Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2014) 1–12

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Heart disease in pregnancy: Ischaemic heart disease John Fryearson, MBChB, MRCP, Cardiology Registrar a, Dawn L. Adamson, BSc (Hons), MBBS, MRCP, PhD, Consultant Cardiologist b, * a b

Queen Elizabeth Hospital, Mindelsohn Way, Edgbaston, Birmingham B15 2WB, UK University Hospital of Coventry and Warwickshire, Clifford Bridge Road, Coventry CV2 2DX, UK

Keywords: cardiovascular pregnancy complications myocardial ischaemia

Coronary artery disease and in particular acute coronary syndromes in pregnancy are increasing with high risk of mortality and significant morbidity. Whilst women with atherosclerotic risk factors are at greater risk of developing problems in pregnancy, it is important to remember that women can develop problems even in the absence of atherosclerosisdsecondary to thrombosis or coronary dissection. A low threshold to investigate women with chest pain is paramount, and women with raised troponin levels should be investigated seriously. Acute coronary syndromes should be managed using an invasive strategy where possible and women should not have coronary angiography withheld for fear of foetal harm. This article aims to review the limited available data of coronary artery disease in pregnancy and give practical advice on the management of stable and acute coronary disease, with particular emphasis on the latter. Ó 2014 Published by Elsevier Ltd.

Introduction Acute coronary syndromes (ACSs) are an increasing worldwide cardiovascular problem with a high risk of serious morbidity and mortality. Fortunately, ACSs in pregnancy are a rare event – but the incidence is increasing with even greater potential for increase in the future. Due to its relative rarity

* Corresponding author. Tel.: þ44 (0) 2476 965673; Fax: þ44 (0) 2476 965657. E-mail addresses: [email protected] (J. Fryearson), [email protected] (D.L. Adamson).

http://dx.doi.org/10.1016/j.bpobgyn.2014.03.011 1521-6934/Ó 2014 Published by Elsevier Ltd.

Please cite this article in press as: Fryearson J, Adamson DL, Heart disease in pregnancy: Ischaemic heart disease, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.03.011

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and nature of presentation, there is little evidence upon which to base management decisions, and until recently there were no society management guidelines. Doctors, cardiologists and obstetricians will encounter these patients. The aim of this article is to outline the problem as well as the potential risk factors and causes, and also to provide some guidance on how the patients should be assessed and managed. Scope of the problem Deaths due to cardiovascular disease in pregnancy have been increasing over the past 30 years, with a recent incidence of around 2.3 per 100,000 maternities, making it the biggest cause of maternal death in the UK. The 2006–2008 CMACE report [1] (formerly CEMACH) identified that ischaemic heart disease (IHD) contributed to 20% of these deaths (11 of 53). This equates to a death rate of 0.48 per 100,000 maternities due to IHD. It also contributes to almost 12% of ‘late’ maternal deaths, that is, those occurring between 42 days and 1 year of delivery, assessed separately from the report. Perhaps more importantly, in almost half of maternal deaths from coronary artery disease (CAD) the care was assessed as being substandard – this is a similar proportion as has been previously identified. Estimating the incidence of ACS or stable IHD in pregnancy presents some difficulties, with conflicting estimate in the literature. Most reports have looked at the incidence of acute myocardial infarction (AMI). Some figures have relied on extrapolation from case series. A report, which analysed admissions to a US hospital for a 2-year period from the year 2000, suggests an incidence of around 1 in 16,000 deliveries [2]. A similar study from the previous decade suggested an incidence of closer to 1 in 36,000 deliveries [3]. One would expect the observed incidence to increase over this time period. Not only is there an increasing prevalence of maternal-related risk factors contributing to cardiovascular illness but also diagnostic criteria for ACS (whilst becoming more robust) to identify patients, who may not have previously been classified in this high-risk group, having ACS. However, in contrast to this expectation, figures from the UK Obstetric Surveillance System (UKOSS) 2011 report [4] stated a myocardial infarction (MI) incidence of 0.7 in 100,000 deliveries based on the analysis of reports from 2005 to 2010. This is not too dissimilar to the rate of death from MI given by the most recent CMACE report. We know that not all these women die, and therefore the data have to be inaccurate. The UKOSS data, as with all data collection, are dependent on accurate reporting, and its importance is emphasised to institutions. There may however be some loss of data due to women in early pregnancy being cared for by a cardiologist with little input from obstetrics and hence not being including in the UKOSS data set. Moreover, postpartum cardiac events are much less likely to be encompassed by the reporting system used in UKOSS, and the definitions of MI during pregnancy may differ from other reporting systems. This does not however fully reconcile the differences. Similar difficulties can be found in estimating the mortality rate. Initial reports suggested rates in excess of 20% as recently as 10 years ago [5]. However, a recent case review suggests a maternal mortality rate of around 11% [6]. The recent population-based study discussed above suggested a maternal mortality rate of just over 5% [2]. Mortality tends to occur peri-infarct, with almost no ischaemic-related deaths occurring 2 weeks after the event. Commonly, death is associated with labour and delivery [7]. Foetal death understandably is closely related to maternal outcomes and has been found to be in the order of 9–13%. [2,7] Risk factors Traditional cardiovascular risk factors are just as important in pregnancy as they are outside of it. The important risk factors, which confer significant susceptibility, include positive family history of premature coronary disease (particularly under 60 years of age), smoking, diabetes, hypercholesterolaemia and hypertension. Their importance cannot be understated – all patients dying from MI in the CMACE report had one or more of these readily identifiable factors present. Pregnancy itself does increase the risk of ACS almost fourfold [8]. There are a number of hypotheses put forward that may contribute to this. Pregnancy is a pro-thrombotic state with associated vascular Please cite this article in press as: Fryearson J, Adamson DL, Heart disease in pregnancy: Ischaemic heart disease, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.03.011

