Accepted Manuscript Review article Echocardiographic differences between preeclampsia and peripartum cardiomyopathy A.T. Dennis, J.M. Castro PII: DOI: Reference:
S0959-289X(14)00075-2 http://dx.doi.org/10.1016/j.ijoa.2014.05.002 YIJOA 2293
To appear in:
International Journal of Obstetric Anesthesia
Accepted Date:
16 May 2014
Please cite this article as: Dennis, A.T., Castro, J.M., Echocardiographic differences between preeclampsia and peripartum cardiomyopathy, International Journal of Obstetric Anesthesia (2014), doi: http://dx.doi.org/10.1016/ j.ijoa.2014.05.002
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IJOA 14-00053
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REVIEW
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Echocardiographic differences between preeclampsia and peripartum cardiomyopathy
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A.T. Dennis,a J. M. Castrob
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a
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Department of Pharmacology and Department of Obstetrics and Gynaecology, University of
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Melbourne, Parkville, Victoria, Australia
8
b
Department of Anaesthesia, The Royal Women’s Hospital, Parkville, Victoria, Australia;
Department of Cardiology, St Vincent’s Hospital, Fitzroy, Australia
9 10
Short title: Ecchocardiography in preeclampsia and peripartum cardiomyopathy
11 12
Correspondence to: Associate Professor Alicia T Dennis, Department of Anaesthesia ,The Royal
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Women’s Hospital, Corner Flemington Road and Grattan Street, Parkville, Australia 3052
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E-mail address: [email protected]
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1
16 17
ABSTRACT
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Peripartum heart failure due to preeclampsia or peripartum cardiomyopathy represents a
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significant global health issue. Transthoracic echocardiography enables differentiation of heart
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failure with preserved ejection fraction, commonly observed in women with preeclampsia, from
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that with peripartum cardiomyopathy in which a reduced ejection fraction is more common. An
22
understanding of the different definitions and diagnostic features of these two diseases, as well as
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accurate characterisation of the haemodynamics in preeclampsia and peripartum
24
cardiomyopathy, allows clinicians to manage these conditions appropriately. This article outlines
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the echocardiographic differences between preeclampsia and peripartum cardiomyopathy, the
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likely mechanisms for heart failure in preeclampsia and the relevance of these differences to
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clinicians in relation to prevention and treatment. It also emphasises the importance of disease
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definitions as a key framework for the more consistent classification of the two diseases.
29 30
Introduction
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Heart disease in pregnant women is the leading cause of maternal mortality in many developed
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countries.1-5 Heart failure caused by pre-existing or newly acquired cardiac disease during
33
pregnancy may present acutely and it is important for anaesthetists to be able to diagnose and
34
manage heart failure in pregnancy within the context of a multidisciplinary team.
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The major contributing pathologies include peripartum cardiomyopathy, preeclampsia,
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valvular heart disease, particularly mitral stenosis, and congenital heart disease. Of these, heart
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failure related to peripartum cardiomyopathy and to preeclampsia present specific diagnostic and
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clinical challenges and echocardiography can be used to differenciate these two conditions.
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In peripartum cardiomyopathy, symptoms and signs of impending heart failure are often
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missed or misinterpreted as part of the spectrum of normal pregnancy symptoms. In
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preeclampsia when heart failure does occur and is recognised, it is sometimes incorrectly
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classified as peripartum cardiomyopathy.6 These omissions and misunderstandings are important
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to acknowledge because failure to diagnose heart failure in pregnant women, failure to obtain
44
appropriate investigations including echocardiography, and failure to manage heart failure
45
appropritately in pregnant women contribute to mortality.1 In women with preeclampsia 50% of
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the deaths are considered preventable.7 2
47 48
Heart failure
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Heart failure is a diverse clinical entity resulting from abnormalities of both heart structure and
50
function. Clinically, adults with heart failure present with breathlessness and fatigue due to an
51
imbalance between oxygen supply and demand throughout the body. Fluid retention is present to
52
varying degrees.8 There is not a single diagnostic test for heart failure and diagnosis depends on
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accurate history and physical examination coupled with appropriate diagnostic tests of which
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echocardiography plays a central role.
