The treatment of hypertension in pregnancy

PHARMACOLOGY

The treatment of hypertension in pregnancy

Learning objectives After reading this, you should be able to: C list the types and implications of hypertensive disorders in pregnancy C understand the various treatment options C manage acute severe hypertension and eclampsia in pregnancy

Bobby Krishnachetty Felicity Plaat

Abstract Hypertension is the commonest medical condition encountered in pregnancy and pre-eclampsia/eclampsia is the second leading cause of maternal mortality in the UK. The precise cause of pre-eclampsia is unknown but the pathophysiology involves abnormal placentation with an exaggerated inflammatory response causing a multisystem disorder. The very presence of rising blood pressure in a pregnant woman should alert the clinician to look for the development of pre-eclampsia. Diagnosis and treatment of hypertensive disorders in pregnancy is vital as they are associated with both worse maternal and fetal outcome. One of the ‘top 10’ recommendations of the most recent report on the Confidential Enquiry into Maternal and Child Health (CEMACH 2003e05), is that all pregnant women with a systolic blood pressure greater than 160 mmHg must have immediate antihypertensive therapy and treatment should be initiated at lower pressures if the overall clinical picture suggests rapid deterioration. Regional anaesthesia is recommended for both labour analgesia and operative delivery. In the presence of compromised placental function and intrauterine growth restriction (IUGR), regional blockade has the beneficial effect of improving placental blood flow.

which does not resolve post-partum, is also classified as chronic hypertension. There is an increased risk of superimposed preeclampsia, intrauterine growth restriction (IUGR) and placental abruption, associated with this condition. Pregnancy-induced hypertension (PIH): the term refers to hypertension occurring >20 weeks’ gestation but without other features of pre-eclampsia, which resolves within 6 weeks of delivery. Fifteen per cent of women developing hypertension at >20 weeks will develop pre-eclampsia. PIH tends to recur in subsequent pregnancies. It is associated with better maternal and fetal outcomes than pre-eclampsia. The treatment of pre-existing hypertension and PIH is the same. Pre-eclampsia and eclampsia: although the classic triad of hypertension, proteinuria and oedema denotes pre-eclampsia, the absence of one or more does not exclude the diagnosis (see also Figure 1).

Keywords Hypertension; labetalol; magnesium sulphate; methyldopa; pre-eclampsia; pregnancy; proteinuria; regional anaesthesia

Hypertension is the commonest medical disorder encountered in obstetric practice. It complicates 10e15% of pregnancies. Preeclampsia and eclampsia occur in 4% of pregnancies and is the second leading cause of maternal mortality in the UK. Worldwide 160,000 women die each year and approximately 20% of special care baby unit (SCBU) cots are occupied by the offspring of women with these conditions. Classification: hypertension is defined as a blood pressure 140/90 mmHg on two separate occasions, at least 4 hours apart. Pre-existing or chronic hypertension: this is defined as hypertension diagnosed prior to pregnancy or before 20 weeks’ gestation. Hypertension newly diagnosed during pregnancy but

Bobby Krishnachetty FRCA is a Specialist Registrar in Anaesthetics at Queen Charlotte’s and Chelsea Hospital, London, UK. Conflicts of interest: none declared.

Figure 1 Magnetic resonance image showing multiple cortico-subcortical areas of hyper-intense signal (arrows) involving the occipital and parietal lobes bilaterally and pons in a patient with posterior reversible encephalopathy syndrome, a complication of eclampsia.

Felicity Plaat FRCA is a Consultant Anaesthetist at Queen Charlotte’s and Chelsea Hospital, London, UK. Conflicts of interest: none declared.

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PHARMACOLOGY

Mild/moderate pre-eclampsia: blood pressure 140/90 mmHg, proteinuria (>0.3 g/24 hours) without renal, hepatic or coagulation dysfunction.

a protocol for the management of eclampsia and acute severe hypertension and that regular fire drills should be conducted.1 Magnesium sulphate is now the drug of choice for reducing the risk of seizures in severe pre-eclamptics, controlling new onset seizures and reducing the risk of their recurrence.2 In eclampsia convulsions are thought to be a result of cerebral vasospasm and reduced cerebral blood flow and this is reversed by the vasodilator property of magnesium. Intracranial hypertension and vasogenic oedema may also occur.3 The prophylactic use of magnesium in severe pre-eclampsia is associated with a trend towards lower maternal morbidity and mortality4 and The World Health Organization (WHO) now recommends magnesium sulphate therapy for prevention of eclampsia in women with severe pre-eclampsia.

