater when there is associated abruptio placentae, disseminated intravascular coagulation (DIC), hypotensive shock, or sepsis.15 Low-dose dopamine (3 μg/kg per min) and furosemide (5 mg/h) infusions have been used after correction of hypovolaemia to improve urine output and renal function in oliguric pre-eclamptic patients,42 but whether this reduces the need for dialysis is undetermined.
There is controversy over the effectiveness of CVP and pulmonary capillary wedge pressure (PCWP) for assisting fluid management in pre-eclamptic patients. CVP and PCWP have poor correlation, especially when CVP is greater than 6 mmHg (0.8 kPa).43 Optimal CVP and PCWP values are unknown but the measured response to fluid challenge may be informative and useful. Pulmonary artery catheterisation has risks in patients who are oedematous and coagulopathic and should only be considered when there are clear indications (e.g. refractory hypertension, pulmonary oedema and refractory oliguria).43 Pulmonary oedema is unlikely with a CVP less than 6 mmHg, but when it occurs, should be managed with oxygen therapy, positive end-expiratory pressure with or without ventilation, inotropes, vasodilators, morphine or diuretics as indicated.
POSTPARTUM CARE
Patients are frequently referred to an ICU for postpartum care, particularly after caesarean delivery. The risk of pulmonary oedema is greatest after delivery and most maternal deaths occur then.44 After delivery, there is often an initial improvement with a relapse in the first 24 hours. Magnesium should be continued for 24–48 hours. Antihypertensive drugs may be reduced according to the blood pressure. Some patients may require a change to oral medication which may need to be continued for several weeks. Psychological support is important, especially if there has been an adverse neonatal outcome. Full recovery from the organ dysfunction of pre-eclampsia is normally expected within 6 weeks.
HELLP SYNDROME AND HEPATIC COMPLICATIONS
HELLP syndrome is a particularly high risk form of pre-eclampsia characterised by more pronounced hepatic rather than cerebral or renal involvement. Diagnosis is based on laboratory findings showing haemolysis (microangiopathic haemolytic anaemia), elevated liver enzymes and low platelets, although exact criteria vary.45,46 Clinical presentation is variable. Many patients have non-specific signs such as right-upper-quadrant or epigastric pain, nausea, malaise or headache. Although most patients will have hypertension and proteinuria, these can be mild or absent. Important differential diagnoses include idiopathic thrombocytopenic purpura, systemic lupus erythematosus, thrombotic thrombocytopenic purpura, haemolytic–uraemic syndrome and acute fatty liver of pregnancy.45,46 Typically, HELLP syndrome presents at early gestational ages and is more common in white and multiparous women.47 In about 30% of cases, it first presents in the postpartum period, sometimes with no evidence of pre-eclampsia before delivery.46 After delivery, patients usually show a continuing deterioration in platelet count and liver enzymes, with a peak in severity 24–48 hours after delivery followed by gradual resolution and complete recovery if complications are avoided. Complications of HELLP syndrome include DIC, abruptio placentae, acute renal failure, pulmonary oedema, severe ascites, pleural effusion, liver haemorrhage or failure, acute respiratory distress syndrome (ARDS), sepsis and stroke.46
Patients with HELLP should be managed aggressively, similarly to pre-eclampsia, with an emphasis on stabilisation and delivery. Expectant management of patients with gestation less than 34 weeks has been described but the relative benefits and risks of this are controversial.45,46 Use of high-dose intravenous corticosteroids (e.g. dexamethasone 10 mg 6-hourly for 2 doses, then 6 mg 6-hourly for 2 doses) has been reported to accelerate recovery, but this is also controversial.45,46,48 Plasma exchange with fresh frozen plasma has been described for postpartum patients with delayed resolution of HELLP with variable response.49
Life-threatening hepatic complications may occur in pre-eclampsia, particularly in patients with HELLP syndrome.45,46 These include segmental hepatic infarction, parenchymal haemorrhage and subcapsular haemotoma with or without rupture. If suspected, patients should have an urgent CT scan.46 Hepatic rupture is a surgical emergency. Hepatic haemorrhage without rupture has been managed conservatively.45
ANAESTHESIA AND ANALGESIA
Platelet count and coagulation tests should be checked before regional anaesthesia. Epidural analgesia in labour reduces fluctuations in arterial pressure and improves placental blood flow.50 For caesarean section, the use of epidural or spinal anaesthesia avoids the risks of aspiration, difficult intubation from airway oedema, exaggerated hypertensive response to intubation and magnesium-induced sensitivity to muscle relaxants associated with general anaesthesia. If general anaesthesia is required, smaller-size endotracheal tubes may be required. The hypertensive response to intubation should be attenutated with drugs such as fentanyl (2.5 μg/kg), alfentanil (10 μg/kg), magnesium sulphate (40 mg/kg), a combination of alfentanil (7.5 μg/kg) with magnesium sulphate (30 mg/kg), or remifentanil (1 μg/kg). Occasionally, awake intubation under topical anaesthesia may be necessary when there is airway obstruction.
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