55
Heart failure is commonly categorised into two groups. One group, heart failure with
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reduced ejection fraction, presents with an ejection fraction usually ≤40%.8 It is frequently
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associated with a dilated ventricle characterised by an increased left ventricular end-diastolic
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diameter.8 The other group, heart failure with preserved ejection fraction, presents with a normal
59
ejection fraction, usually between 40-55%.8
60
Reduced ejection fraction heart failure is due to ‘pump failure’ with decreased forward
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flow, increased back pressure to the lungs, activation of the renin-angiotensin system and fluid
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retention. Preserved ejection fraction heart failure is due to diastolic dysfunction, a ‘stiff heart’
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with ‘increased back pressure’ to the lungs that causes pulmonary oedema. A commonly known
64
form is due to hypertensive heart disease of the elderly where left ventricular hypertrophy is
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associated with diastolic dysfunction, but normal systolic function.9 In the non-pregnant
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population, hypertension is a recognised cause of both heart failure with preserved ejection
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fraction and heart failure with reduced ejection fraction.8 Malignant hypertension and acute
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hypertensive heart failure are also life-threatening complications of endocrine and vascular
69
diseases as well as after administration of large doses of vasoactive pharmacological agents.10
70 71
Transthoracic echocardiography
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Transthoracic echocardiography (TTE) is central to diagnosing and managing heart failure 11
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Advances in TTE machine portability and image quality, as well as increased awareness of its
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utility and accuracy in pregnant women,11 mean that TTE is used more commonly in pregnant
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women in the clinical and research setting.11 Structural and functional information in real time
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can be obtained with TTE and cardiac systolic and diastolic function can be conceptualized
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allowing an understanding of the relationships between velocity, pressure, volume changes and 3
78
heart rate. This relationship in a healthy adult is shown in Figure 1. In addition to these
79
advantages, TTE is accepted by pregnant women due to their understanding of the safety of
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ultrasound and it enables risk free assessment of heart function in healthy and sick pregnant
81
women.12 Recent studies using TTE in women with untreated preeclampsia have provided
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insights into both peripartum cardiomyopathy and preeclampsia.12-15
83 84
Definitions
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Peripartum cardiomyopathy
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Peripartum cardiomyopathy is a rare disease that initially presents as heart failure with reduced
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ejection fraction ≤45%, fractional shortening ≤30% or both, and an end-diastolic dimension >2.7
88
cm/m2 body surface area.8,15,16 Fundamental to the definition is that there is no other pre-existing
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condition that could cause the heart failure. Therefore, the diagnosis should only be made after
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underlying heart disease including valvular heart disease and hypertensive disease, endocrine
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diseases, drug therapy or iatrogenic complications such as excessive fluid administration, are
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excluded.17,18 Peripartum cardiomyopathy is usually diagnosed at the end of pregnancy or in the
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few months after delivery although it may occur earlier in pregnancy.13,17-24 The incidence varies
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throughout the world from approximately 1 in 300 in Haiti, to 1 in 3000–4000 pregnant women
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in the USA.17,19,23 The differing incidences throughout the world as well as different rates of
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disease reported in reviews may in part be accounted for by authors including women with pre-
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existing hypertensive disease or including woman receiving vasoactive substances that may
98
precipitate heart failure.25 There are few prospective population-based studies investigating this
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disease. Much of the information regarding peripartum cardiomyopathy comes from
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retrospective studies and survey data.8,17,19,23 The inclusion of women with pre-existing
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hypertensive disease in some of these reviews has contributed to preeclampsia being considered
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a risk factor for the development of peripartum cardiomyopathy and to the hypothesis that both
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diseases may share a common origin.
104 105
Preeclampsia
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Preeclampsia is usually diagnosed after 20 weeks of gestation. It is a common cardiovascular
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disease of pregnancy with an incidence of approximately 1 in 15 women.18 The incidence of
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preeclampsia complicated by heart failure is approximately 1 in 2000 pregnant women or 3% of 4
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women with severe preeclampsia.26 Preeclampsia is diagnosed when a pregnant woman presents
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with sustained new onset hypertension (≥ 140/90 mmHg) and other organ system involvement,
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often proteinuria, with resolution of hypertension in the postpartum period.1,18,27-31 Preeclampsia
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is frequently subdivided into mild and severe disease. Severe disease is characterised by
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markedly elevated blood pressure and/or severe perturbations of organ systems and symptomatic
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disease. Preeclampsia is also commonly classified into preterm disease considered ≤34 weeks of
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gestation and disease occurring at >34 weeks of gestation. This classification is based on
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increased mortality in women who develop preeclampsia early in pregnancy and suggestions that
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haemodynamics may differ in these two groups, with women who develop early preeclampsia
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demonstrating lower cardiac outputs at 24 weeks than women who develop preeclampsia at >34
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weeks of gestation.32,33
120 121
Clinical features and haemodynamic findings at diagnosis
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Peripartum cardiomyopathy
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Classically, peripartum cardiomyopathy presents as systolic dysfunction with reduced ejection
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fraction. Clinically, women with peripartum cardiomyopathy present with breathlessness and
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fatigue often with an unexplained tachycardia in the presence of normal or reduced blood
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pressure.8,9,17,18,34-36 Peripartum cardiomyopathy is a low cardiac output condition with a dilated
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left ventricle, left atrium and increased filling pressures (Table 1),13,17,18 often with right
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ventricular involvement. It is fundamentally a myocardial disease and this is reflected in
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alterations of myocardial wall movement evidenced by changes in the tissue Doppler assessment
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of the left ventricle. Fluid overload is often a presenting feature and it does not improve rapidly
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with delivery of the fetus. Recovery often takes weeks to months with treatment including
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angiotensin converting enzyme inhibitors and beta blockers. Recovery is unpredictable and in
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some women progressive cardiac failure requiring cardiac transplantation may be necessary.17,18
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Recurrence or worsening of the disease with subsequent pregnancies is common.
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Autopsy findings in women include an enlarged heart, a dilated cardiomyopathy,
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irregular myofibres and fibrosis with variable T-cell infiltration on histopathology1 and when no
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other cause for these changes is identified the diagnosis of peripartum cardiomyopathy is made.
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Even amongst pathologists there is a lack of familiarity regarding this specific definition and the
5
139
criteria for diagnosing peripartum cardiomyopathy which leads to incorrect classification of the
140
heart failure.1
141
Recent work in healthy term pregnant women has found reductions in systolic function
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and impairment of diastolic function quantified by a reduction in cardiac output to pre-pregnancy
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values and increased mitral valve E/e’ in some asymptomatic women.9,12,37 This suggests that
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asymptomatic heart dysfunction may be more common than previously thought and it may be
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that these women are at greater risk of developing heart failure with reduced ejection fraction
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(i.e. peripartum cardiomyopathy) with a longer pregnancy or in the postpartum period.9 Large
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longitudinal serial studies using TTE are needed in healthy women to explore this hypothesis.
148 149
Preeclampsia
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Preeclampsia, without heart failure, classically presents as diastolic dysfunction with raising
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filling pressures and a preserved ejection fraction (Table 1). Haemodynamic variables have been
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extensively studied in preeclampsia.12,14,15,32,38-47 Cardiac output is maintained in uncomplicated,
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untreated disease and the ventricles are of normal size. Left ventricular remodeling and left
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ventricular hypertrophy are common findings.12,14,15 There are no reports of involvement of the
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right ventricle.