Severe pre-eclampsia: blood pressure 160/110 mmHg, significant proteinuria (>1 g/litre), in the presence of biochemical evidence of renal, hepatic and coagulation dysfunction. Eclampsia: one or more seizures occurring in the presence of pre-eclampsia. Pathogenesis: the pivotal role of placenta in pathogenesis of the disorder has long been recognized, and the removal of placenta leads to the resolution of the disease. Abnormal placentation with inadequate trophoblast invasion of the spiral arteries is thought to cause placental ischaemia with the exaggerated release of circulating inflammatory mediators culminating in widespread endothelial cell dysfunction, affecting maternal renal, cardiovascular, hepatic, coagulation and central nervous systems as well as fetal growth retardation.

Fluid management Because of the predisposition to pulmonary oedema, fluid input should be limited to 2 litres per 24 hours. It should be noted that although temporary renal dysfunction is common, the need for dialysis is rare, and permanent dysfunction extremely rare: fluid overload poses a much greater threat in this condition. Invasive monitoring (invasive blood pressure and central venous pressure) is indicated if there is uncertainty regarding fluid status (especially challenging when haemorrhage is superimposed on pre-eclampsia) and non-invasive monitoring is problematic and in severe cases where intensive care is likely to be required. Colloid fluid challenges to maintain urine output at 0.5 ml/ kg/hour should be given with caution and under central venous pressure control.

Management General measures Pregnant women with hypertension require closer antenatal surveillance to check for the development of pre-eclampsia (regular measurement of blood pressure, urinalysis for proteinuria, plasma urate levels and uterine artery Doppler blood flow analysis). Haemoglobin concentration, platelet count, coagulation function, plasma urea and creatinine and liver function tests should be regularly checked in women who develop pre-eclampsia. Fetal monitoring in the form of fetal growth and biophysical profile with ultrasound scans to detect IUGR should be performed every 4 weeks after 24e26 weeks’ gestation. These women should have an early referral to an obstetric anaesthetic clinic. Not only are they at increased risk of obstetric intervention, requiring anaesthetic input but also management of the condition itself may include regional blockade and this should be discussed antenatally.

Control of hypertension Recent reports on maternal mortality indicate that the foremost cause of mortality due to hypertensive disorders is intracerebral haemorrhage and inadequate management was the main type of substandard care identified. Hence the recommendation in the latest CEMACH reports that all pregnant women with a systolic blood pressure 160 mmHg should be immediately started on antihypertensive therapy.5 Management of these women should be in a high dependency area. Oral (labetalol) or intravenous (labetalol or hydrallazine) antihypertensives should be employed according to the clinical condition.

Management of chronic hypertension, PIH and mild/moderate pre-eclampsia In normal pregnancy blood pressure falls in the first trimester before the increase in cardiac output compensates for the decrease in systemic vascular resistance. Systemic blood pressure continues to decrease during the second trimester up to 22e24 weeks after which there is a steady rise to pre-pregnant levels by term. Because of the initial decrease hypertension may not be detected till late in pregnancy. A combination of antihypertensive agents is preferable to monotherapy to minimize side effects, for example labetalol or methyldopa with long-acting nifedipine. The drugs used, their dose and route of administration along with the mode of action and side effects are given in Table 1. Management of pre-eclampsia depends on prevention of seizures, blood pressure, and prevention of pulmonary oedema.

