Cardiac Drugs in Pregnancy (Current Cardiovascular Therapy), 2014th Ed.

Management of Hypertension

Eckhart J. Buchmann 

(1)

Department of Obstetrics and Gynaecology, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa

Eckhart J. Buchmann

Email: eckhart.buchmann@wits.ac.za

Abstract

High blood pressure affects about 10 % of pregnancies worldwide (Duley 2009), and is the second-most frequent cause of maternal death (Khan et al. 2006). The most serious form of pregnancy hypertension is pre-eclampsia, a progressive multisystem disorder only curable by delivery of the infant. Pre-eclampsia is found in about 2–8 % of pregnancies (Duley 2009), with 5–8 % of pre-eclamptic women in less-developed countries going on to eclamptic convulsions (World Health Organization 2011). Other complications of pre-eclampsia include intracerebral haemorrhage, pulmonary oedema, liver rupture, placental abruption, fetal growth restriction, and HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome.

Epidemiology and Pathogenesis

High blood pressure affects about 10 % of pregnancies worldwide (Duley 2009), and is the second-most frequent cause of maternal death (Khan et al. 2006). The most serious form of pregnancy hypertension is pre-eclampsia, a progressive multisystem disorder only curable by delivery of the infant. Pre-eclampsia is found in about 2–8 % of pregnancies (Duley 2009), with 5–8 % of pre-eclamptic women in less-developed countries going on to eclamptic convulsions (World Health Organization 2011). Other complications of pre-eclampsia include intracerebral haemorrhage, pulmonary oedema, liver rupture, placental abruption, fetal growth restriction, and HELLP (haemolysis, elevated liver enzymes, low platelets) syndrome.

Factors associated with a high risk for developing pre-eclampsia include a previously affected pregnancy, family history of pre-eclampsia, thrombophilia, multiple pregnancy, and pre-existing chronic hypertension. Pre-eclampsia originates from abnormal placental development, possibly explained by immune factors, oxidative stress, placental enzyme (haemoxygase-1) abnormalities or chronic placental hypoxia (Powe et al. 2011). The essential defect is failure of placental cytotrophoblast cells to invade uterine spiral artery muscular walls early in pregnancy. Normally, invasion of the spiral artery walls provides the placenta with high-flow low-resistance feeder vessels that facilitate placental growth and function. Defective spiral artery invasion results in poor placental function, suboptimal fetal growth, and the maternal syndrome of pre-eclampsia. The mechanism of disease for the maternal syndrome appears to be the release of antiangiogenic factors (soluble FMS-like tyrosine kinase-1 and soluble endoglin) from the diseased placenta into the maternal circulation (Powe et al. 2011; Pennington et al. 2012). These factors bind maternal angiogenic factors (vascular endothelial growth factor, placental growth factor, transforming growth factor-beta), and inhibit the angiogenic factors’ endothelial maintenance functions. The result is endothelial damage, vasospasm, capillary leakiness, and vessel wall platelet aggregation in multiple organ systems. This occurs most notably in the kidney, brain, liver, and uteroplacental circulation, leading to hypertension, proteinuria, oedema, and thrombocytopaenia, with the clinical complications as mentioned above. Overall, the pre-eclamptic woman’s circulation becomes contracted, with reduced plasma volume and underperfusion of vital organs.

Definitions and Classification of Hypertensive Disorders of Pregnancy

Not all women with hypertension in pregnancy have pre-eclampsia. To plan clinical management, knowledwge of the spectrum of pregnancy hypertensive disorders and their classification is necessary. These disorders can be grouped into three categories: pre-eclampsia, gestational hypertension and pre-existing hypertension. The definitions and classification given below are based on those of the Society for Obstetric Medicine of Australia and New Zealand (SOMANZ), the American College of Obstetricians and Gynecologists (ACOG), and the European Society of Cardiology (ESC) (SOMANZ 2008; American College of Obstetricians and Gynecologists 2002; The Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC) 2011).