156
Early important work by Visser and Wallenburg highlighted the finding of increased left
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ventricular stroke work index in women with preeclampsia and suggested that contractility was
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increased in these women.43 Subsequent echocardiographic work in women with untreated
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disease characterised the diastolic changes in women with preeclampsia and confirmed
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preservation of systolic function.12 This diastolic impairment coupled with the lack of human
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studies demonstrating reduced ejection fraction in women with untreated preeclampsia casts
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significant doubt on the proposal that preeclampsia and peripartum cardiomyopathy share
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common aetiological origins through specific circulating biochemical markers such as sFLT1.48
164
Clinically, women with preeclampsia and heart failure present with breathlessness,
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fatigue, and often tachycardia in the presence of hypertension which may be critically high and
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may have developed rapidly. Hypertension may also be significantly increased relative to pre-
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pregnancy levels. Heart failure in preeclampsia is often associated with a cluster of other
168
symptoms and signs including proteinuria, oedema, and abnormalities of hepatic, haematological
169
and cerebral function. 6
170
Heart failure as a complication of preeclampsia may show a spectrum of abnormalities
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from diastolic failure with preserved ejection fraction, to systolic failure with reduced ejection
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fraction.9,49-53 It is uncommon for a woman with severe untreated preeclampsia to present with
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acute pulmonary oedema. There are no published data regarding the haemodynamic state in this
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clinical situation and studies are needed to determine more precisely the haemodynamic changes.
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In women with preeclampsia complicated by heart failure reduced ejection fraction may
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occur as a result of hypovolemia from haemorrhage, hypoxaemia from acute pulmonary oedema
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or intracerebral haemorrhage, or the adverse effects of pharmacological agents and intravenous
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fluids.9 It is also possible that it may occur as a result of worsening disease leading to extreme
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disturbances in the mechanics of heart function such as extreme afterload, alterations in preload
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due to fluid redistribution, myocardial oedema or fibrosis, and heart rate changes impairing heart
181
filling.9
182
Effective management of women with severe preeclampsia involves maternal
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neuroprotective therapy with magnesium sulphate to treat and prevent seizures, effective and
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safe antihypertensive agents to reduce blood pressure, as well as strict fluid balance.54-59 A
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skilled multidisciplinary team approach to the management of these women should be adopted.60
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In a woman with acute pulmonary oedema, stabilisation is a priority with fluid redistribution
187
away from the lungs initially using non-invasive ventilation and diuretics, as well as blood
188
pressure reduction. Planned delivery of the fetus is usually necessary in the antenatal situation. If
189
caesarean section is required, ablating the response to tracheal intubation and extubation during
190
general anaesthesia and high acuity monitoring environments are necessary. 1,28,60
191
Regarding the time course of recovery, the disease process responds to delivery of the
192
fetus and there is usually rapid improvement in clinical symptoms after birth. Whilst
193
preeclampsia may recur with subsequent pregnancies it is only in approximately one in seven
194
cases and in many of these women the disease is not as severe.27 Preeclampsia, especially early-
195
onset severe disease, is known to be associated with long-term increased risks of ischaemic heart
196
disease, renal disease, hypertension and stroke. Unlike peripartum cardiomyopathy, however,
197
clinical recovery and return of function to New York Heart Association class I before the
198
development of these long-term risks is usually the case in most women.61
199
Cardiac autopsy findings in women with preeclampsia include significant left ventricular
200
hypertrophy, a non-dilated ventricle, myofibre hypertrophy and interstitial fibrosis.1 The cardiac 7
201
structural changes observed in women with preeclampsia are also commonly seen in non-
202
pregnant adults with hypertension. Unfortunately, similar to the problems with classification of
203
peripartum cardiomyopathy at autopsy, post-mortem findings in women who die as a
204
consequence of preeclampsia often result in incomplete reports or reports that are missing
205
examination of key organs, such as the kidneys, liver or uterine placental bed.1 This is important
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because the causes of death in women with preeclampsia may not be directly related to the heart.
207
This further exacerbates the problems associated with understanding the disease and
208
disseminating useful information to clinicians managing pregnant women.
209 210
Clinical relevance
211
The diagnosis of heart failure needs to be considered in any pregnant women with increasing
212
breathlessness and fatigue. Vital signs need to be regularly monitored, recorded and abnormal
213
values acted upon. The presence or absence of hypertension in the presence of breathlessness
214
enables a simple classification of women into those requiring further investigation for the
215
presence of preeclampsia and those who require further evaluation for the presence of a dilated
216
cardiomyopathy. Echocardiography plays a central role in the diagnostic process enabling
217
characterisation of heart function into those women with both preserved and reduced ejection
218
fraction heart failure.
219
In antenatal heart failure, neuraxial or general anaesthesia is often required for delivery of
220
the fetus and information obtained from echocardiography can assist with anaesthetic choices.
221
Proceeding to general anaesthesia in the absence of stabilisation and with uncertainty regarding
222
underlying heart function is dangerous as doses of general anaesthetic agents such as thiopental
223
may have profound and life-threatening haemodynamic responses. In the absence of
224
contraindications and after stabilisation, slowly titrated neuraxial anaesthesia can be achieved
225
with low-dose intrathecal local anaesthetic and opioid combined with titrated epidural
226
supplementation as part of a combined spinal-epidural technique.
