Preeclampsia and maternal death
Preeclampsia is a hypertensive disorder of pregnancy and is a multisystem disease that affects 5 to 8% of pregnancies. It is defined as the new onset of hypertension and proteinuria after 20 weeks’ gestation. Although haemorrhage continues to be the leading cause of maternal death worldwide, in some geographical areas such as Latin America and the Caribbean, hypertensive disorders are the most common cause of maternal death.1 Data from the most recent UK confidential enquiry into maternal and child health2 confirm that deaths from preeclampsia occur primarily due to intracranial haemorrhage, although other fatal complications can include acute pulmonary oedema, and respiratory and hepatic failure. The condition not only affects the mother, but it is also a leading cause of foetal growth restriction, intrauterine foetal death and preterm delivery. This article is intended to provide an update on the pathophysiology of preeclampsia and a current overview of the medical and anaesthetic management of the condition.
Risk factors: a role for genetics and immunology?
The question of what is the cause of preeclampsia has had many answers; the known risk factors are as follows3:
- Age 40 years or older
- Pregnancy interval of more than 10 years
- Family history of preeclampsia
- Previous history of preeclampsia
- BMI of 30 kg m−2 or above
- Preexisting vascular disease such as hypertension
- Preexisting renal disease
- Diabetes mellitus
- Multiple pregnancy
They suggest that there is both a genetic and an immunological component to the development of the disease in addition to a contribution from preexisting maternal diseases such as obesity and renal impairment. Support for a genetic link comes from the higher incidence in pregnant women with a maternal history of the disorder. The immune system also appears to play a major role in the development of preeclampsia with epidemiological evidence suggesting that nulliparity and a new partner are both important risk factors, although long-term exposure to paternal antigens in sperm is protective.4
Preeclampsia is a disease of abnormal placentation
There are two excellent reviews of the pathophysiology of preeclampsia which are recommended for a more comprehensive overview.5,6 Similar to risk factors, the pathogenesis is complex and incompletely understood. However, there is consensus that the primary disease is an abnormality of placentation. In order to understand the part that this plays, it is important to have some knowledge of normal placentation.
With normal placentation, maternal uterine spiral arteries run through the myometrium and into the endometrium, which in pregnancy is replaced by the decidua. Trophoblasts of foetal origin invade these spiral arteries resulting in a loss of elasticity and vascular smooth muscle tone. Consequently, these arteries are remodelled into low resistance capacitance vessels, which provide sufficient placental perfusion to sustain the growing foetus.
However, in preeclampsia, trophoblastic invasion is much shallower, affecting only the spiral arteries in the decidua. The myometrial sections remain small and constricted, resulting in a defective uteroplacental circulation with a higher resistance. This gives rise to subsequent placental ischaemia. Why this should happen to a minority of individuals is unknown, but genetic and immunological mechanisms are thought to be important contributors.
Preeclampsia is a two-stage disease characterised by endothelial dysfunction
Preeclampsia is a two-stage disorder. The asymptomatic first stage occurs early in pregnancy and corresponds to the period of abnormal placentation. Some women have abnormal placentation but do not go on to develop preeclampsia, for example those with intrauterine growth restriction or spontaneous preterm birth. However, others go on to the symptomatic second stage of preeclampsia and develop the maternal syndrome, characterised by hypertension, proteinuria and multiorgan involvement. The underlying cause of the maternal syndrome is thought to be systemic endothelial dysfunction.
Endothelial dysfunction is associated with antiangiogenic protein
In normal pregnancy, vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) are two potent angiogenic substances in the circulation, which seem to exert some control over endothelial function.
An antiangiogenic protein called soluble fms-like tyrosine kinase-1 (sFlt-1) blocks the transmembrane receptor for VEGF and inhibits PlGF. High concentrations of sFlt-1 have been demonstrated in preeclampsia, and this has been associated with decreased concentrations of VEGF and PlGF in blood. Furthermore, in vitro studies have demonstrated that the endothelial dysfunction caused by high levels of sFlt-1 can be rescued by administration of exogenous VEGF and PlGF.
It would appear therefore that sFlt-1 made by the placenta of women with preeclampsia results in lower concentrations of VEGF and PlGF, leading to an antiangiogenic state and the maternal syndrome of preeclampsia.