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dysfunction. There are reduced tissue plasminogen activator (tPA) levels and increased tPA inhibitor activity, as well as a reduction in functional protein S levels, excess oestrogen and progesterone [2,6,7]. Circulating blood volume can increase by up to 50% with similar increases in cardiac output and heart rate [9]. Not only does this increase myocardial oxygen demand but also shear forces on potentially vulnerable arteries. Progesterone has been linked to smooth muscle hyperplasia, reduction in acid mucopolysaccharides and weakening of the arterial wall. Oestrogens have shown to increase the activity of matrix metalloproteinases, which can also lead to breakdown of the medial layer within the artery. Circulating relaxin, which also helps to prepare the female pelvis for delivery, causes inhibition of endothelin-1 stimulation, which can further exacerbate endothelial dysfunction [10]. Older patients are noted to have much higher risks of ACS in pregnancy with around two-thirds of patients being more than 30 years of age [6], and those who are more than 40 years of age have a 30fold higher risk when compared with the under 20s. The number of women undergoing pregnancy above the age of 35 increased from 8% in 1985 to 19% in 2003. Multiparous women have consistently been found to be at higher risk, with some series indicating that around two thirds of patients were multigravidas [3,6,11]. Slightly more contentious is the presence of eclampsia or pre-eclampsia. Some studies have suggested this as a risk for ACS during pregnancy [3,7], whilst one study suggested that when other confounding factors were eliminated, it no longer conferred a risk [2]. Pathophysiologically, there is widespread endothelial dysfunction seen in the pre-eclamptic and eclamptic state with increased vascular reactivity in the presence of noradrenaline and angiotensin II [7]. Aetiology ACS is an umbrella term that encompasses three different clinical entities characterised by a similar pathophysiological process – vulnerable plaque rupture or instability. ST elevation myocardial infarction (STEMI) is characterised by ST segment deviation upward from the baseline on an electrocardiogram (ECG), usually associated with pain and cardiac enzyme rise and pathologically characterised by occlusion of a coronary artery (usually thrombotic) (Figs. 1 and 2). Non-STEMI (NSTEMI) is the association of cardiac pain with elevation in the cardiac enzyme troponin levels, occasionally with ECG changes such as ST segment depression or T wave changes (not ST elevation), and is usually pathologically characterised by vulnerable plaque rupture without occlusion but probable distal embolisation. Lastly, unstable angina (UA) is characterised by cardiac ischaemia occurring at rest or for prolonged periods on minimal exertion, without enzyme rise and often without documented ECG changes that are characterised by an unstable or vulnerable plaque that may have the potential to rupture – there may be associated arterial spasm. The most common cause of ACS during pregnancy is vulnerable atherosclerotic plaque rupture – just as it is outside of pregnancy. When looking at reported series, around 40% of AMIs are caused by this during pregnancy [6,7], explaining why it is important to assess for the presence of atherosclerotic risk factors. For the reasons outlined above, there is the potential for the pregnant state to cause