227 228
Conclusion
229
Peripartum heart failure is a significant clinical problem and peripartum cardiomyopathy and
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preeclampsia are two potential causes of morbidity and mortality. Preeclampsia typically
231
presents with diastolic dysfunction with left ventricular hypertrophy and a non-dilated ventricle 8
232
whereas peripartum cardiomyopathy presents with systolic dysfunction, minimal left ventricular
233
hypertrophy and a dilated ventricle. From an epidemiological perspective women with
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preeclampsia complicated by heart failure should be considered a separate group from those with
235
peripartum cardiomyopathy. Focused attention should be paid to preventable causes of the heart
236
failure in women with preeclampsia and the development of strategies for long term follow up
237
and early intervention. The more widespread application of TTE in the setting of acute heart
238
failure in pregnant women and also in the setting of severe preeclampsia should reduce the
239
diagnostic uncertainty and enable immediate quantification of heart function. It is hoped that
240
ongoing research and education in the area of haemodynamics in women with preeclampsia
241
during and after pregnancy will provide more information about heart function in women with
242
preeclampsia. This will enable further efforts to reduce morbidity and mortality related to both
243
preeclampsia and peripartum cardiomyopathy.
244 245
Disclosure
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The authors have no competing interests to declare.
247 248
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50.
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echocardiographic insights and implications for treatment. Obstet Gynecol 1993;81:227-34.
378
51.
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pulmonary edema in pregnancy. Obstet Gynecol 2003;101:511-5.
380
52.
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complicated by pulmonary edema. Am J Obstet Gynecol 1985;152:330-4.
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53.
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pulmonary oedema as a complication of hypertension during pregnancy. Hypertension
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Pregnancy 2011;30:169-79.
385
54.
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eclampsia. Cochrane Database of Systematic Reviews 2010, Issue 9 Art No: CD002960 DOI:
Khaw A, Kametas NA, Turan OM, Bamfo JE, Nicolaides KH. Maternal cardiac function
Visser W, Wallenburg HC. Central hemodynamic observations in untreated preeclamptic
Bosio PM, McKenna PJ, Conroy R, O'Herlihy C. Maternal central hemodynamics in
Bamfo JE, Kametas NA, Chambers JB, Nicolaides KH. Maternal cardiac function in
Simmons LA, Gillin AG, Jeremy RW. Structural and functional changes in left ventricle
Mabie WC, Ratts TE, Sibai BM. The central hemodynamics of severe preeclampsia. Am J
Patten IS, Rana S, Shahul S, et al. Cardiac angiogenic imbalance leads to peripartum
Desai DK, Moodley J, Naidoo DP, Bhorat I. Cardiac abnormalities in pulmonary oedema
Mabie WC, Hackman BB, Sibai BM. Pulmonary edema associated with pregnancy:
Sciscione AC, Ivester T, Largoza M, Manley J, Shlossman P, Colmorgen GH. Acute
Benedetti TJ, Kates R, Williams V. Hemodynamic observations in severe preeclampsia
Thornton CE, von Dadelszen P, Makris A, Tooher JM, Ogle RF, Hennessy A. Acute
Duley L, Gulmezoglu AM, Chou D. Magnesium sulphate versus lytic cocktail for
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101002/14651858CD002960pub2 2010.
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anticonvulsants for women with pre-eclampsia. Cochrane Database of Systematic Reviews 2003,
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Issue 2 Art No: CD000025 DOI: 101002/14651858CD000025 2003:CD000025.
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Cochrane Database of Systematic Reviews 2003, Issue 4 Art No: CD000128 DOI:
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101002/14651858CD000128 2003.
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Cochrane Database of Systematic Reviews 2003, Issue 4 Art No: CD000127 DOI:
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101002/14651858CD000127 2003.
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during pregnancy. Cochrane Database of Systematic Reviews 2006, Issue 3 Art No: CD001449
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DOI: 101002/14651858CD001449pub2 2006.
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59.
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its consequences: generic protocol (Protocol). Cochrane Database of Systematic Reviews 2009,
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Issue 2. Art. No.: CD007756. DOI: 10.1002/14651858.CD007756. 2010.
403
60.
404
eclamptic patient. Curr Opin Anaesthesiol 2007;20:168-74.
405
61.
406
after pre-eclampsia: population based cohort study. BMJ 2001;323:1213-7.
Duley L, Gulmezoglu AM, Henderson-Smart DJ. Magnesium sulphate and other
Duley L, Henderson-Smart D. Magnesium sulphate versus phenytoin for eclampsia.
Duley L, Henderson-Smart D. Magnesium sulphate versus diazepam for eclampsia.
Duley L, Henderson-Smart DJ, Meher S. Drugs for treatment of very high blood pressure
Duley L, Henderson-Smart DJ, Walker G JA. Interventions for treating pre-eclampsia and
Dyer RA, Piercy JL, Reed AR. The role of the anaesthetist in the management of the pre-
Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers
407
14
408 409
Legend to Figure
410
Figure 1 Conceptualising cardiac function using transthoracic echocardiography
411
This figure incorporates the systolic cardiac velocities of left ventricular outflow tract velocity
412
and the septal tissue Doppler systolic movement of the myocardium (s′) and the diastolic cardiac
413
velocities of mitral valve inflow Doppler velocities (E wave and A wave) and septal tissue
414
Doppler diastolic movements of the myocardium (e′ and a′), in addition to volume and pressure
415
changes in the ventricle. The figure is the relationship as it exists in a healthy person.