Definitions

Hypertension in pregnancy is defined as a systolic blood pressure (BP) ≥140 mmHg, and/or a diastolic BP ≥90 mmHg, confirmed by repeated findings of elevated BP over several hours. Severe hypertension is defined as a systolic BP ≥160 mmHg and/or a diastolic BP ≥110 mmHg. The BP should be recorded with the woman sitting or in a semi-lateral position with the inflatable cuff at the level of the heart, using Korotkoff 5 for diastolic BP. The gold standard recording method is a mercury sphygmomanometer. Automated BP measurement devices may be used, but should be calibrated regularly against a mercury sphygmomanometer to ensure reliable BP recordings.

Proteinuria in the context of hypertension in pregnancy is defined as urinary protein excretion ≥300 mg in 24 h, or a spot urine protein:creatinine ratio ≥30 mg/mmol, or, in the absence of laboratory services, persistent proteinuria ≥1+ (30 mg/dL) on urine reagent strips.

Classification

Pre-eclampsia is new-onset hypertension, with proteinuria or organ system dysfunction (Table 1), arising after 20 weeks of gestation. Severe pre-eclampsia is pre-eclampsia with BP ≥160/110 mmHg or organ system dysfunction (American College of Obstetricians and Gynecologists 2002). The term ‘mild pre-eclampsia’ is sometimes used to describe pre-eclampsia with BP <160/110 mmHg and no evidence of organ dysfunction (Koopmans et al. 2009).

Table 1

Definition of pre-eclampsia

Pre-eclampsia is new-onset hypertension (BP ≥140/90 mmHg) that arises after 20 weeks of gestation and is accompanied by at least one of the following (SOMANZ 2008):

Renal involvement

 Proteinuria

 Oliguria

 Serum creatinine ≥90 μmol/L

Haematological involvement

 Thrombocytopaenia

 Haemolysis

 Disseminated intravascular coagulation

Liver involvement

 Raised serum transaminases

Severe epigastric or right upper quadrant pain

Liver subcapsular haemorrhage or rupture

Neurological involvement

 Convulsions (eclampsia)

 Hyperreflexia with sustained clonus

 Visual disturbances

 Stroke

Cardiorespiratory involvement

 Pulmonary oedema

Uteroplacental involvement

 Fetal growth restriction

 Placental abruption

Gestational hypertension is new-onset hypertension arising after 20 weeks of gestation, with no evidence of proteinuria and no organ dysfunction. The ESC guidelines consider pre-eclampsia as a proteinuric or multisystem-involved subgroup of gestational hypertension (The Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC) 2011).

Pre-existing (chronic) hypertension is hypertension known to have been present before the pregnancy, or new-onset hypertension detected before 20 weeks of gestation. This may be essential hypertension (no known cause) or hypertension secondary to cardiovascular, renal or endocrine disorders. When pre-existing hypertension is associated with increasing blood pressure or proteinuria after 20 weeks, this is termed superimposed pre-eclampsia.

It may be difficult to classify women who present themselves with new-onset hypertension only after 20 weeks of gestation. Follow up at 3 months after delivery is then necessary to confirm or exclude pre-existing hypertension.

General Principles in Managing Hypertension in Pregnancy

Initial Assessment

On presentation of a pregnant woman with hypertension, the two essential elements of management are to: (1) treat any presenting emergency; and (2) classify the hypertensive disorder to plan ongoing management (Fig. 1).

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Figure  1

Initial assessment, classification and management of a woman presenting with hypertension in pregnancy. Women who cannot be classified because their blood pressure was not measured in the first half of pregnancy may be provisionally classified as pre-eclampsia or gestational hypertension, depending on the presence or absence of proteinuria and organ dysfunction. Such women should be followed up 3 months after delivery to determine if their hypertension is pre-existing or was pregnancy-related

Emergencies associated with hypertension in pregnancy include eclampsia, severe hypertension, stroke, hypovolaemia from placental abruption or liver rupture, and acute pulmonary oedema. These conditions need to be managed appropriately according to local guidelines.

