Hypertension in pregnancy

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Chapter 45 Hypertension in pregnancy

Nikki Whelan

Cardiovascular changes in pregnancy

There are significant physiological adaptations of the cardiovascular system to pregnancy. Blood volume rises from an average non-pregnant 2600 mL to 3800 mL at about 32 weeks gestation. The total red cell volume grows constantly until term from 1400 mL to 1700 mL, so there is a fall in haemoglobin concentration as gestation progresses. Cardiac output rises from 5 L/minute to 7.5 L/minute, mostly during the first trimester, and the heart rate rises by 10% with an average resting rate of 88 beats/minute. The peripheral resistance is lowered by a combination of increased vasodilatory substances during pregnancy and decreased sensitivity to vasopressor substances.

Blood pressure falls in the first trimester and is at its lowest in the second trimester. The reduction in diastolic blood pressure is about 10 mmHg by mid-pregnancy. Blood pressure rises to non-pregnant levels towards the end of the third trimester.

Uterine blood flow increases steeply from 24 weeks gestation.

Other factors affecting blood pressure in pregnancy include posture (via the supine hypotension syndrome) and uterine contractions, which raise blood pressure.

Definitions. Hypertension in pregnancy is defined as:

• systolic blood pressure ≥140 mmHg, and/or
• diastolic blood pressure ≥90 mmHg (Korotkoff 5)

These measurements should be confirmed by repeated readings over several hours. Elevations of both systolic and diastolic blood pressure have both been associated with adverse fetal outcome and therefore both are important.

Severe hypertension in pregnancy is defined as:

• a systolic blood pressure ≥170 mmHg, and/or
• diastolic blood pressure ≥110 mmHg

This represents a level of blood pressure above which cerebral autoregulation is overcome in normotensive individuals. It is generally acknowledged that severe hypertension should be lowered promptly, albeit carefully, to avoid cerebral haemorrhage and hypertensive encephalopathy.

Classification

Classifications of hypertensive disorders in pregnancy are:

• pre-eclampsia/eclampsia
• gestational hypertension
• chronic hypertension

• essential
• secondary
• white coat

• pre-eclampsia superimposed on chronic hypertension

Pre-eclampsia

Incidence. While 20% of women are hypertensive at some stage of their pregnancy (blood pressure ≥140/90 mmHg), about 5%–10% of primigravid women and 2% of multiparous women fulfil a diagnosis of pre-eclampsia.

Definition. Pre-eclampsia is a multisystem disorder unique to human pregnancy, characterised by hypertension and involvement of one or more other organ systems and/or the fetus. Proteinuria is the most commonly recognised additional feature after hypertension, but should not be considered mandatory to make the diagnosis.

A diagnosis of pre-eclampsia can be made when hypertension arises after 20 weeks gestation and is accompanied by one or more of the following:

• renal involvement

• significant proteinuria: dipstick proteinuria, subsequently confirmed by spot urine protein/creatinine ratio ≥30 mg/mmol
• serum or plasma creatinine >90 μmol/L
• oliguria

• haematological involvement

• thrombocytopaenia
• haemolysis
• disseminated intravascular coagulation

• liver involvement

• raised serum transaminases
• severe epigastric or right upper quadrant pain

• neurological involvement

• convulsions (eclampsia)
• hyperreflexia with sustained clonus
• severe headache
• persistent visual disturbances (photopsia, scotomata, cortical blindness, retinal vasospasm)
• stroke

• pulmonary oedema
• intrauterine growth restriction
• placental abruption

Pathophysiology

Two placental conditions predispose to the development of pre-eclampsia. Ischaemia results from the failure of the normal development of the uteroplacental circulation with the presence of small defective spiral arteries, which then may become blocked by acute atherosis or thrombosis. Excessive placental size also predisposes to pre-eclampsia, as seen in multiple pregnancy, hydatidiform mole, fetal triploidy and placental hydrops.

Maternal contribution to pre-eclampsia occurs when endothelial activation results in acceleration of the normal systemic inflammatory response, which is present in all pregnancies. Activation of leucocytes and the coagulation process, and subsequent metabolic changes, result in the clinical features which are typically seen in pre-eclampsia: hypertension, oedema, proteinuria, platelet dysfunction, clotting derangements and possibly eclampsia.

The specific placental factor or factors that generate the systemic inflammatory response of pre-eclampsia remain unknown, but recent research has highlighted the contribution of three circulating placental products: soluble fms-like tyrosine kinase 1 (sFlt-1), endoglin and placental growth factor.