Reduced haem oxygenase-1 activity
Haem oxygenase-1 (HO-1) is an anti-inflammatory enzyme that inhibits sFlt-1 release. Women who go on to develop preeclampsia have been shown to have decreased HO-1 mRNA expression at 11 weeks’ gestation. This might result in an excessive elevation of sFlt-1 with corresponding endothelial dysfunction. HO-1 might also have a role as a therapeutic target in the treatment of preeclampsia. Statins, commonly used in cardiovascular disease, stimulate HO-1 expression and inhibit sFlt-1 release both in vivo and in vitro, and so may have the potential to ameliorate early-onset preeclampsia. Trials are currently under way to explore this exciting possibility.
The origin of cardiovascular changes
The underlying mechanisms for hypertension in preeclampsia remain unknown. The commonly held view is that hypertension occurs because of increased systemic vascular resistance (SVR) with a concomitant reduction in cardiac output. However, others believe that the hypertension of preeclampsia arises from an increased cardiac output state but with only a modest increase in SVR. Dennis et al.7 compared haemodynamic changes in untreated preeclamptics with healthy parturients and nonpregnant controls using transthoracic echocardiography. They demonstrated that the untreated preeclamptic group had increased cardiac output due primarily to an increase in left ventricular fractional shortening and increased inotropy. There was only mild peripheral vasoconstriction (Fig. 1). However, one criticism of that study is that the mean arterial pressures in women in the preeclamptic group were too low to represent a severe disorder. Before new treatment options for the cardiovascular changes emerge, further research is needed to clarify the picture.
Prediction by B-type natriuretic peptides
The knowledge that derangements in serum proteins can occur in preeclampsia has opened up the possibility of using sFlt-1 and PlGF, and other proteins, as biomarkers for the prediction of disease, but at present, their incorporation into some form of screening test remains investigational. More recently, there has been interest in the possibility that B-type natriuretic peptides may be used to predict complications in preeclampsia. In a systematic review, Afshani et al.8 concluded that preeclampsia is associated with elevated natriuretic peptide concentrations, but larger prospective trials are required to determine whether elevated concentrations predict development of severe preeclampsia and its complications.
Other avenues have also been explored to aid in prevention of preeclampsia. The observation that preeclampsia was associated with a low dietary calcium intake led to a multicentre trial studying the addition of elemental calcium to the daily diet, but this failed to reduce the incidence of preeclampsia in the treatment group.9 Similarly, the knowledge that preeclampsia may be a result of oxidative stress led to investigations into the possibility of antioxidant supplementation of the diet to prevent or treat preeclampsia. Again however, a large multicentre study using dietary supplementation with Vitamins C and E failed to show any benefit.10
Consequently, current UK National Institute for Health and Clinical Excellence (NICE) guidelines11 for reducing the risk of preeclampsia do not recommend the use of nutritional supplements such as calcium, folic acid, vitamins C and E, fish oils or garlic. Nor do they recommend the use of pharmaceutical agents such as nitric oxide donors, progesterone, diuretics or low-molecular weight heparin. The guidelines do recommend that women should take low-dose aspirin if they are at a high risk of developing preeclampsia. The rationale for this is based on some of the factors listed in the section ‘Risk factors: a role for genetics and immunology?’.
Distinguishing preeclampsia from other causes of hypertension in pregnancy can be difficult. However, clear diagnostic criteria are now available. Chronic hypertension is hypertension that is present before 20 weeks’ gestation. Gestational hypertension is new-onset hypertension presenting after 20 weeks’ gestation without significant proteinuria. Preeclampsia is new-onset hypertension presenting after 20 weeks’ gestation with significant proteinuria that resolves after delivery.11 Hypertension in its mildest form is defined as a blood pressure of at least 140/90 mmHg taken with a manual device. Significant proteinuria is defined as more than 0.3 g protein excreted in 24 h, or more than 30 mg mmol−1 in a spot urinary protein:creatinine sample.
Preeclampsia can be further classified into mild, moderate or severe, and typically, worsening severity is associated with more abnormalities in other organ systems of the body (Table 1).
The management of preeclampsia is reviewed in an excellent article by Dennis.12 Management should be undertaken with a multidisciplinary team approach. Delivery of the placenta is the only cure. Many units have developed guidelines and protocols, and although they may vary slightly in their content, they all have common management goals which are to treat hypertension, prevent seizures, control fluid intake and optimise the timing of delivery. When protocols and guidelines for management are implemented, there is evidence to suggest that this is associated with less mortality and fewer complications for preeclamptic mothers. However, it is not clear whether this is due to specific management recommendations within the protocol or, more likely, because protocols are often introduced as part of a package of improved healthcare involving better education, communication and multidisciplinary team working.13 Much of the treatment for preeclampsia lacks an evidence base.