416
ECG: electrocardiograph
417
15
418
Figure 1 Conceptualising cardiac function using transthoracic echocardiography
419 420
421 422
16
423 424 425
From Dennis, A. T. Cardiac function in women with preeclampsia. PhD thesis, Department of Pharmacology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne. 2010. http://repository.unimelb.edu.au/10187/9005. [accessed January 2014]
426
17
427
Table 1 Comparison of heart failure in peripartum cardiomyopathy and heart failure in preeclampsia Peripartum cardiomyopathy
Pre-eclampsia
Systolic dysfunction
Diastolic dysfunction
Hypertension
No
Yes
Proteinuria
No
Often
Haemolysis
No
Yes
Abnormal liver function
No
Yes
Thrombocytopenia
No
Yes
Seizures
No
Yes
Renal dysfunction
No
Yes (proteinuria)
Vascular thrombus
Yes*
Not reported
Arrhythmia
Yes^
Not reported
Mitral regurgitation
Yes
Not reported
Left atrium volume
Dilated
Normal
Left ventricular volume
Dilated
Normal
Right ventricular volume
Dilated
Normal
Infrequent and small
Frequent and larger
No†
Frequent
Left ventricular systolic function
Reduced
Preserved¶
Contractility
Reduced
Preserved
Cardiac output
Reduced
Preserved/ increased
Myocardial tissue Doppler systolic
Reduced
Normal range¶
Pathological mechanism Additional features
Associated features
Echocardiography features Cardiac volumes and structure
Pericardial effusions Left ventricular hypertrophy Cardiac function
18
velocities Ejection fraction
Reduced
Preserved¶
Right ventricular systolic function
Reduced
Not affected
Diastolic function
Normal†
Abnormal/reduced
Commonly used
Uncommonly used
Systemic anticoagulation
Yes
Uncommonly used
Antihypertensive agents
No
Yes
Parenteral magnesium sulphate
No
Yes
Initial pharmacological treatment Inotropic agents
428
*Reported with severe ventricular dysfunction
429
^
Atrial fibrillation, ventricular tachycardia and ectopics reported
430
†
Unless hypertension present before pregnancy
431
¶*
Systolic function may be reduced in the presence of malignant hypertension
432 433
19
434
Highlights
435
•
Heart failure in pre-eclampsia & peripartum cardiomyopathy is a global health issue
436
•
Transthoracic echocardiography enables classification of heart failure
437
•
Preserved ejection fraction heart failure is common in pre-eclampsia
438
•
Reduced ejection fraction heart failure is common in peripartum cardiomyopathy
439
•
The likely mechanisms for heart failure in pre-eclampsia are discussed
440 441
20
S0959-289X(14)00075-2 http://dx.doi.org/10.1016/j.ijoa.2014.05.002 YIJOA 2293
To appear in:
International Journal of Obstetric Anesthesia
Accepted Date:
16 May 2014
Please cite this article as: Dennis, A.T., Castro, J.M., Echocardiographic differences between preeclampsia and peripartum cardiomyopathy, International Journal of Obstetric Anesthesia (2014), doi: http://dx.doi.org/10.1016/ j.ijoa.2014.05.002
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
IJOA 14-00053
2
REVIEW
3
Echocardiographic differences between preeclampsia and peripartum cardiomyopathy
4
A.T. Dennis,a J. M. Castrob
5
a
6
Department of Pharmacology and Department of Obstetrics and Gynaecology, University of
7
Melbourne, Parkville, Victoria, Australia
8
b
Department of Anaesthesia, The Royal Women’s Hospital, Parkville, Victoria, Australia;
Department of Cardiology, St Vincent’s Hospital, Fitzroy, Australia
9 10
Short title: Ecchocardiography in preeclampsia and peripartum cardiomyopathy
11 12
Correspondence to: Associate Professor Alicia T Dennis, Department of Anaesthesia ,The Royal
13
Women’s Hospital, Corner Flemington Road and Grattan Street, Parkville, Australia 3052
14
E-mail address: [email protected]
15
1
16 17
ABSTRACT
18
Peripartum heart failure due to preeclampsia or peripartum cardiomyopathy represents a
19
significant global health issue. Transthoracic echocardiography enables differentiation of heart
20
failure with preserved ejection fraction, commonly observed in women with preeclampsia, from
21
that with peripartum cardiomyopathy in which a reduced ejection fraction is more common. An
22
understanding of the different definitions and diagnostic features of these two diseases, as well as
23
accurate characterisation of the haemodynamics in preeclampsia and peripartum
24
cardiomyopathy, allows clinicians to manage these conditions appropriately. This article outlines
25
the echocardiographic differences between preeclampsia and peripartum cardiomyopathy, the
26
likely mechanisms for heart failure in preeclampsia and the relevance of these differences to
27
clinicians in relation to prevention and treatment. It also emphasises the importance of disease
28
definitions as a key framework for the more consistent classification of the two diseases.
29 30
Introduction
31
Heart disease in pregnant women is the leading cause of maternal mortality in many developed
32
countries.1-5 Heart failure caused by pre-existing or newly acquired cardiac disease during
33
pregnancy may present acutely and it is important for anaesthetists to be able to diagnose and
34
manage heart failure in pregnancy within the context of a multidisciplinary team.
35
The major contributing pathologies include peripartum cardiomyopathy, preeclampsia,
36
valvular heart disease, particularly mitral stenosis, and congenital heart disease. Of these, heart
37
failure related to peripartum cardiomyopathy and to preeclampsia present specific diagnostic and
38
clinical challenges and echocardiography can be used to differenciate these two conditions.
39
In peripartum cardiomyopathy, symptoms and signs of impending heart failure are often
40
missed or misinterpreted as part of the spectrum of normal pregnancy symptoms. In
41
preeclampsia when heart failure does occur and is recognised, it is sometimes incorrectly
42
classified as peripartum cardiomyopathy.6 These omissions and misunderstandings are important
43
to acknowledge because failure to diagnose heart failure in pregnant women, failure to obtain
44
appropriate investigations including echocardiography, and failure to manage heart failure
45
appropritately in pregnant women contribute to mortality.1 In women with preeclampsia 50% of
46
the deaths are considered preventable.7 2
47 48
Heart failure
49
Heart failure is a diverse clinical entity resulting from abnormalities of both heart structure and
50
function. Clinically, adults with heart failure present with breathlessness and fatigue due to an
51
imbalance between oxygen supply and demand throughout the body. Fluid retention is present to
52
varying degrees.8 There is not a single diagnostic test for heart failure and diagnosis depends on
53
accurate history and physical examination coupled with appropriate diagnostic tests of which
54
echocardiography plays a central role.