Placentation also depends on the invasion of the placental bed by cytotrophoblasts. Immune tolerance must occur in this setting to allow a continued relationship between the mother and the fetus.

Hence, at least four factors are likely to contribute to the development of pre-eclampsia: placental, endothelial, inflammatory and immunological.

Risk factors associated with pre-eclampsia

Risk factors are listed in Table 45.1. Other factors associated with pre-eclampsia include chronic hypertension, preexisting renal disease, autoimmune disease, more than 10 years since a previous pregnancy, a short sexual relationship prior to conception, and other thrombophilias (e.g. Factor V Leiden and possibly periodontal disease).

Table 45.1 Pre-eclampsia risk factors

Risk factor Relative risk
Previous history of pre-eclampsia 7.19
Antiphospholipid antibodies 9.72
Preexisting diabetes 3.56
Multiple pregnancy 2.91
Nulliparity 2.90
Family history of pre-eclampsia 2.90
Elevated body mass index (BMI) >25 2.47
Maternal age >40 1.96
Diastolic blood pressure >80 mmHg at first antenatal visit 1.38

Recurrence risk

Studies of the risk of recurrent pre-eclampsia in women with a history of a hypertensive disorder in a prior pregnancy show variable results. Recurrence rates vary from 6%–55%, with the greatest risk in women with early-onset pre-eclampsia and chronic hypertension. An Australian study suggests a 14% risk of developing pre-eclampsia, and also a 14% risk of developing gestational hypertension in their next pregnancy.

Clinical spectrum

Pre-eclampsia is a multisystem disorder with both maternal and fetal consequences.

Hypertension

Hypertension may be labile, often with flattened or the reverse of normal diurnal rhythm. This is thought to be due to decreased responsiveness to angiotensin II. Many of the complications of pre-eclampsia are due to arterial damage and loss of vascular autoregulation.

Renal system

Glomerular swelling of endothelial cells and intracapillary cells known as endotheliosis is the main response to pre-eclampsia. This causes a reduced glomerular filtration rate, which slows urate clearance and raises serum creatinine levels. In uncomplicated pregnancy, glomerular filtration normally increases. A serum creatinine level of 0.09 μmol/L in pregnancy may predict renal involvement.

Proteinuria is often a late sign of pre-eclampsia and indicates poorer prognosis for the mother and fetus.

The commonest cause of nephrotic syndrome in pregnancy is pre-eclampsia. There is a reduced maternal plasma volume due to increased leakiness of capillaries, and hypoalbuminaemia predisposing to reduction in colloid oncotic pressure and raised fluid in interstitial spaces. The complications of fluid changes include pulmonary and laryngeal oedema, and acute renal failure.

Platelets

The reduction of platelets in pre-eclampsia is due to increased consumption and lowered platelet lifespan. However, this is an inconsistent feature of pre-eclampsia.

Coagulation

There is increased factor VIII consumption in early pre-eclampsia, and anti-thrombin III is lowered. Disseminated intravascular coagulation is a late and inconsistent feature of pre-eclampsia. The complications of coagulation/clotting changes include disseminated intravascular coagulation with widespread fibrin deposition, haemorrhage and necrosis.

Hepatic changes

• Liver dysfunction with elevated hepatic enzymes is often evident. Raised alkaline phosphatase is normal, due to the placental production, although raised transaminase levels reflect hepatic ischaemia of pre-eclampsia.
• Epigastric pain from the rare complication of subcapsular haematoma has associated mortality.
• The syndrome of haemolysis, elevated liver enzymes and low platelets is associated with microangiopathic haemolysis and is a variant of severe pre-eclampsia.

Central nervous system involvement

• Eclampsia has an incidence of <0.1%, with 50% occurring before labour. Most postpartum fits occur within 24 hours of delivery. Proteinuria increases the risk by seven to eight times.
• Hypertensive encephalopathy may be acute or subacute, with diffuse cerebral dysfunction, which improves with the lowering of blood pressure. The clinical presentation includes headache, nausea, vomiting and convulsions.
• Stroke in pre-eclampsia and or eclampsia is usually preceded by severe hypertension. In women who had experienced a stroke, 96% had a systolic blood pressure >160 mmHg, 21% had a diastolic blood pressure >105 mmHg and 13% had a diastolic blood pressure >110 mmHg; mean arterial pressure was >125 mmHg in 46% and >130 mmHg in 21% of women who had experienced a stroke.
• Only 11% women who experienced a stroke had a complete recovery without significant morbidity.
• Visual disturbance with cortical blindness occurs in 1%–3% of eclamptics and recovers with reduction in blood pressure.
• The cerebral pathology of eclampsia resembles hypertensive encephalopathy, with evidence of thrombosis, fibrinoid necrosis and microinfarction.
• Cerebral autoregulation is altered in hypertensive pregnant women, making them more sensitive to severe changes in blood pressure. Acute arterial hypertension can lead to damage to the blood–brain barrier with extravasation of fluid into the parenchyma resulting in cerebral haemorrhage and infarction. A mean arterial pressure of 140 mmHg (blood pressure 180/120) is an obstetric emergency and requires immediate treatment.

