EXPLORE PAST ISSUES
Pharmacology
Vol. 16 No 2 | Winter 2014
Feature
Pre-eclampsia
Dr Dean Fourie
BSc, PGDipHSc (Cardiac Rehabilitation), BHB, MBChB.
Dr Lucille Wilkinson
MBChB (Otago), FRACP


This article is 6 years old and may no longer reflect current clinical practice.

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

 

Medication Dose Route and dose Onset of action (min) Half-life (hrs) Adverse effects/
Precautions
Initial Maximum
Labetalol (alpha and beta blockade) 20mg 300mg IV bolus (over 2 min). Doses of 40–80mg every 10 min till max dose reached. 5 2.5 Bradycardia
Hypotension
Asthma
Nifedipine
(calcium channel blockade)
5–10mg 40mg Oral. Repeat after 45 min. 5–20 2-4 Headache
Flushing
Hydralazine (peripheral vasodilator) 5–10mg 30mg IV bolus. Repeat after 20 min. 20 0.75-3 Headache
Flushing
Nausea
Tachycardia
Hypotension
Diazoxide (peripheral vasodilator) 15–45mg 300mg IV bolus. Repeat after 5 min. 3–5 28 Flushing
Hypotension
Hyperglycaemia –
caution with diabetics

 

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

Medication Dose Onset of action (hours) Half-life (hrs) Drug metabolism Adverse effects/
Precautions
Methyldopa (centrally acting anti-adrenergic agent) 250–1750mg TDS 12–24 1.75 Bioavailability 50%
Predominant renal excretion
Sedation
Dry mouth, blurred vision
Contraindicated in depression
Caution in renal impairment
Labetalol (alpha and beta blockade) 100–400mg TDS 1–2 6–8 50% protein bound Metabolised hepatically Metabolites excreted in urine Bradycardia
Headache
Bronchospasm: caution in obstructive lung disease
Oxprenolol
(beta blockade with sympatomimetic activity)
20–160mg IDS 1–2 1–2 Variable bioavailability (20–70%)
Metabolised hepatically
Metabolites excreted in urine
Bradycardia
Headache
Bronchospasm: caution in obstructive lung disease
Fetal growth restriction
Nifedipine SR
(calcium channel blockade)
20–60mg BD 1.5–4 6–11 Hepatically metabolised Headache
Flushing
Tachycardia
Peripheral oedema
Constipation
Elimination half-life increased with liver impairment
Hydralazine (peripheral vasodilator) 25–50mg TDS 1 0.75–3 Significant first pass metabolism
Low oral bioavailability (35%)
Metabolised hepatically
Metabolites excreted in urine
Flushing
Headache
Nausea
Lupus-like syndrome
Clearance reduced with renal impairment
Prazosin (alpha blockade) 0.5–5mg TDS 1–3 2–3 Variable bioavailability (40–85%)
Metabolised hepatically – some metabolites active
Orthostatic hypotension (most marked after first dose)
Clearance reduced in liver impairment
Clonidine
(Centrally acting vasodilator)
75–300µg TDS 1–3 5–25 50% hepatic metabolism
Excreted renally
Dizziness
Dry mouth
Constipation
Sleep disturbance
Clearance reduced in renal impairment

 

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

Medication Dose Route and dose Onset of action (hrs) Half-life (hrs) Adverse effects/
Precautions
Prevention
Magnesium sulphate 4g IV over 15–20 min followed by infusion
(1–2g/hr)
Blocks neuromuscular transmission and reduces the amount of acetylcholine released at the end-plate by the motor nerve impulses Immediate (Effect lasts 30 min after IV bolus) Overdose can cause respiratory depression and bradycardia. Contraindicated in myasthenia gravis and heart block. Caution in renal impairment.
Phenytoin dose 1g. Maintenance 250mg daily Loading dose 1g. Maintenance 250mg daily Anticonvulsant. Inhibits spread of seizure activity in the motor cortex 0.5–1 10–15 Metabolised in the liver. Contraindicated in patients with bradyarrhythmias.
Acute treatment
Diazepam (IV) 2mg/min. Repeated doses every 10 mins to max 10mg Acts at limbic and subcortical levels of CNS – anxiolytic, sedative,skeletal muscle relaxant and anticonvulsant effects Rapid 20–40 Sedation. Tolerance. Cross the placenta – may cause hypotension, hypotonia,respiratory depression and hypothermia in the newborn as well as withdrawal if prolonged exposure.
Clonazepam (IV) 1–2mg over 2–5 min

 

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.

References

  1. Lowe SA, Brown MA, Dekker GA, Gatt S, McLintock CK, McMahon LP, et al. Guidelines for the management of hypertensive disorders of pregnancy 2008. Aust N Z J Obstet Gynaecol. 2009;49(3): 242-6.
  2. WHO recommendations for prevention and treatment of pre-eclampsia and eclampsia [Internet]. WHO. Available from:www.who.int/reproductivehealth/publications/maternal_perinatal_ health/9789241548335/en/.
  3. Abalos E, Duley L, Steyn DW. Antihypertensive drug therapy for mild to moderate hypertension during pregnancy. Cochrane Database of Systematic Reviews [Internet]. John Wiley & Sons, Ltd; 1996. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858. CD002252.pub3/abstract .
  4. Isoherranen N, Thummel KE. Drug Metabolism and Transport During Pregnancy: How Does Drug Disposition Change during Pregnancy and What Are the Mechanisms that Cause Such Changes? Drug Metab Dispos. 2013 Feb 1;41(2):256-62.
  5. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 9th ed. Lippincott Williams & Wilkins; 2011.
  6. The Complete Drug Reference. 36th ed. Chicago: Pharmaceutical Press; 2009.
  7. Schaefer C, Peters P, Miller RK. Drugs during pregnancy and lactation. Amsterdam; New York: Elsevier; 2007.

Leave a Reply

Your email address will not be published. Required fields are marked *