55
Heart failure is commonly categorised into two groups. One group, heart failure with
56
reduced ejection fraction, presents with an ejection fraction usually ≤40%.8 It is frequently
57
associated with a dilated ventricle characterised by an increased left ventricular end-diastolic
58
diameter.8 The other group, heart failure with preserved ejection fraction, presents with a normal
59
ejection fraction, usually between 40-55%.8
60
Reduced ejection fraction heart failure is due to ‘pump failure’ with decreased forward
61
flow, increased back pressure to the lungs, activation of the renin-angiotensin system and fluid
62
retention. Preserved ejection fraction heart failure is due to diastolic dysfunction, a ‘stiff heart’
63
with ‘increased back pressure’ to the lungs that causes pulmonary oedema. A commonly known
64
form is due to hypertensive heart disease of the elderly where left ventricular hypertrophy is
65
associated with diastolic dysfunction, but normal systolic function.9 In the non-pregnant
66
population, hypertension is a recognised cause of both heart failure with preserved ejection
67
fraction and heart failure with reduced ejection fraction.8 Malignant hypertension and acute
68
hypertensive heart failure are also life-threatening complications of endocrine and vascular
69
diseases as well as after administration of large doses of vasoactive pharmacological agents.10
70 71
Transthoracic echocardiography
72
Transthoracic echocardiography (TTE) is central to diagnosing and managing heart failure 11
73
Advances in TTE machine portability and image quality, as well as increased awareness of its
74
utility and accuracy in pregnant women,11 mean that TTE is used more commonly in pregnant
75
women in the clinical and research setting.11 Structural and functional information in real time
76
can be obtained with TTE and cardiac systolic and diastolic function can be conceptualized
77
allowing an understanding of the relationships between velocity, pressure, volume changes and 3
78
heart rate. This relationship in a healthy adult is shown in Figure 1. In addition to these
79
advantages, TTE is accepted by pregnant women due to their understanding of the safety of
80
ultrasound and it enables risk free assessment of heart function in healthy and sick pregnant
81
women.12 Recent studies using TTE in women with untreated preeclampsia have provided
82
insights into both peripartum cardiomyopathy and preeclampsia.12-15
83 84
Definitions
85
Peripartum cardiomyopathy
86
Peripartum cardiomyopathy is a rare disease that initially presents as heart failure with reduced
87
ejection fraction ≤45%, fractional shortening ≤30% or both, and an end-diastolic dimension >2.7
88
cm/m2 body surface area.8,15,16 Fundamental to the definition is that there is no other pre-existing
89
condition that could cause the heart failure. Therefore, the diagnosis should only be made after
90
underlying heart disease including valvular heart disease and hypertensive disease, endocrine
91
diseases, drug therapy or iatrogenic complications such as excessive fluid administration, are
92
excluded.17,18 Peripartum cardiomyopathy is usually diagnosed at the end of pregnancy or in the
93
few months after delivery although it may occur earlier in pregnancy.13,17-24 The incidence varies
94
throughout the world from approximately 1 in 300 in Haiti, to 1 in 3000–4000 pregnant women
95
in the USA.17,19,23 The differing incidences throughout the world as well as different rates of
96
disease reported in reviews may in part be accounted for by authors including women with pre-
97
existing hypertensive disease or including woman receiving vasoactive substances that may
98
precipitate heart failure.25 There are few prospective population-based studies investigating this
99
disease. Much of the information regarding peripartum cardiomyopathy comes from
100
retrospective studies and survey data.8,17,19,23 The inclusion of women with pre-existing
101
hypertensive disease in some of these reviews has contributed to preeclampsia being considered
102
a risk factor for the development of peripartum cardiomyopathy and to the hypothesis that both
103
diseases may share a common origin.
104 105
Preeclampsia
106
Preeclampsia is usually diagnosed after 20 weeks of gestation. It is a common cardiovascular
107
disease of pregnancy with an incidence of approximately 1 in 15 women.18 The incidence of
108
preeclampsia complicated by heart failure is approximately 1 in 2000 pregnant women or 3% of 4
109
women with severe preeclampsia.26 Preeclampsia is diagnosed when a pregnant woman presents
110
with sustained new onset hypertension (≥ 140/90 mmHg) and other organ system involvement,
111
often proteinuria, with resolution of hypertension in the postpartum period.1,18,27-31 Preeclampsia
112
is frequently subdivided into mild and severe disease. Severe disease is characterised by
113
markedly elevated blood pressure and/or severe perturbations of organ systems and symptomatic
114
disease. Preeclampsia is also commonly classified into preterm disease considered ≤34 weeks of
115
gestation and disease occurring at >34 weeks of gestation. This classification is based on
116
increased mortality in women who develop preeclampsia early in pregnancy and suggestions that
117
haemodynamics may differ in these two groups, with women who develop early preeclampsia
118
demonstrating lower cardiac outputs at 24 weeks than women who develop preeclampsia at >34
119
weeks of gestation.32,33
120 121
Clinical features and haemodynamic findings at diagnosis
122
Peripartum cardiomyopathy
123
Classically, peripartum cardiomyopathy presents as systolic dysfunction with reduced ejection
124
fraction. Clinically, women with peripartum cardiomyopathy present with breathlessness and
125
fatigue often with an unexplained tachycardia in the presence of normal or reduced blood
126
pressure.8,9,17,18,34-36 Peripartum cardiomyopathy is a low cardiac output condition with a dilated
127
left ventricle, left atrium and increased filling pressures (Table 1),13,17,18 often with right
128
ventricular involvement. It is fundamentally a myocardial disease and this is reflected in
129
alterations of myocardial wall movement evidenced by changes in the tissue Doppler assessment
130
of the left ventricle. Fluid overload is often a presenting feature and it does not improve rapidly
131
with delivery of the fetus. Recovery often takes weeks to months with treatment including
132
angiotensin converting enzyme inhibitors and beta blockers. Recovery is unpredictable and in
133
some women progressive cardiac failure requiring cardiac transplantation may be necessary.17,18
134
Recurrence or worsening of the disease with subsequent pregnancies is common.