Most women presenting with hypertension in pregnancy have no or minimal symptoms, their hypertension having been detected on routine BP measurement at prenatal clinics. History-taking should include previous medical history; previous hypertension; known cardiovascular, endocrine or kidney disease; course and outcome of previous pregnancies; family history of hypertension, kidney disease or thrombophilia; and symptoms associated with pre-eclampsia (Table 1). Physical examination, other than raised BP, may be entirely normal, but may detect clinical evidence of pre-existing hypertension. Oedema is a non-specific finding that is frequent in normal pregnancy, and, unless severe, should not be considered as evidence of pre-eclampsia (SOMANZ 2008; The Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC) 2011).

Special investigations that help in classifying hypertensive orders include urine reagent strip testing for protein, or, preferably, spot urine protein:creatinine ratio. Blood investigations include haemoglobin level, platelet count, and serum creatinine and aspartate transaminase (AST). In settings with limited laboratory services, these blood tests may be omitted if the woman feels well and has a BP <160/110 mmHg, with no proteinuria and no clinical evidence of pre-eclampsia (Table 1). Assessment of uteroplacental involvement includes ultrasound fetal biometry, amniotic fluid volume assessment and umbilical artery Doppler indices. In low-resource settings, ultrasound fetal assessment can be omitted if there is no evidence of pre-eclampsia, and if uterine fundal growth is clinically assessed as normal.

The management principles of specific hypertensive disorders are discussed below, based on clinical experience and on evidence-based recommendations suggested by the World Health Organization (WHO) (Table 2).

Table 2

World Health Organization recommendations for management of pre-eclampsia and eclampsia, with GRADE assessment of evidence and strength of recommendation (World Health Organization 2011)

Recommendation

Quality of evidence

Strength of recommendation

In women with mild pre-eclampsia or mild gestational hypertension at term, induction of labour is recommended

Moderate

Weak

Strict bed rest is not recommended for improving pregnancy outcomes in women with hypertension (with or without proteinuria)

Low

Weak

Women with severe hypertension in pregnancy should receive treatment with antihypertensive drugs

Very low

Strong

The choice of antihypertensive for severe hypertension in pregnancy should be based primarily on the clinician’s experience, considering also cost and local availability

Very low

Weak

In women with severe pre-eclampsia at term, early elective delivery is recommended

Low

Strong

In women with severe pre-eclampsia, a viable fetus and before 34 weeks of gestation, expectant management is recommended, provided that uncontrolled hypertension, worsening organ dysfunction and fetal distress are absent and can be monitored

Very low

Weak

In women with severe pre-eclampsia at 34–36 weeks of gestation, expectant management may be recommended, provided that uncontrolled hypertension, worsening organ dysfunction and fetal distress are absent and can be monitored

Very low

Weak

Elective termination of pregnancy is recommended for women with severe pre-eclampsia at a gestational age where the fetus is not viable or unlikely to achieve viability within 1–2 weeks

Very low

Strong

Magnesium sulphate is recommended for prevention of eclampsia in women with severe pre-eclampsia in preference to other anticonvulsants

High

Strong

Magnesium sulphate is recommended for treatment of women with eclampsia in preference to other anticonvulsants

Moderate

Strong

GRADE quality of evidence and recommendation definitions (Guyatt et al. 2008):

Quality of evidence:

High: further research is very unlikely to change confidence in the estimate of effect

Moderate: further research is likely to have an important effect on confidence in the estimate of effect and may change the estimate

Low: further research is very likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate

Very low: any estimate of effect is very uncertain

Recommendation:

Strong: desirable effects of an intervention clearly outweigh the undesirable effects, or clearly do not.

Weak: desirable and undesirable effects are closely balanced

Mild Pre-eclampsia

Women with mild pre-eclampsia are usually not at immediate risk for complications. However, remission will not occur while pregnancy continues, and deterioration is likely over subsequent days and weeks. Little is gained by continuation of pregnancy at term, and therefore elective delivery (usually labour induction) is recommended from 37 weeks of gestation (Koopmans et al. 2009). Women at less than 37 weeks are best observed in hospital, with regular monitoring of BP, twice-weekly blood tests for platelet count, creatinine and AST levels, and ultrasound fetal assessment every 2 weeks. Where home BP monitoring and urine testing is feasible, women may be assessed twice weekly as outpatients. There is uncertainty about the value of antihypertensive drug treatment for mild pre-eclampsia (Abalos et al. 2007) (discussed below). There is no evidence to support bed rest in the management of pre-eclampsia (Meher et al. 2005).