Placental and fetal involvement

Abnormal placentation reduces uteroplacental blood flow by changing the uteroplacental circulation from a low-resistance system to one of high resistance and underperfusion. The complications of this to fetuses are intrauterine growth restriction, death and complications of prematurity, when delivery is indicated.

Management of pre-eclampsia

Pre-eclampsia is a progressive disease that will inevitably worsen if pregnancy continues. Current therapy does not ameliorate the placental pathology, nor alter the pathophsiology or natural history of pre-eclampsia. Delivery is the definitive management and is followed by resolution, generally over a few days but sometimes over a much longer course. At a mature gestational age, delivery should not be delayed.

Prevention

• Prophylactic therapy with aspirin is associated with a reduction in the recurrence rate of pre-eclampsia, delivery prior to 34 weeks gestation, preterm birth and perinatal death. Risk reduction is greatest if therapy is commenced prior to 20 weeks gestation and if doses >75 mg are taken.
• The use of calcium supplementation has been demonstrated to reduce the risk of pre-eclampsia, especially in women with a low calcium intake. Calcium supplementation (1.5 g/day) should be offered to women at increased risk of pre-eclampsia, particularly those with a low dietary calcium intake.
• Randomised trials of antioxidants vitamins C and E have failed to show any significant benefit, and there was an increased risk of stillbirth and birthweight <2.5 kg in the treatment arm of the study. Hence, prophylactic treatment with vitamins C and E is not recommended.
• Heparin with and without aspirin has not been assessed using large randomised trials. At present, therefore, there is no evidence for this treatment in the absence of a thrombophilia or antiphosphlipid antibody syndrome.
• Observational studies have suggested that multivitamin supplementation containing folic acid may reduce the risk of pre-eclampsia, perhaps by improving placental and systemic endothelial function or by lowering blood homocysteine levels.
• Preconception counselling should be offered to all women at increased risk of pre-eclampsia, and particularly to women with preexisting disorders that may need to be stabilised prior to pregnancy.

Investigations

• initial assessment may be in a day assessment unit, unless severe hypertension, headache, epigastric pain or nausea and vomiting are present, which necessitate urgent admission
• urine dipstick testing for proteinuria, with spot protein/creatinine ratio if >1+ (30 mg/dL)
• full blood count
• urea, creatinine, electrolytes
• liver function tests
• ultrasound assessment of fetal growth, amniotic fluid volume and umbilical blood flow

Additional investigations that may be useful in certain women include urine microscopy on a mid-stream specimen, coagulation studies, blood film, lactate dehydrogenase, fibrinogen, investigations for underlying systemic lupus erythematosus, renal disease, antiphospholipid syndrome, thrombophilias, fasting plasma free metanephrines/normetanephrines and 24-hour urinary catecholamines.

Indications for delivery in pre-eclampsia or gestational hypertension

For indications for delivery in pre-eclampsia or gestational hypertension, see Table 45.2.

Table 45.2 Indications for delivery in pre-eclampsia or gestational hypertension

Maternal Fetal
Gestational age >37 weeks Severe intrauterine growth restriction
Inability to control hypertension Non-reassuring fetal status
Deteriorating platelet count  
Deteriorating liver function tests  
Deteriorating renal function tests  
Placental abruption  
Persistent neurological symptoms  
Eclampsia  
Persistent epigastric pain, nausea or vomiting with abnormal liver function tests  
Acute pulmonary oedema  

Antihypertensive therapy

Severe hypertension

Antihypertensive treatment (see Table 45.3) should be started in all women with a systolic blood pressure >170 mmHg or a diastolic blood pressure >110 mmHg because of the risk of intracerebral haemorrhage and eclampsia. A Cochrane review has concluded that there is no good evidence to support the use of any short-acting agent over any other and practice should therefore be guided by local experience and familiarity.

