A short review of the medical therapy for prevention and acute treatment of conditions related to pre-eclampsia.

Pre-eclampsia is a multi-system disorder, unique to human pregnancy, characterised by hypertension with involvement of one or more maternal organ systems (renal/hepatic/haematological/neurological/respiratory) and/or fetal health (growth restriction/abruption).¹ It is a leading cause of maternal and perinatal morbidity and mortality worldwide.²

The pathogenesis of pre-eclampsia is incompletely understood, but is related to disturbances in placentation, resulting in generalised inflammation and progressive endothelial damage.² Despite advancing knowledge, there is still controversy surrounding the diagnosis, screening, classification of severity and management of pre-eclampsia.²

The only definitive treatment for pre-eclampsia is delivery of the placenta and, while prolongation of pregnancy conveys no benefit for the mother, at early gestations this results in an improvement in fetal outcomes. However, this strategy usually results in progression of pre-eclampsia with subsequent placental insufficiency and maternal organ dysfunction, increasing the risks of maternal mortality and morbidity.^1,2 It has been estimated that up to a quarter of women with pre-eclampsia managed expectantly will develop severe morbidity, including HELLP syndrome, abruption, pulmonary oedema and eclampsia, with a mean duration of prolongation of <12 days.¹ No conclusive evidence exists that treating mild-to-moderate hypertension in pregnancy provides any benefit with regards to critical outcomes, including progression to severe pre-eclampsia, HELLP, eclampsia and maternal or perinatal death.^2,3 The World Health Organisation has recommended treatment of severe hypertension during pregnancy with antihypertensive agents, acknowledging only very low-quality evidence for this recommendation.² The rationale for treating severe hypertension stems from the fact that under normal conditions, cerebral blood flow is kept constant by cerebral vasoconstriction in response to increases in blood pressure. However, when systolic blood pressure is increased above the upper limits of auto-regulation (>170mmHg), arterioles dilate creating hyper-perfusion and cerebral oedema, which increases the risks of posterior reversible encephalopathy syndrome (PRES), hypertensive encephalopathy and stroke. This needs to be balanced against the risk of treating hypertension, in particular overly aggressive treatment, with concerns that sudden, significant reduction in blood pressure may result in impaired fetal-placental perfusion resulting in fetal distress.¹ This is particularly important in the compromised fetus with grossly abnormal arterial blood flow.

Pregnancy is associated with a number of physiological changes that may influence drug absorption, distribution, metabolism and excretion. These include an increase in gastric pH, reduction in intestinal motility, increased cardiac output, increased glomerular filtration rate and reduction in plasma albumin levels, as well as modifications in gene regulation that result in changes in enzyme/transporter expression and catalytic function.⁴ An example of this is increased function of CYP2D6, resulting increased clearance of both clonidine and metoprolol.⁴ However, as the exact magnitude of these effects are as yet unknown and there is an incomplete understanding of pregnancy-related changes on a significant number of medications, it is important to titrate medications to clinical effect rather than be exclusively guided by standard dosing regimens.

While certain guidelines may make recommendations regarding the choice of antihypertensive, there is limited evidence for such recommendations.² Certain medications, such as hydralazine, methyldopa, beta-blockers and nifedipine, have been extensively used and therefore are reasonable first-line choices until further evidence becomes available to guide decision-making. Certain agents, including angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs) and sodium nitroprusside, should be avoided owing to concerns regarding their safety profiles.^1,2 ACEi use in mid-to-late pregnancy has been associated with fetal death and neonatal renal failure, and ARBs are avoided owing to their similarities to ACEi. Sodium nitroprusside may cause profound hypotension, methaemaglobinaemia, cyanide and thiocyanate toxicity and transient fetal bradycardia, although many of these reactions are related to prolonged infusions.¹

The choice of agent and route of administration should be guided by the experience of clinician with the medication of choice, its cost and local availability, and indications and/or contraindications specific to the patient and clinical situation.^1,2 Tables 1 and 2 outline medication options, pharmacological parameters, precautions and contraindications to a number of antihypertensive agents for both acute management of severe hypertension and more prolonged control of hypertension, respectively.

Eclampsia is characterised by the manifestation of generalised seizures, not attributable to other causes, in women with pre-eclampsia and complicates approximately one per cent of cases of pre-eclampsia in developed countries.^1,2

The aetiology and pathology of eclampsia remains incompletely understood, but is related to central nervous system ischaemia and vasogenic oedema resulting in confusion, seizures and visual loss, with MRI findings typically showing symmetrical white matter oedema in the posterior cerebral hemispheres, particularly the occipito-parietal regions. While changes may initially be reversible with treatment, infarction is the end result if untreated.²

Table 1. Acute treatment of severe hypertension/pre-eclampsia.^1,2,5-7

Table 2: Chronic treatment of severe hypertension/pre-eclampsia.^1,2,5-7

Table 3. Medical therapy for prevention and acute treatment of eclampsia.^1,2,5-7

Table 3 outlines the agents for preventative and acute abortive treatment of eclampsia. Parenteral magnesium sulphate is the drug of choice for preventing eclampsia and, compared with placebo or no anticonvulsant, has been associated with a significant reduction in the risk of eclampsia, with no difference in terms of risk of maternal death, serious maternal morbidity, stillbirth or neonatal death.² It is clearly indicated to prevent recurrent eclamptic seizures and is also used as primary prevention in cases of severe pre-eclampsia, especially in the setting of uncontrolled hypertension or neurological symptomatology.

Magnesium sulphate is more effective in reducing the risk of eclampsia than phenytoin, however, phenytoin has a therapeutic role in those patients where the use magnesium sulphate is contraindicated. Magnesium sulphate is renally excreted and its use in patients impaired renal function should be undertaken with caution, with monitoring of serum magnesium concentrations, aiming for levels between 2 and 4mmol/L.¹

Eclamptic seizures are usually self-limiting, and the use of abortive treatment may not always be required if seizures are witnessed, self-limiting and of short duration. Where seizures are unwitnessed and duration of seizure is unclear, abortive treatment with benzodiazepines (diazepam/clonazepam), while preparing administration of magnesium sulphate, is indicated.^1,2

Conclusion

Familiarity with the medications used to prevent and treat pre-eclampsia and eclampsia in the maternity patient is essential, including their dosing, pharmacokinetics and potential adverse effects. The information provided, in particular with regard to dosing schedules, is meant as a guide and should be used in conjunction with local guidelines and clinical judgement.