Severe Pre-eclampsia

The first priority in caring for pregnant women with severe pre-eclampsia is maternal stabilization, in particular lowering the BP to <160/110 mmHg. This is achieved with intravenous or short-acting oral antihypertensive drugs, followed by maintenance therapy with oral agents (discussed below). Magnesium sulphate is frequently given during stabilization, to prevent eclamptic convulsions (discussed below). For severe pre-eclampsia, hospital admission is mandatory, with close observation of maternal and fetal condition at referral level by obstetricians experienced in managing severe pre-eclampsia (Society for Maternal-Fetal Medicine and Sibai 2011). Severe pre-eclampsia places the woman and fetus at immediate threat of complications, and deterioration requiring delivery can be expected within 1–2 weeks. Once a woman is classified as having severe pre-eclampsia, she retains that classification until she delivers. Successful lowering of an elevated BP does not convert the woman to a mild category.

Early elective delivery is advised for pregnancies at term (≥37 weeks). At <37 weeks, an expectant approach is appropriate in the absence of complications. However, from 34 to 36 weeks, the risks of continuing pregnancy may be greater than the risks of prematurity for the newborn, hence the threshold for delivery is lower than at <34 weeks. If there are complications or organ system deterioration (persistent symptoms and signs, worsening kidney or liver function, eclampsia, pulmonary oedema, or deteriorating fetal condition), emergency delivery, often by caesarean section, is indicated, irrespective of gestational age (Society for Maternal-Fetal Medicine and Sibai 2011). With expectant management at <34 weeks, intramuscular betamethasone is given for 24 h before delivery to accelerate fetal lung maturity (Roberts and Dalziel 2006). In women with severe pre-eclampsia with a non-viable fetus (20–22 weeks, up to 26 weeks in low-resource settings), elective termination of pregnancy is advised in the maternal interest.

HELLP Syndrome

Women with severe pre-eclampsia who have thrombocytopaenia and a raised AST level, or who appear ill (nausea, vomiting, pallor) should be further tested for haemolysis (haptoglobin and serum lactate dehydrogenase levels, peripheral blood smear). Evidence of haemolysis suggests HELLP syndrome, a microangiopathic form of severe pre-eclampsia. In HELLP syndrome, delivery is indicated, irrespective of gestational age, as soon as maternal condition is stabilized (Society for Maternal-Fetal Medicine and Sibai 2011). However, the syndrome may continue to deteriorate in the first 2 days after delivery. A strong case has been made for intramuscular dexamethasone rescue treatment as specific treatment for HELLP syndrome (Martin 2013), despite findings of a Cochrane systematic review that suggested little beneficial effect (Woudstra et al. 2010).

Eclampsia

Eclamptic convulsions are generalized tonic-clonic seizures indistinguishable from epileptic convulsions. Other causes of convulsions should always be considered, especially if the seizures are atypical. Computerized tomography or magnetic resonance imaging scanning may be recommended to exclude other causes of convulsions, or to detect cerebral damage associated with eclampsia. Immediate care for eclampsia is left lateral positioning, and oxygen by mask. Intravenous magnesium sulphate is the treatment of choice to prevent further convulsions (discussed below). Full clinical, laboratory and ultrasound assessment for pre-eclampsia, and appropriate treatment of severe hypertension, are part of initial management of eclampsia. Pregnancy should not be allowed to continue (SOMANZ 2008), and delivery is indicated within about 12 h of the first convulsion, vaginally or by caesarean section, depending on obstetric considerations. Intensive care unit admission and/or artificial ventilation may be needed for women who do not regain consciousness rapidly after convulsions, or who have co-existent complications of severe pre-eclampsia.