Table 45.3 Antihypertensive agents for treatment of severe hypertension

image

Mild to moderate hypertension

There is controversy regarding the treatment of mild to moderate hypertension in women with pre-eclampsia. No controlled trial to date exists. However, a small placebo-controlled study looked at treating women with mild hypertension. Placebo-treated women were delivered significantly earlier, mainly as a result of severe hypertension or premonitory signs of eclampsia, and there was more neonatal morbidity secondary to prematurity.

In the absence of compelling evidence, treatment of mild to moderate hypertension in the range 140–160/90–100 mmHg should be considered an option and will reflect local practice (see Table 45.4). Above these levels, treatment should be considered mandatory.

• First-line drugs include methyldopa, labetalol and oxprenolol.
• Second-line drugs are hydralazine, nifedipine and prazosin.
• Angiotensin-converting enzyme (ACE) and angiotensin receptor blockers are contraindicated.
• All first-line and second-line drugs, plus enalapril, captopril and quinapril, are compatible with breastfeeding.

Table 45.4 Oral antihypertensives for moderate hypertension

image

Intravenous fluids

Although maternal plasma volume is often reduced in women with pre-eclampsia, there is no maternal or fetal benefit to maintenance fluid therapy. As vascular permeability is increased in women with pre-eclampsia, administration of large volumes of intravenous fluids may cause pulmonary oedema and worsen peripheral oedema.

Management of eclampsia

The drug of choice for the prevention of eclampsia is magnesium sulfate. However, the case for its routine use in women with pre-eclampsia in countries with low maternal and perinatal mortality rates is controversial and is perhaps best determined by individual units monitoring their outcomes. In some units, the presence of severe headache, hyperreflexia with clonus, epigastric pain or severe hypertension are considered indications for prophylaxis.

Trial data suggest the use of magnesium does not appear to affect rates of caesarian section, infectious morbidity, haemorrhage or neonatal depression, nor the duration of labour (although necessitated higher doses of oxytocin).

Resuscitation

• Usually self-limiting. Intravenous diazepam (2 mg/minute to maximum of 10 mg) or clonazepam (1–2 mg over 2–5 minutes) can be used while MgSO4 is being prepared.
• Magnesium sulfate. The possible mechanisms of action include cerebral vasodilatation, thereby decreasing cerebral ischaemia or perhaps blocking neuronal damage associated with ischaemia. It prevents but does not terminate seizures. The dose includes an intravenous loading dose of 4 g over 10–15 minutes followed by an infusion of 1–2 g/hour for 24 hours. Side effects are hypocalcaemia, hyporeflexia and cardiac arrest. The Eclampsia Trial Collaborative Group found magnesium sulfate to be superior to phenytoin or diazepam in decreasing recurrent seizures, maternal mortality and intensive care admission.

Control hypertension

Stabilise blood pressure (see above).

Delivery

In the presence of eclampsia, there is no role for continuation of the pregnancy once the woman is stable.

When delivery is indicated, the mode of delivery depends on favourability of the cervix, the speed required for delivery and the fetal condition. In many cases, induction of labour and vaginal delivery is appropriate. In severe pre-eclampsia, prophylactic antihypertensive and anticonvulsant therapy are continued. Lumbar epidural is favoured for analgesia due to its ability to lower blood pressure and possibly increase uterine blood flow. Caution with epidural with strict investigation of platelet levels, coagulation profile and clotting times is important to avoid complications of bleeding and spinal haematoma. The use of general anaesthesia for caesarean section is associated with a marked hypertensive response to laryngoscopy and intubation.

Oxytocin in doses over 2 milliunit/minute intravenously acts as an antidiuretic and, although it is not contraindicated in severe pre-eclampsia, strict fluid balance must be adhered to.

Fetal wellbeing is monitored by continuous cardiotocography. The maternal pushing in the second stage should be shortened.

The use of ergometrine in the third stage is contraindicated, and the immediate postpartum period requires intensive monitoring of blood pressure, renal function and fluid balance.

Chronic hypertension in pregnancy

This is a major predisposing factor to pre-eclampsia, although alone it may not be associated with the maternal and fetal risks of pre-eclampsia. If superimposed on chronic hypertension, pre-eclampsia tends to recur in subsequent pregnancies, and it is therefore often difficult to differentiate between the two. A diagnostic guide includes decreasing platelet count, serum urate level (<0.30 mmol/L is unlikely to be pre-eclampsia), a 24-hour urinary protein concentration (except if hypertension is due to chronic renal failure) and liver biochemistry.

Management

• Cease therapy if hypertension is mild to moderate before pregnancy.
• Use a first-line drug where possible for controlling the hypertension.
• Watch closely for the development of pre-eclampsia, using the tests described above.
• Fetal monitoring should include an early dating ultrasound scan and 4-weekly growth scans in the third trimester, tracking growth, liquor volume and umbilical artery blood flow.
• Manage jointly with obstetric physicians.