135
Autopsy findings in women include an enlarged heart, a dilated cardiomyopathy,
136
irregular myofibres and fibrosis with variable T-cell infiltration on histopathology1 and when no
137
other cause for these changes is identified the diagnosis of peripartum cardiomyopathy is made.
138
Even amongst pathologists there is a lack of familiarity regarding this specific definition and the
5
139
criteria for diagnosing peripartum cardiomyopathy which leads to incorrect classification of the
140
heart failure.1
141
Recent work in healthy term pregnant women has found reductions in systolic function
142
and impairment of diastolic function quantified by a reduction in cardiac output to pre-pregnancy
143
values and increased mitral valve E/e’ in some asymptomatic women.9,12,37 This suggests that
144
asymptomatic heart dysfunction may be more common than previously thought and it may be
145
that these women are at greater risk of developing heart failure with reduced ejection fraction
146
(i.e. peripartum cardiomyopathy) with a longer pregnancy or in the postpartum period.9 Large
147
longitudinal serial studies using TTE are needed in healthy women to explore this hypothesis.
148 149
Preeclampsia
150
Preeclampsia, without heart failure, classically presents as diastolic dysfunction with raising
151
filling pressures and a preserved ejection fraction (Table 1). Haemodynamic variables have been
152
extensively studied in preeclampsia.12,14,15,32,38-47 Cardiac output is maintained in uncomplicated,
153
untreated disease and the ventricles are of normal size. Left ventricular remodeling and left
154
ventricular hypertrophy are common findings.12,14,15 There are no reports of involvement of the
155
right ventricle.
156
Early important work by Visser and Wallenburg highlighted the finding of increased left
157
ventricular stroke work index in women with preeclampsia and suggested that contractility was
158
increased in these women.43 Subsequent echocardiographic work in women with untreated
159
disease characterised the diastolic changes in women with preeclampsia and confirmed
160
preservation of systolic function.12 This diastolic impairment coupled with the lack of human
161
studies demonstrating reduced ejection fraction in women with untreated preeclampsia casts
162
significant doubt on the proposal that preeclampsia and peripartum cardiomyopathy share
163
common aetiological origins through specific circulating biochemical markers such as sFLT1.48
164
Clinically, women with preeclampsia and heart failure present with breathlessness,
165
fatigue, and often tachycardia in the presence of hypertension which may be critically high and
166
may have developed rapidly. Hypertension may also be significantly increased relative to pre-
167
pregnancy levels. Heart failure in preeclampsia is often associated with a cluster of other
168
symptoms and signs including proteinuria, oedema, and abnormalities of hepatic, haematological
169
and cerebral function. 6
170
Heart failure as a complication of preeclampsia may show a spectrum of abnormalities
171
from diastolic failure with preserved ejection fraction, to systolic failure with reduced ejection
172
fraction.9,49-53 It is uncommon for a woman with severe untreated preeclampsia to present with
173
acute pulmonary oedema. There are no published data regarding the haemodynamic state in this
174
clinical situation and studies are needed to determine more precisely the haemodynamic changes.
175
In women with preeclampsia complicated by heart failure reduced ejection fraction may
176
occur as a result of hypovolemia from haemorrhage, hypoxaemia from acute pulmonary oedema
177
or intracerebral haemorrhage, or the adverse effects of pharmacological agents and intravenous
178
fluids.9 It is also possible that it may occur as a result of worsening disease leading to extreme
179
disturbances in the mechanics of heart function such as extreme afterload, alterations in preload
180
due to fluid redistribution, myocardial oedema or fibrosis, and heart rate changes impairing heart
181
filling.9
182
Effective management of women with severe preeclampsia involves maternal
183
neuroprotective therapy with magnesium sulphate to treat and prevent seizures, effective and
184
safe antihypertensive agents to reduce blood pressure, as well as strict fluid balance.54-59 A
185
skilled multidisciplinary team approach to the management of these women should be adopted.60
186
In a woman with acute pulmonary oedema, stabilisation is a priority with fluid redistribution
187
away from the lungs initially using non-invasive ventilation and diuretics, as well as blood
188
pressure reduction. Planned delivery of the fetus is usually necessary in the antenatal situation. If
189
caesarean section is required, ablating the response to tracheal intubation and extubation during
190
general anaesthesia and high acuity monitoring environments are necessary. 1,28,60
191
Regarding the time course of recovery, the disease process responds to delivery of the
192
fetus and there is usually rapid improvement in clinical symptoms after birth. Whilst
193
preeclampsia may recur with subsequent pregnancies it is only in approximately one in seven
194
cases and in many of these women the disease is not as severe.27 Preeclampsia, especially early-
195
onset severe disease, is known to be associated with long-term increased risks of ischaemic heart
196
disease, renal disease, hypertension and stroke. Unlike peripartum cardiomyopathy, however,
197
clinical recovery and return of function to New York Heart Association class I before the
198
development of these long-term risks is usually the case in most women.61
199
Cardiac autopsy findings in women with preeclampsia include significant left ventricular
200
hypertrophy, a non-dilated ventricle, myofibre hypertrophy and interstitial fibrosis.1 The cardiac 7
201
structural changes observed in women with preeclampsia are also commonly seen in non-
202
pregnant adults with hypertension. Unfortunately, similar to the problems with classification of
203
peripartum cardiomyopathy at autopsy, post-mortem findings in women who die as a
204
consequence of preeclampsia often result in incomplete reports or reports that are missing
205
examination of key organs, such as the kidneys, liver or uterine placental bed.1 This is important
206
because the causes of death in women with preeclampsia may not be directly related to the heart.