Gestational Hypertension

Women with gestational hypertension have no abnormalities other than a raised BP. Some go on to develop pre-eclampsia. Weekly attendance as outpatients is recommended with BP measurement, urine testing for protein, and, if feasible, blood testing for platelet count, creatinine and AST. Four-weekly ultrasound fetal assessment may give some reassurance. As with mild pre-eclampsia, there is uncertainty about the place and value of antihypertensive drug treatment (Abalos et al. 2007). At ≥37 weeks of gestation, there is little benefit in continuing the pregnancy, and elective delivery is advised based on evidence from a large randomized trial (Koopmans et al. 2009).

Pre-existing Hypertension

Only limited investigations are possible in pregnancy for causes of pre-existing hypertension, and these should be based on clinical findings, focusing on renal, endocrine and cardiovascular causes. Where a secondary cause for hypertension is found, this may require expert medical management with appropriate specialists.

Women with uncomplicated essential hypertension are managed as for gestational hypertension, the most important concern being the development of superimposed pre-eclampsia. The physiological decrease in BP during the second trimester of pregnancy may allow antihypertensive drugs to be stopped, at least temporarily. However, in women with end-organ damage (heart, kidneys, optic fundi), antihypertensive treatment should be continued (Podymov and August 2011). For pre-existing hypertension, the recommended drugs are those used for mild hypertension in pregnancy (discussed below). Certain drugs may need to be discontinued and/or replaced. Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are contraindicated in pregnancy, having been implicated in fetal death and neonatal renal failure (Bullo et al. 2012). Selective beta-blockers such as atenolol may adversely affect fetal growth. Diuretics may interfere with physiological plasma volume expansion during pregnancy and should not be continued unless indicated for treatment of heart failure (SOMANZ 2008).

Pharmacological Management of Hypertension in Pregnancy

The choices for pharmacological treatment of hypertension in pregnancy are restricted to older, tried and tested drugs. Justifiable fears about adverse effects on the fetus have retarded research into the efficacy of newer drugs for hypertension in pregnancy, thus not allowing newer formulations into general use for these disorders.

Pharmacological management of hypertension in pregnancy is essentially the same irrespective of the classification of the hypertensive disorder, and is dictated by the level of the BP. It is recommended that individual clinicians or clinical units develop experience and expertise with a small range of the drugs that may be used, depending on cost and local availability (World Health Organization 2011). Information for discussion of the drugs below is sourced mainly from three authoritative reviews (Podymov and August 2011; Magee et al. 2011; SOMANZ 2008) and clinical experience.

Acute Blood Pressure Lowering for Severe Hypertension

A systolic BP ≥160 mmHg or diastolic BP ≥110 mmHg (severe hypertension) may overcome cerebral autoregulation and result in intracerebral haemorrhage or cerebral oedema. There is general agreement that severe hypertension needs urgent treatment. There is still some disagreement about the systolic BP cut-off level, with most guidelines favouring 160 mmHg, but at least one reputable guideline suggests 170 mmHg (SOMANZ 2008). The treatment goal is reduction in mean arterial pressure by <25 % over minutes to hours (Podymov and August 2011; Magee et al. 2011), with half-hourly monitoring of BP and heart rate. There are concerns that a rapid fall in BP might result in fetal distress, so a small preload of intravenous fluid, such as Ringer-Lactate 250 mL, may be given just before starting treatment (SOMANZ 2008). Fluid loading and plasma volume expansion are otherwise not recommended in managing pre-eclampsia, and excessive fluid loads may precipitate pulmonary oedema.

A Cochrane systematic review of randomized trials found little difference in effect between different drugs used for severe hypertension in pregnancy (Duley et al. 2006). Those most frequently compared were intravenous labetalol, oral nifedipine and intravenous hydralazine. The Cochrane reviewers recommended that choice of antihypertensive drugs should depend on local experience and familiarity with the different agents, but discouraged use of diazoxide, ketanserin, nimodipine and magnesium sulphate. A summary of drugs used in severe hypertension is given in Table 3.