Fig. 1. ECG of inferior STEMI. There is ST elevation in leads II, III and aVf with reciprocal ST depression in I, aVL and V2.

Please cite this article in press as: Fryearson J, Adamson DL, Heart disease in pregnancy: Ischaemic heart disease, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.03.011

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Fig. 2. ECG of patient with NSTEMI. There is clear ST depression V2 to V6 along with sinus tachycardia.

increased vulnerability and instability of coronary plaques, which can subsequently rupture and cause problems. Raised cholesterol level is well known to be a risk factor for the development of CAD, and in pregnancy, levels are known to increase by 40–60%. Similarly, coronary thrombus in the setting of normal coronary arteries is also reasonably prevalent occurring in 8–21% of cases [6,7]. There are numerous case reports of thromboembolism causing ACS in pregnancy via a presumed venous (paradoxical) thromboembolism in the presence of a patent foramen ovale [12,13]. Coronary dissection is a rare cause of ACS outside of pregnancy, usually accounting for 1% of patients having coronary angiography [14]; however, more than a third of these occur in pregnant patients. It accounts for around 16–27% of cases of ACS during pregnancy and may affect more than one artery [6,7,15,16]. It can present as STEMI or NSTEMI. It occurs more commonly in the over-30 age group, though its incidence decreases after age 40 and in multiparous women [11,14]. Interestingly, it is seen more commonly in the peripartum and postpartum period, being three times more common and accounting for around 50% of ACS episodes during this time. [6] In addition to increased stress and reduced arterial integrity, some report a role for eosinophilic infiltration, whose activity may be upregulated during pregnancy [10,17]. Whether this is a causative factor or a secondary healing response is unclear. Around 25% of patients may have apparently normal coronary arteries, this also predominantly occurs in the peripartum period [6,7]. There are a number of potential explanations for this. These include the possibility of a dissection flap spontaneously healing by the time angiography is performed, small dissections in branch arteries being missed or indeed dissections being contained within the arterial wall without an intimal tear. With the increasing use of coronary intravascular ultrasound (IVUS), this may become a more identifiable phenomenon. There are numerous reports of prolonged coronary spasm being demonstrated at angiography in pregnant patients with ACS, especially associated with ergot-based drugs and prostaglandins, and it is possible that temporary spasm can cause ACS, although may not be identified during angiography [18–20]. A less likely possibility is that of coronary thrombosis with spontaneous lysis. Please cite this article in press as: Fryearson J, Adamson DL, Heart disease in pregnancy: Ischaemic heart disease, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.03.011