Delivery of the fetus The severity of the condition will determine timing and hence mode of delivery. Controlling maternal blood pressure with antihypertensives is essentially a holding mechanism for expectant management. There is fine balance at early gestations between delaying delivery in order to obtain the maximum possible maturity for the baby, and the risk of the worsening maternal condition. Anaesthetic considerations (Box 1) Recent evidence has allayed previously held fears that haemodynamic instability due to regional blockade would be exaggerated in the pre-eclamptics. A large multicentre trial showed that in severe pre-eclamptics, haemodynamic stability was no more clinically compromised with spinal compared with epidural blockade.6 In fact pre-eclamptic patients show less hypotension

Prevention of seizures The Royal College of Obstetricians and Gynaecology recommends that all maternity units should be equipped with

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Antihypertensive management in pregnancy-induced hypertension and pre-eclampsia Drug e dose and route Methyldopa Oral only 250 mge3 g tds

Mode of action Central e acts as a false neurotransmitter to norepinephrine

Labetalol Oral 200e1600 mg tds Intravenous (IV) 50 mg slow bolus followed by 20e160 mg/hour infusion

Combined a and b adrenoceptor antagonist with specific a1 (peripheral vasodilation) and nonspecific b (prevents reflex tachycardia) actions. The ratio of a1:b blocking effects depends on the route of administration e 1:3 for oral and 1:7 for IV Calcium channel antagonist. Blocks the entry of calcium ions through the L-type channels.

Nifedipine Oral only 20e90 mg od Avoid sublingual route Hydrallazine IV 5 mg slow bolus followed by 5 mg/hour infusion

Activation of guanylate cyclase and increase in intracellular cyclic GMP leading to decrease in intracellular calcium causing vasodilatation

ACE inhibitors and ARB drugs

a-Blockers Prazosin b-Blockers

Highly selective a1 adrenoceptor blocker b adrenoceptor antagonists

Diuretics

Various sites of the renal glomerulus Only use in pulmonary oedema

Magnesium sulphate IV 4 g bolus over 10 minutes followed by 1 g/hour infusion for 24 hours or 0.5 g/hour in case of oliguria or toxicity

Calcium antagonist at calcium channels and intracellular sites reducing systemic and cerebral vasospasm N-methyl D-aspartate receptor antagonist mediates anticonvulsant action Increased production of endothelial prostacyclin may help to restore the thrombaxaneeprostacyclin imbalance

Further 2 g bolus for recurring seizures

Side effects Postural hypotension, sedation, depression, bradycardia, headache, auto-immune haemolytic anaemia Bradycardia, bronchospasm, gastrointestinal disturbances, fatigue

Contraindication and caution Depression Liver disease Phaeochromocytoma Avoid in breastfeeding women Asthma Phaeochromocytoma Known cardiac disease

Headache, flushing, dizziness, tachycardia, rash, visual disturbances

Aortic stenosis Liver disease

Tachycardia, palpitations, flushing, fluid retention, headache, dizziness, peripheral neuropathy, lupus erythematosus type syndrome Fetal renal dysgenesis, oligohydramnios, fetal skull defects affecting all trimesters Severe postural hypotension, syncope, headache, vertigo

Severe tachycardia

Bradycardia and neonatal hypoglycaemia Neonatal thrombocytopenia Avoided in pregnancy as they prevent the physiologic volume expansion seen in normal pregnancy Therapeutic range e 2e4 mmol/litre Drowsiness, flushing Toxicity >5 mmol/litre Loss of deep tendon reflexes weakness, sedation, blurred vision Respiratory depression >7 mmol/litre Cardiorespiratory arrest >10 mmol/litre

Pregnancy

No evidence of teratogenicity Use only when benefit outweighs risk May cause IUGR Avoid in pregnancy Do not cause fetal malformations Not used to treat hypertension in pregnancy Can cause inadequate milk production Avoid using in conjunction with nifedipine In the case of cardiorespiratory arrest, stop infusion, start CPR and give 10 ml of 10% calcium gluconate

ACE inhibitor, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CPR, cardiopulmonary resuscitation; GMP, guanosine monophosphate; IUGR, intrauterine growth restriction