Table 3

Drugs used for acute blood pressure lowering in severe hypertension (BP ≥160/110 mmHg) in pregnancy, in descending order of preference (SOMANZ 2008; Podymov and August 2011; Magee et al. 2011)

Drug

Dose and route

Onset of action

Labetalol

20 mg IV over 2 min, repeat if necessary every 30 min with 20–80 mg, to a maximum of 300 mg/day. An infusion regimen may also be used

5 min

Nifedipine

5–10 mg capsules orally swallowed, repeat if necessary every 30 min, with 10 mg, to a maximum of 120 mg/day

10–20 min

Hydralazine

5 mg IV, repeat if necessary every 30 min with 5–10 mg, with a maximum dose of 20 mg

20 min

Diazoxide

30–50 mg IV every 5–15 min

3–5 min

Sodium nitroprussidea

0.25–5 μg/kg/min IV infusion, titrated to blood pressure response

Near-immediate

IV intravenous

aSodium nitroprusside is a rarely used last-resort drug, with potential fetal toxicity, given in intensive care settings ideally after delivery of the infant

Labetalol

Labetalol is a non-selective beta-blocker with alpha-1 receptor blocker activity. There have been reports of neonatal bradycardia, but these effects did not have clinical consequences (Magee et al. 2011). Labetalol should not be used in women with asthma or with congestive cardiac failure.

Nifedipine

Nifedipine is the only calcium channel blocker for which there is extensive experience in treating severe hypertension in pregnancy. Short-acting oral nifedipine 5 or 10 mg capsules are given orally to be swallowed. Sublingual administration may cause hypotension. Side-effects of oral nifedipine include headache and tachycardia. The capsules cannot be used if the woman is unable to swallow, and are best avoided in the presence of tachycardia (≥120/min), coronary artery disease or fixed cardiac output valvular disease. Theoretical fears of serious interactions with magnesium sulphate have not been realised in practice, and the simultaneous use of the two agents, for example in eclampsia accompanied by severe hypertension, is acceptable. Nicardipine is a calcium channel blocker that may be given intravenously to control severe hypertension in pregnancy (Nij Bijvank and Duvekot 2010).

Hydralazine

Hydralazine is a direct vasodilator of arteriolar smooth muscle. Intravenous use has been associated with maternal hypotension and fetal distress. Side effects include tachycardia, headache, and nausea. As with nifedipine, hydralazine is best avoided in the presence of tachycardia (≥120/min) or fixed cardiac output valvular disease.

Other Drugs

Diazoxide is rarely used, and may cause a rapid drop in BP. Magnesium sulphate has little antihypertensive effect and should not be considered as an antihypertensive drug for pre-eclamptic women. Sodium nitroprusside is potentially valuable as a last resort treatment in an intensive care setting with intra-arterial BP monitoring. The main concern is fetal cyanide poisoning, and therefore, the drug should ideally only be used postpartum.

Treatment of Mild Hypertension, and Maintenance of Antihypertensive Effect

There is no certainty on the value of treating mild hypertension in pregnancy (140–159/90–109 mmHg). The WHO states explicitly in its guideline that no recommendation can be made, hence no statement appears in Table 2 (World Health Organization 2011). Importantly, antihypertensive treatment does not reduce progression to pre-eclampsia or severe pre-eclampsia. Theoretically, another benefit of treatment, besides BP reduction, could be vasodilatation with better organ system perfusion, and therefore prolongation of pregnancy. The harms of treatment may include reduction in uteroplacental blood flow, masking of progression of pre-eclampsia, and as yet unknown epigenetic effects on fetal programming that could increase risk of cardiovascular disease in later life (Magee et al. 2011). A frequent recommendation is that treatment should be considered in the higher range of 140–159/90–109 mmHg. For maintenance of antihypertensive effect in women who have been treated for severe hypertension, there is little doubt about the need for ongoing treatment. The drugs used are the same as those given for mild hypertension (Table 4).