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Diagnosis and investigations Many patients do not present with typical crushing chest pain that radiates to the jaw and arms associated with autonomic features, and this often underlies the difficulty in diagnosing cardiac pain in any patient presenting to a health-care professional. In pregnancy, this is compounded further by the fact that women often present with atypical pain and features; and pregnant patients (and health-care professionals) often ascribe such symptoms to dyspepsia. Added to this is the fact that many pregnant women develop minor exertional breathlessness and can perspire much more easily. One of the main areas of concern and criticism in previous CEMACH reports is, however, that chest pain in patients with known cardiac risk factors is too readily dismissed without further assessment or an inadequate assessment. Patients who present with pain to a health-care professional should be taken seriously and assessed thoroughly, especially if they have cardiovascular risk factors. The normal changes on the resting ECG in the pregnant woman include sinus tachycardia, 15 left axis deviation due to diaphragmatic elevation, T-wave inversion in III and aVF, subtle non-specific ST depression, supra-ventricular and ventricular ectopics and the development of small non-pathological Q waves (Fig. 3). STEMI should be a clinical diagnosis based on the presence of pain with typical ECG changes (either 1 mm of ST elevation in contiguous leadsdcorresponding to an arterial territorydor new left bundle branch block). All patients with a history of pain that may be due to cardiac ischaemia should have a prompt 12-lead ECG. ST elevation on an ECG remains fairly specific during pregnancy and labour, though other ECG changes have been observed in the absence of chest pain usually in patients undergoing C-section with regional anaesthesia. STEMI is a cardiovascular emergency and requires prompt treatment (see later). Diagnosing NSTEMI will be based on the presence of elevated cardiac troponin levels (or a documented rise and fall) in the setting of pain compatible with cardiac ischaemia. There may not be ECG changes, or if present, they may be subtle and non-specific. Troponin testing has revolutionised the diagnosis and management of ACS patients over the past 10 years or so, and has been shown to be much more sensitive than previous cardiac enzymes. This has led to an increase in the proportion of patients presenting with chest pain diagnosed with ACS. Their role in the diagnosis of ACS features heavily in international guidelines, with recommendations advising levels to be taken at presentation and 12 h after pain. Troponin levels have been demonstrated to remain sensitive and specific for myocardial cell injury in the setting of pregnancy in comparison with previously used cardiac enzymes

Fig. 3. This is an ECG of a 37-year-old lady who was 26 weeks pregnant. She has multiple ventricular ectopics, forming a salvo of VT, small Q waves in II and III and slight left axis deviation.

Please cite this article in press as: Fryearson J, Adamson DL, Heart disease in pregnancy: Ischaemic heart disease, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.03.011

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[21]. Patients with severe hypertension or pre-eclampsia may have elevated troponin levels in the absence of an ACS; however, all studies in this area have been very small and there are as many supportive studies for this phenomenon as there are discreditary [22–25]. It is now accepted that whilst troponin levels in the pre-eclamptic woman are raised when compared with the normotensive pregnant women, they should not exceed the diagnostic threshold for ACS. UA may present similarly to NSTEMI but without an elevated troponin level. Often these patients are still at high risk of future events, or developing more extensive ACS if not managed appropriately. These patients may not have ECG changes, and may therefore not be diagnosed. This underlines the importance of having a high index of suspicion in pregnant patients with unexplained chest pain especially in the presence of cardiovascular risk factors. It has been noted that female patients can not only have non-specific ECG changes at baseline but also dynamic changes around the peripartum period. In the absence of chest pain, this significance of this remains unclear [26]. In patients who are presenting with stable symptoms (symptoms or exertion), non-invasive investigations of cardiac ischaemia is the preferred management. Exercise testing is safe in pregnancy provided there are no obstetric complications such as per vaginal (PV) bleeding or significant placenta praevia. The disadvantage of this test, however, is the high false-positive rate in the non-pregnant woman. Dobutamine stress echo is an alternative. Whilst there is sparse literature regarding its use in pregnancy, there are no reported adverse effects, and therefore it is being increasingly used. MRI has been safely used in the second and third trimesters; however, there is no safety data on the use of gadolinium. Myocardial perfusion scanning is not used in pregnancy, as there are safer alternatives, which do not require the use of radiolabelled isotopes. Management Acute coronary syndromes Patients should be rapidly evaluated to obtain a history, assess cardiovascular haemodynamic status and establish any important clinical findings that may be a complication of ACS (such as pulmonary oedema, murmur, shock). An ECG should be performed as soon as possible and ideally within 5 min if chest pain is present. In addition to the initiation of supportive measures for the patient, diagnosis or exclusion of STEMI should be a priority. Opiate analgesia with appropriate anti-emetic therapy should be given, as well as oxygen supplementation in the presence of low arterial saturations [27]. Patients should be loaded with antiplatelet agents in the form of 300 mg of aspirin and at least 300 mg of clopidogrel. Outside of pregnancy, prasugrel or ticagrelor is the thienopyridine of choice for STEMI [28,29]; however, there is no safety data for their use in pregnancy, and therefore we would currently still recommend the use of clopidogrel. It is important that experienced members of the obstetric, cardiology and anaesthetic teams are involved in the management of these patients as soon as possible. Some case reports have advocated the use of hydrocortisone at an early stage in the management of these patients to promote foetal lung maturity in the event of emergency delivery [9,30]. ST elevation myocardial infarction A rapid diagnosis of a STEMI in a pregnant patient is of paramount importance to allow fast and effective management and reduce myocardial damage. The misinterpretation of diagnostic ECGs was a criticism of the CMACE report. The mainstay of treatment is effective reperfusion therapy to the occluded artery. Increasingly, this is being done with primary percutaneous coronary intervention (PPCI). This is not yet widespread throughout the UK or the developed world, largely due to problems with infrastructure, but has consistently been proven to have improved outcomes over and above the alternative of thrombolytic therapy, especially if performed in a timely manner. There are a number of advantages to PPCI over thrombolysis in the setting of pregnancy in particular. As described elsewhere in this article, there is a high proportion of ACS patients who have either coronary dissection or normal coronary arteries, which means that patients may be exposed to the risks of thrombolysis in the case of normal arteries, or in the presence of coronary dissection, the Please cite this article in press as: Fryearson J, Adamson DL, Heart disease in pregnancy: Ischaemic heart disease, Best Practice & Research Clinical Obstetrics and Gynaecology (2014), http://dx.doi.org/10.1016/ j.bpobgyn.2014.03.011