The purpose of treating acute hypertension in preeclampsia is to prevent serious complications such as intracerebral haemorrhage and stroke, hypertensive encephalopathy, myocardial ischaemia and cardiac failure.
Worldwide, there is no consensus yet about what the target blood pressure should be and which drugs to use to achieve it. In the USA, targeted values are less than 150/100 mmHg; in Canada and Australia, the target is a DBP of 90 to 109 mmHg, and 90 to 105 mmHg in Germany. All are higher than the UK recommendation, which is to aim for a DBP of 80 to 100 mmHg. This is important because a balance has to be achieved between accepting higher blood pressure in an attempt to prolong the pregnancy but with possible adverse consequences to the mother, and the possible consequences of failure to achieve a more exacting blood pressure value resulting in increased preterm delivery rates. However, there is agreement that when embarking upon the acute control of hypertension, great care must be taken to avoid precipitous decreases in blood pressure, as this can adversely affect uteroplacental perfusion.
The current Cochrane review14 does not support the choice of any one antihypertensive over another, concluding that the choice should depend on the clinician's experience with a specific drug. Consequently, around the world, there is a variety of antihypertensive agents in use. Drugs that are in common use are hydralazine, labetalol, nifedipine, urapidil and methyldopa.
There is great familiarity with hydralazine, which is a direct-acting vasodilator. It is potent and there is a risk of maternal hypotension that can be avoided by the careful use of a 500-ml infusion of crystalloid prior to its administration. It is considered well tolerated in pregnancy, but nevertheless there are side-effects such as maternal tachycardia and palpitations. A systematic review of randomised controlled trials of severe hypertension showed hydralazine to be associated with poorer maternal and perinatal outcomes than other antihypertensive agents and to be more poorly tolerated.15 Consequently, in many countries, hydralazine is no longer the first-line drug of choice.
Labetalol is a combined α-receptor and β-receptor antagonist. It is currently the first-line drug in the UK where UK NICE guidelines11 recommend that moderate hypertension (150/100 to 159/109 mmHg) and severe hypertension (160/110 mmHg or higher) are treated initially with oral labetalol with the aim of reducing SBP to less than 150 mmHg and DBP to between 80 and 100 mmHg. Its efficacy is similar to that of hydralazine, but it is associated with fewer maternal side-effects such as tachycardia and palpitations. However, it should be avoided in the presence of asthma or congestive cardiac failure.
This calcium channel blocker lowers blood pressure by arterial smooth muscle relaxation. It is given orally and, when given in the enteral rather than sublingual form, it has been shown to be more effective than hydralazine at reducing blood pressure to the target range, with less hypotension. However, its slower onset of action than other antihypertensives can lead to overtreatment. Sublingual nifedipine capsules are no longer recommended because they are associated with myocardial infarction and cerebral ischaemia. In theory, nifedipine can interact with magnesium to produce hypotension and neuromuscular blockade, but in practice, the combination can be used safely.
Urapidil is a sympatholytic antihypertensive drug. It acts as an α1-adrenoceptor antagonist and has been shown to be as effective as hydralazine but gives better control and is better tolerated. It has a minimal effect on maternal heart rate. Urapidil is currently not approved by the US Food and Drug Administration, but it is used widely in Europe.
Methyldopa continues to be a popular choice of antihypertensive in pregnancy, with a good safety profile. It is an α2-adrenergic agonist, reducing blood pressure through a sympatholytic action. In some countries, it is still regarded as a first-line medication, but in many others, it has been superseded by the drugs outlined above, which are often much better tolerated.