Table 4

Orally administered drugs frequently used for treatment of mild hypertension (BP 140–159/90–109 mmHg) in pregnancy, or for maintenance of antihypertensive effect after acute blood pressure lowering for severe hypertension, in descending order of preference (SOMANZ 2008; Podymov and August 2011; Magee et al. 2011)

Drug

FDA category

Dosage

Methyldopa

B

0.5–3.0 g/day in 2–4 divided doses. There is no evidence to support use of a loading dose.

Labetalol

C

200–1,200 mg/day in 2–3 divided doses

Nifedipine slow release

C

30–120 mg/day as a once-daily dose

Hydralazine

C

50–300 mg/day in 2–4 divided doses

United States of America Food and Drug Administration (FDAdrugs in pregnancy categories:

Category Aadequate and well-controlled studies have failed to show risk to the fetus in pregnancy.

Category Banimal studies have failed to show risk to the fetus but there are no adequate and well-controlled studies in humans.

Category Canimal studies have shown risk to the fetus, and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Category D: there is evidence of human fetal risk based on data from research or clinical experience, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Category X: studies in animals or humans have shown fetal abnormalities and/or there is evidence of human fetal risk based on research or clinical experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

Methyldopa

Methyldopa is a centrally acting alpha-2 adrenergic agonist prodrug that is converted to alpha-methylepinephrine, which replaces norepinephrine in adrenergic nerve terminals. Extensive experience and safety data exist for methyldopa used in pregnancy, including follow-up of children exposed during fetal life. Side-effects include depression, fatigue, dry mouth, and, rarely, haemolytic anaemia and hepatitis. Methyldopa is considered the first-line drug of choice by most authorities.

Beta-Blockers

The most commonly used beta-blocker is labetalol, backed up by extensive experience with the drug in pregnancy with a good safety record. There are still concerns about effects on uteroplacental flow and fetal growth. Side-effects include exercise intolerance, sleep disturbances and bronchoconstriction. The selective beta-blocker atenolol has been implicated in fetal growth restriction and is best avoided in pregnancy.

Calcium Channel Blockers

Slow-release nifedipine is the most favoured of the calcium channel blockers for treatment of mild hypertension. Other calcium channel blockers, for example amlodipine, have been used with safety and success, but have not matched the extensive experience gained with nifedipine used in pregnancy. Nifedipine is often used as a second-line drug ahead of labetalol. Side-effects include headache, tachycardia, palpitations and oedema.

Hydralazine

Oral hydralazine has a long history of use in pregnancy. It is now used mainly as a fourth-line agent in refractory cases of hypertension, owing to side-effects such as headache, nausea and palpitations, which may mimic symptoms of pre-eclampsia. Long-term use has rarely been associated with a polyneuropathy, and a lupus-like syndrome. Neonatal thrombocytopaenia and lupus have also been reported.

Other Drugs

Few other drugs are recommended. Prazosin and clonidine may occasionally be used. Thiazide diuretics are generally discouraged. ACE inhibitors and ARBs are implicated in cardiovascular teratogenesis if used in the first trimester, and in fetal death and neonatal renal failure if used later in pregnancy (Bullo et al. 2012), and are contraindicated in pregnancy.

Prevention and Treatment of Eclampsia

Magnesium sulphate is superior to other anticonvulsants (phenytoin and diazepam) for treatment and prevention of eclamptic convulsions. (The Collaborative Eclampsia Trial Group 1995). The exact mechanism of action of magnesium sulphate in eclamptic seizures in poorly understood, but could be related to cerebral vasodilatation, N-methyl-D-aspartate receptor antagonism, or calcium antagonism (James 2010).

Magnesium sulphate is given as an intravenous loading dose of 4 g in 200 mL saline, followed by an intravenous infusion at 1 g/h for up to 24 h after delivery, or for 24 h after the convulsion if the convulsion occurred postpartum. Where convulsions persist after magnesium loading, an additional dose of magnesium sulphate 2 g may be given intravenously, with clonazepam 1 mg over 5 min intravenously if necessary. In low-resource settings with limited monitoring capacity, intramuscular magnesium sulphate can be used with equivalent effect. A loading dose of 4 g IV is given as above, with 5 g intramuscularly in each buttock (total 14 g). This is followed by 4 hourly injections of 5 g into alternate buttocks for a total of 24 h after delivery or after the last postpartum convulsion.