Table1

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PHARMACOLOGY

attenuated pharmacologically prior to induction, and possibly before extubation. Magnesium, labetalol, lignocaine and potent parenteral opioids may be used.9 In the case of the latter, fetal respiratory depression should be anticipated. Transfer to an intensive care unit may be necessary, for those who require ventilatory support, and those with persistent anuria after colloid fluid challenge. Postnatally, women who have had hypertensive disorders of pregnancy should be reviewed in view of stopping, reducing or changing the antihypertensive medication. Although there is little evidence in the use of prophylaxis against pre-eclampsia, use of aspirin and calcium have shown to reduce its incidence in moderate- and high-risk women. A

Anaesthetic concerns in pre-eclampsia General anaesthesia Exaggerated pressor response to airway instrumentation Increased risk of intubation difficulties (airway oedema) Regional blockade Coagulopathy (thrombocytopenia, abnormal platelet and hepatic function) Haemodynamic instability Difficulty (landmarks obscured by oedema) Predisposition to pulmonary oedema Box 1

REFERENCES 1 RCOG guideline number 10(A) management of severe pre-eclampsia/ eclampsia. London: RCOG, 2006. 2 Altman D, Carroli G, Duley L, et al. Do women with preeclampsia, and their babies, benefit from magnesium sulphate? The Magpie trial: a randomised, placebo-controlled trial. Lancet 2002; 359: 1187e90. 3 Cunningham FG, Twickler D. Cerebral edema complicating eclampsia. Am J Obstet Gynecol 2000; 182: 94e100. 4 Knight M, on behalf of UKOSS. Eclampsia in the United Kingdom in 2005. Br J Obs Gynaecol 2007; 114: 1072e8. 5 Lewis G, ed. The Confidential Enquiry into Maternal and Child Health (CEMACH). Saving mothers’ lives: reviewing maternal deaths to make motherhood safer e 2003e5. The seventh report on Confidential Enquiries into maternal deaths in the United Kingdom. London: CEMACH, 2007. 6 Visalyaputra S, Rodanant O, Somboonviboon W, et al. Spinal versus epidural anesthesia for cesarean delivery in severe preeclampsia: a prospective, randomised, multicenter study. Anesth Analg 2005; 101: 862e8. 7 Aya AGM, Vialles N, Tanoubi I, et al. Spinal anesthesia-induced hypotension: a risk comparison between patients with severe preeclampsia and healthy women undergoing preterm cesarean delivery. Anesth Analg 2005; 101: 869e75. 8 Sharma SK, Philip J, Whitten CW, Padakandla UB, Landers DF. Assessment of changes in coagulation in parturients with preeclampsia using thromboelastography. Anesthesiol 1999; 90: 385e90. 9 Allen RW, James MF, Uys PC. Attenuation of the pressor response to tracheal intubation in hypertensive proteinuric pregnant patients by lignocaine, alfentanil and magnesium sulphate. Br J Anaesth 1991; 66: 216e23.

and require less vasoconstrictor than normal parturients at the same gestation, following spinal anaesthesia.7 However prior to regional blockade, assessment of coagulation status of the blood is essential. Thrombocytopenia is common in severe pre-eclampsia and platelet function is compromised. If the platelet count is >75  109/litre evidence from thromboelastograph studies suggests that spinal anaesthesia is safe.8 Below this level, further assessment of the coagulation status is justified and lack of evidence means that an individual assessment of relative risks of different techniques is required. Epidural analgesia e patients with high blood pressure should be advised to have regional analgesia, unless contraindicated, as it helps to control the hypertensive response to pain and can also improve the placental blood flow in these patients. A functioning epidural may safely be extended for caesarean section. Subarachnoid anaesthesia e spinal or combined spinal epidural anaesthesia is the anaesthetic of choice in case of operative delivery. The advantages include better haemodynamic stability and avoidance of the difficulty with general anaesthesia. General anaesthesia e will be required if regional blockade is contraindicated. It may be indicated in the post-ictal patient with obtunded level of consciousness and in the presence of pulmonary oedema associated with hypoxia. Intubation may be complicated by oedema of the upper airways and poor ventilation because of decreased pulmonary compliance. Marked biphasic haemodynamic response e an initial fall in blood pressure followed by an exaggerated raise during laryngoscopy should be anticipated. This must be

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