Magnesium sulphate for seizure treatment and prophylaxis
Eclampsia is the manifestation of end-organ damage in the brain from severe preeclampsia. It is associated with intracerebral haemorrhage, cardiac arrest and death. There is clear evidence that magnesium sulphate is the treatment of choice for eclamptic seizures.16 A loading dose of 4 g should be given over 5 min, followed by an infusion of 1 g h−1 for 24 h. Given in this way, it is better than phenytoin, diazepam or lytic cocktail in reducing the risk of subsequent seizures. The mechanism of action of magnesium sulphate is unclear. Initially, eclampsia was thought to occur as a result of cerebral vasospasm. Magnesium sulphate is a known vasodilator and was thought to reduce seizures by relieving this vasospasm. However, it is more likely that eclampsia occurs as a result of sustained hypertension causing cerebral hyperperfusion and oedema. Magnesium sulphate may possess a direct anticonvulsant activity because it has been shown to be a N-methyl-D-aspartate (NMDA) antagonist. Stimulation of NMDA receptors may lead to convulsant activity. In addition, magnesium is a calcium antagonist and may act at the site of cellular membranes to oppose factors that promote cerebral oedema and seizure activity. Magnesium sulphate does not appear to be an effective antihypertensive drug and this is not thought to be a reason why it is protective against seizures.17
For prevention of seizures in women with preeclampsia, there is now clear evidence that magnesium sulphate reduces the risk of eclampsia by more than half.17 However, despite this obvious beneficial effect, there is no evidence that it improves maternal morbidity rates or perinatal outcomes. Magnesium sulphate therapy is not without side-effects, such as chest pain, palpitations, nausea and vomiting, sedation and respiratory weakness. These are more likely in patients with renal impairment and should be monitored clinically using patellar reflex testing. Worldwide, there is no consensus about when to start magnesium therapy in women with preeclampsia. UK NICE guidelines suggest starting magnesium sulphate if a woman has severe preeclampsia and has had, or has a history of, an eclamptic seizure, and also when a woman has severe preeclampsia and birth is planned within 24 h. The infusion is commonly continued for 24 h postpartum.11
Pulmonary oedema is a recognised cause of death in women with preeclampsia. It occurs because the combination of low colloid osmotic pressure from loss of protein, increased capillary permeability and high hydrostatic pressure from hypertension all make preeclamptic women more susceptible to side-effects of fluid therapy. Despite this, preeclampsia is regarded as a pathological state of intravascular volume depletion, and acute renal failure secondary to acute tubular necrosis is another well recognised, albeit rare, complication. Consequently, most units now have a fluid management protocol to guide intravenous fluid replacement so that the risks of pulmonary oedema and renal failure are minimised, and this usually takes the form of a fluid restriction protocol. The use of intravenous fluids to increase plasma volume or treat oliguria in women with normal renal function is not recommended.18
A requirement for invasive central venous pressure monitoring is not common and tends to be reserved for women with oliguria and also to monitor responses to fluid administration. Several maternal deaths have been reported as a result of complications from central line insertion,19,20 and one regional study13 found that the use of central venous pressure monitoring did not add significantly to the management of severe preeclampsia. More recently, there has been interest in cardiac output monitoring to help guide management in preeclampsia using invasive intra-arterial techniques and transthoracic echocardiography, but this still remains experimental.21,22
Timing of delivery
Obstetricians decide on the timing of delivery having weighed up the benefits of continuing a pregnancy for the foetus against the risk of maternal morbidity and mortality rising with increasing gestation. There is general agreement that women with severe preeclampsia after 34 weeks’ gestation should be delivered but only after blood pressure has been controlled and, if appropriate, a course of corticosteroids completed to aid foetal lung maturation. For women with mild or moderate preeclampsia between 34 and 37 weeks’ gestation, the timing of delivery should be determined by the maternal and foetal condition. For any woman with mild to moderate preeclampsia after 37 weeks’ gestation, delivery should be planned within the next 24 to 48 h.
For women who develop preeclampsia before 34 weeks’ gestation, the pregnancy should be managed conservatively up to 34 weeks. However, delivery may be required if severe hypertension develops and is refractory to treatment or if other significant maternal and foetal indications develop.11
Neuraxial anaesthesia during labour
Epidural or combined spinal-epidural techniques are recommended for preeclamptic women in labour.11,23,24 This is because they provide high-quality analgesia that smoothes out hypertensive surges due to pain and reduces circulating catecholamine concentrations. In addition, there may be a possible improvement in uteroplacental flow to the foetus and of course the presence of the epidural catheter allows for anaesthesia for Caesarean delivery, thus avoiding the requirement for general anaesthesia. However, hypotension can be a problem for preeclamptic women in labour with regional analgesia. In a retrospective labour cohort study with epidural analgesia comparing 100 women with preeclampsia with 100 normotensive women, Vricella et al.25 reported significantly more episodes of hypotension that were also more severe, had a higher vasopressor requirement and were associated with more frequent foetal heart rate abnormalities in the preeclamptic group. Consequently, although epidural analgesia has advantages compared with no analgesia, it is important to remain vigilant with regard to hypotension.