Magnesium sulphate causes neuromuscular depression, and toxic levels may suppress respiration. While monitoring with magnesium levels is not necessary with the suggested dosage, hourly observation of respiratory rate and deep tendon reflexes is advised. Magnesium is only eliminated in the urine, so urine output must be monitored hourly using an indwelling urinary catheter, and magnesium sulphate infusion should be stopped with output <25 mL/h or <100 mL/4 h. If magnesium toxicity is suspected, airway management and ventilation may be required, with monitoring of serum magnesium levels. The antidote for magnesium toxicity is calcium gluconate 1 g given intravenously, repeated if necessary.

For prevention of eclampsia in women with severe pre-eclampsia, or with symptoms suggesting imminent convulsions (headache, visual disturbances, epigastric pain), magnesium sulphate has been shown to be effective in reducing the risk of convulsions, compared with placebo (Duley et al. 2010). Magnesium used for this indication is given in the same dosage as used for eclampsia, but need not be used for a full 24 h.

Antihypertensive Treatment After Delivery and During Breastfeeding

Pre-eclampsia and gestational hypertension do not remit immediately after delivery. It is therefore prudent to continue with antenatally prescribed antihypertensive medication during the early postpartum period. Medication may be adjusted if clinically indicated, for example if methyldopa is poorly tolerated. Pre-pregnancy medications that were discontinued during pregnancy may be restarted in women with pre-existing hypertension. Severe hypertension is treated as described above, although fetal considerations do not apply. Women may be discharged from hospital once the BP has settled at below 160/110 mmHg, with outpatient follow-up until the BP is normal. Hypertension that has not remitted by 3 months postpartum is likely to have been pre-existing and may require investigation.

There are theoretical and real concerns about antihypertensive drugs given during breastfeeding. The beta-blockers atenolol and acebutolol are concentrated in breastmilk and have been reported to cause neonatal hypotension, bradycardia and cyanosis (Beardmore et al. 2002). Other beta-blockers given to the mother, such as labetalol and propranolol, appear to be safe for the nursing infant. Diuretics reduce circulating blood volume and could reduce breastmilk volume, although there are insufficient data to support this contention. ACE inhibitor drugs are found in breastmilk in small quantities, but the American Academy of Paediatrics has passed captopril, enalapril and quinapril as safe during breastfeeding (American Academy of Pediatrics Committee on 2001). Caution is advised with prescribing these drugs in the 1st week or 2 after delivery, and for women who are breastfeeding preterm infants. ARBs should not be given to breastfeeding women, as there are insufficient data on safety. The other commonly used antihypertensive drugs (methyldopa, calcium channel blockers and hydralazine) appear to be safe (American Academy of Pediatrics Committee on 2001).

Future Therapeutic Possibilities for Pre-eclampsia

Recent advances in the understanding of the pathogenesis of pre-eclampsia have exposed new targets for therapeutic interventions to prevent or treat the syndrome. One such possibility is treatment with recombinant vascular endothelial growth factor, which has shown promise in a rat model (Young et al. 2010). A more realistic and exciting option is treatment with statins. The so-called pleiotropic effects of statins include positive effects on haemoxygenase-1, nitric oxide and angiogenic factors, as well as antioxidant activity. These effects target critical pathways in the pathogenesis of pre-eclampsia (Lecarpentier et al. 2012). Statins have so far been contraindicated in pregnancy for fear of teratogenesis, but the first trial is now underway (the StAmP trial – Statins for the Amelioration of Pre-eclampsia) in the United Kingdom. In a double-blind placebo-controlled randomised trial, pravastatin is being given to women with early-onset pre-eclampsia. Obstetricians should eagerly await the results (Ahmed 2011).

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