207
This further exacerbates the problems associated with understanding the disease and
208
disseminating useful information to clinicians managing pregnant women.
209 210
Clinical relevance
211
The diagnosis of heart failure needs to be considered in any pregnant women with increasing
212
breathlessness and fatigue. Vital signs need to be regularly monitored, recorded and abnormal
213
values acted upon. The presence or absence of hypertension in the presence of breathlessness
214
enables a simple classification of women into those requiring further investigation for the
215
presence of preeclampsia and those who require further evaluation for the presence of a dilated
216
cardiomyopathy. Echocardiography plays a central role in the diagnostic process enabling
217
characterisation of heart function into those women with both preserved and reduced ejection
218
fraction heart failure.
219
In antenatal heart failure, neuraxial or general anaesthesia is often required for delivery of
220
the fetus and information obtained from echocardiography can assist with anaesthetic choices.
221
Proceeding to general anaesthesia in the absence of stabilisation and with uncertainty regarding
222
underlying heart function is dangerous as doses of general anaesthetic agents such as thiopental
223
may have profound and life-threatening haemodynamic responses. In the absence of
224
contraindications and after stabilisation, slowly titrated neuraxial anaesthesia can be achieved
225
with low-dose intrathecal local anaesthetic and opioid combined with titrated epidural
226
supplementation as part of a combined spinal-epidural technique.
227 228
Conclusion
229
Peripartum heart failure is a significant clinical problem and peripartum cardiomyopathy and
230
preeclampsia are two potential causes of morbidity and mortality. Preeclampsia typically
231
presents with diastolic dysfunction with left ventricular hypertrophy and a non-dilated ventricle 8
232
whereas peripartum cardiomyopathy presents with systolic dysfunction, minimal left ventricular
233
hypertrophy and a dilated ventricle. From an epidemiological perspective women with
234
preeclampsia complicated by heart failure should be considered a separate group from those with
235
peripartum cardiomyopathy. Focused attention should be paid to preventable causes of the heart
236
failure in women with preeclampsia and the development of strategies for long term follow up
237
and early intervention. The more widespread application of TTE in the setting of acute heart
238
failure in pregnant women and also in the setting of severe preeclampsia should reduce the
239
diagnostic uncertainty and enable immediate quantification of heart function. It is hoped that
240
ongoing research and education in the area of haemodynamics in women with preeclampsia
241
during and after pregnancy will provide more information about heart function in women with
242
preeclampsia. This will enable further efforts to reduce morbidity and mortality related to both
243
preeclampsia and peripartum cardiomyopathy.
244 245
Disclosure
246
The authors have no competing interests to declare.
247 248
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Legend to Figure
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Figure 1 Conceptualising cardiac function using transthoracic echocardiography
411
This figure incorporates the systolic cardiac velocities of left ventricular outflow tract velocity
412
and the septal tissue Doppler systolic movement of the myocardium (s′) and the diastolic cardiac
413
velocities of mitral valve inflow Doppler velocities (E wave and A wave) and septal tissue
414
Doppler diastolic movements of the myocardium (e′ and a′), in addition to volume and pressure
415
changes in the ventricle. The figure is the relationship as it exists in a healthy person.
416
ECG: electrocardiograph
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Figure 1 Conceptualising cardiac function using transthoracic echocardiography
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421 422
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423 424 425
From Dennis, A. T. Cardiac function in women with preeclampsia. PhD thesis, Department of Pharmacology, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne. 2010. http://repository.unimelb.edu.au/10187/9005. [accessed January 2014]
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Table 1 Comparison of heart failure in peripartum cardiomyopathy and heart failure in preeclampsia Peripartum cardiomyopathy
Pre-eclampsia
Systolic dysfunction
Diastolic dysfunction
Hypertension
No
Yes
Proteinuria
No
Often
Haemolysis
No
Yes
Abnormal liver function
No
Yes
Thrombocytopenia
No
Yes
Seizures
No
Yes
Renal dysfunction
No
Yes (proteinuria)
Vascular thrombus
Yes*
Not reported
Arrhythmia
Yes^
Not reported
Mitral regurgitation
Yes
Not reported
Left atrium volume
Dilated
Normal
Left ventricular volume
Dilated
Normal
Right ventricular volume
Dilated
Normal
Infrequent and small
Frequent and larger
No†
Frequent
Left ventricular systolic function
Reduced
Preserved¶
Contractility
Reduced
Preserved
Cardiac output
Reduced
Preserved/ increased
Myocardial tissue Doppler systolic
Reduced
Normal range¶
Pathological mechanism Additional features
Associated features
Echocardiography features Cardiac volumes and structure
Pericardial effusions Left ventricular hypertrophy Cardiac function
18
velocities Ejection fraction
Reduced
Preserved¶
Right ventricular systolic function
Reduced
Not affected
Diastolic function
Normal†
Abnormal/reduced
Commonly used
Uncommonly used
Systemic anticoagulation
Yes
Uncommonly used
Antihypertensive agents
No
Yes
Parenteral magnesium sulphate
No
Yes
Initial pharmacological treatment Inotropic agents
428
*Reported with severe ventricular dysfunction
429
^
Atrial fibrillation, ventricular tachycardia and ectopics reported
430
†
Unless hypertension present before pregnancy
431
¶*
Systolic function may be reduced in the presence of malignant hypertension
432 433
19
434
Highlights
435
•
Heart failure in pre-eclampsia & peripartum cardiomyopathy is a global health issue
436
•
Transthoracic echocardiography enables classification of heart failure
437
•
Preserved ejection fraction heart failure is common in pre-eclampsia
438
•
Reduced ejection fraction heart failure is common in peripartum cardiomyopathy
439
•
The likely mechanisms for heart failure in pre-eclampsia are discussed
440 441
20