Neuraxial anaesthesia for Caesarean delivery
For Caesarean delivery, neuraxial techniques are also preferred to general anaesthesia. However, the traditional view that epidural anaesthesia should be the neuraxial method of choice has now been rejected. Concerns that spinal anaesthesia might produce severe hypotension in this subgroup have dissipated as a result of familiarity with the technique and the evidence from clinical research. It has been shown that women with severe preeclampsia experience less hypotension under spinal anaesthesia than normotensive patients.26 Wallace et al.27 showed that there was no significant difference in the incidence of hypotension in severely preeclamptic women having spinal as compared with epidural anaesthesia. Other studies have shown that there was only a mild clinically insignificant difference in the lowest mean arterial pressure between preeclamptic women having spinal and epidural anaesthesia.28,29 In growth-restricted foetuses with impaired Doppler flow, differences in neonatal biochemistry and Apgar scores when compared with general anaesthesia are clinically unimportant.30
One well recognised complication of preeclampsia is thrombocytopaenia, and a low platelet count is a relative contraindication to regional blockade because of concerns regarding epidural haematoma formation. When considering this risk for Caesarean delivery, it must be balanced against the risks of general anaesthesia. There is no threshold for platelet count that divides high risk and low risk for epidural haematoma, and it is necessary to rely on expert and consensus opinion. A common view is that a stable platelet count of more than 75 × 109 l−1 in the absence of other coagulation abnormalities should be well tolerated and should provide no greater risk than performing a general anaesthetic for a preeclamptic woman in labour with a full stomach.31
Occasionally, it is necessary to provide general anaesthesia for Caesarean delivery. This may be appropriate for women with contraindications to regional anaesthesia such as coagulopathy, or for those who have developed severe complications such as pulmonary oedema or depressed consciousness following eclamptic seizures. If general anaesthesia is chosen, particular attention should be paid to the airway because tracheal intubation can be difficult. It is also extremely important to reduce the hypertensive response to laryngoscopy, which can be severe and has been identified as a cause of maternal mortality. Opioids such as fentanyl, alfentanil or remifentanil can be used in addition to antihypertensives such as labetalol or esmolol; magnesium sulphate has also been used in this role. Finally, consideration should also be paid to the interaction between magnesium sulphate and nondepolarising muscle relaxants, whose action can be prolonged in the presence of a magnesium infusion;32 magnesium inhibits acetylcholine release at the neuromuscular junction, decreases sensitivity to acetylcholine and depresses excitability of muscle fibre membranes. Sometimes, this leads to the requirement for prolonged ventilation.
HELLP syndrome is considered to be an extreme form of severe preeclampsia. It is characterised by haemolysis, elevated liver enzyme concentrations and a low platelet count (HELLP), and is associated with disseminated intravascular coagulation, placental abruption, pulmonary oedema, acute renal failure, liver failure and acute respiratory distress syndrome. As with preeclampsia, it can occur in the antepartum or postpartum period. Clinical management is similar to that of preeclampsia and includes seizure prophylaxis and antihypertensive medication. The initial priority is to stabilise the mother and to correct coagulopathy, which may include the need for platelet transfusion. An assessment of the foetal condition should be made and, if appropriate, corticosteroids should be prescribed to accelerate foetal lung maturity. There is controversy about the role of corticosteroids for the treatment of HELLP. Some believe that they might be of benefit to induce biochemical remission, but current UK guidelines do not recommend steroids to treat HELLP syndrome.11 A decision for delivery should be considered only when the maternal condition is more stable.
Improved strategies for preeclampsia
In the developed world, there has certainly been a reduction in morbidity and mortality from preeclampsia/eclampsia. Several factors have led to this improvement. Better antenatal care with an understanding of risk factors and pathogenesis has led to improved surveillance and better treatment. Lessons concerning when to deliver and mode of delivery have been learned, with an appreciation of the importance of stabilising the mother before embarking with undue haste upon Caesarean delivery. We now manage blood pressure much more effectively using appropriate antihypertensives and consistent blood pressure targets. The use of magnesium sulphate to prevent and manage convulsions is now standard practice. The early use of epidural analgesia in labour not only helps to control blood pressure but also avoids the need for general anaesthesia for Caesarean section, with its inherent risks. However, if general anaesthesia is required, we now understand the importance of preventing the pressor response to laryngoscopy. Finally, the role of consensus guidelines and protocols cannot be overstated in providing an overall package of care to improve outcomes for newborns and their mothers with this life-threatening condition.
Acknowledgements relating to this article
Assistance with the article: Dr Gordon Lyons helped with preparation of the manuscript.
Financial support and sponsorship: none.
Conflicts of interest: none.
Presentation: this review is based on a Refresher Course lecture at Euroanaesthesia 2013 in Barcelona.
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