Unusual causes of hypertension in pregnancy

Phaeochromocytoma

This is a tumour of the adrenal medulla associated with significant maternal and fetal mortality.

• Clinical presentation: sustained or paroxysmal hypertension; the patient complains of headache, palpitation, sweating, chest and abdominal pain, and visual symptoms.
• It may be familial or associated with other syndromes, such as multiple endocrine neoplasias, neurofibromatosis and thyrotoxicosis.
• Diagnosis: involves 24-hour urinary assessment for metanephrines, creatinine, vanillylmandelic acid and catecholamines. Diagnostic imaging using magnetic resonance and computed tomography are safe in pregnancy. Ultrasound is often inadequate to assess the adrenals. If phaeochromocytoma is diagnosed, examine for multiple endocrine neoplasia.
• Management: use alpha-blockers, and then beta-blockers. Surgery can remove the tumour, but there may be difficulties with the large uterus.

Coarctation of aorta

Cushing’s syndrome

• rare in pregnancy
• clinical presentation: hypertension, pigmentation, striae, hyperglycaemia
• investigations: dexamethasone suppression test, computed tomography scan of the pituitary and adrenals

Conn’s syndrome

• rare in pregnancy
• clinical presentation: hypokalaemia and hypertension (possibility of remission in pregnancy may be due to the antagonism of the action of aldosterone by progesterone)

Renal artery stenosis

Autoimmune connective tissue disorders

Women with systemic lupus erythematosus may present with hypertension, renal complications or superimposed pre-eclampsia.

Long-term consequences

Women who have been diagnosed with either pre-eclampsia or gestational hypertension are at an increased risk of subsequent cardiovascular morbidity, including hypertension and coronary heart disease. Recent studies suggest the relative risks for hypertension were 3.7 after 14 years follow-up, for ischaemic heart disease 2.16 after 12 years, for stroke 1.81 after 10 years, and for venous thromboembolism 1.87 after 5 years. Overall mortality after pre-eclampsia was increased 1.5-fold after 14 years.

It is recommended all women with hypertensive disease in pregnancy have an annual review for blood pressure and other cardiovascular risk factors.

Further reading

Askie L.M., Duley L., Henderson-Smart D.J., Stewart L.A. PARIS Collaborative Group. Antiplatelet agents for the prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007;369(9575):1791-1798.

Australasian Society for the Study of Hypertension in Pregnancy. Management of hypertension in pregnancy: executive summary. Medical Journal of Australia. 1993;158:700-702.

Brown M. Pre-eclampsia: a lifelong disorder. Medical Journal of Australia. 2003;179:182-184.

CLASP Collaborative Group. CLASP: a randomised trial of low dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet. 1994;343:619-629.

Eclampsia Trial Collaborative Group. Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial. Lancet. 1995;345:1455-1463.

Khong T.Y., Mott C. Immunohistologic demonstration of endothelial disruption in acute atherosis in pre-eclampsia. European Journal of Obstetrics and Gynecology and Reproductive Biology. 1993;51:193-197.

Levine R.J., Maynard S.E., Qian C., et al. Circulating angiogenic factors and the risk of preeclampsia. New England Journal of Medicine. 2004;350:672-683.

Magpie Collaborative Group. Do women with pre-eclampsia and their babies benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet. 2002;359:1877-1890.

Maynard S.E., Min J.Y., Merchan J., et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. Journal of Clinical Investigation. 2003;111:649-658.

Redman C.W.G. The placenta and preeclampsia. Placenta. 1991;2:301-308.

Redman C.W.G., Sacks G.P., Sargent I.L. Preeclampsia: an excessive maternal inflammatory response to pregnancy. American Journal of Obstetrics and Gynecology. 1999;180:499-506.

Roberts J.M., Redman C.W.G. Pre-eclampsia: more than pregnancy-induced hypertension. Lancet. 1993;341:1447-1451.

Scott J.S. Pregnancy toxaemia associated with hydrops foetalis, hydatidiform mole and hydramnios. Journal of Obstetrics and Gynaecology of the British Empire. 1958;65:689-701.

SOMANZ Society of Obstetric Medicine of Australia and New Zealand. Guidelines for the management of hypertensive disorders of pregnancy. www.somanz.org, 2008. Available at:

Therapeutic Guidelines. Therapeutic guidelines: cardiovascular 2008. In Version 5. Melbourne: Therapeutic Guidelines; 2008.

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