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problem is made worse by thrombolysis [31,32]. There are also the understandable concerns that peripartum MIs may be complicated by major life-threatening bleeding in the context of thrombolysis. Most authorities would advocate the use of PPCI for these reasons. If a diagnosis of STEMI is made, then measures should be taken to perform urgent coronary angiography, which may involve liaising with the local tertiary cardiology centre if transfer time is not >60 min. There will be rare occasions when there is no availability of coronary angiography. In these situations, potentially life-saving thrombolytic therapy should not be withheld. Pregnancy alone should not be considered a contraindication to thrombolysis. The evidence and safety data for thrombolysis in pregnancy come mostly from trials for the treatment of venous thromboembolism and pulmonary embolism (PE) in particular, with pregnant patients being excluded from trials for the treatment of STEMI. With thrombolysis for PE, the complication rate is in the order of 1% [8] with little placental transfer of lytic agents, though foetal haemorrhage has still been documented. [7] Non-ST elevation myocardial infarction/unstable angina For this group of patients, (cardiovascular) risk stratification should be performed as soon as possible. There are numerous risk score models that facilitate this (thrombolysis in myocardial infarction, TIMI; global registry of acute cardiac events, GRACE; etc.) and allow the identification of intermediate-to-high-risk patient groups versus low-risk groups. Evidence has shown that higher-risk patients benefit more from an (early) invasive strategy, that is, angiography with a view to coronary stenting, whereas low-risk patients can be managed medically with comparable outcomes in the absence of ongoing symptoms. In practice, this often translates to patients with elevated troponin levels, dynamic ECG changes and ongoing pain being identified for an invasive strategy. Although we would have a threshold for pregnant patients being managed invasively, there are cases of such patients being managed medically to term successfully [33]. Patients managed medically should be treated with aspirin, clopidogrel and a short course of low-molecular-weight heparin (LMWH), as well as ongoing anti-anginal agents. Coronary angiography The decision to perform coronary angiography is often felt to be a difficult one in the pregnant patient due to the radiation risk to the foetus (and mother). However, when the procedure is performed with lead shielding covering the mother’s abdomen and back, minimising the number of views obtained, reducing screening time and importantly high-dose acquisition time, foetal doses can be limited to

Heart disease in pregnancy: ischaemic heart disease.

Coronary artery disease and in particular acute coronary syndromes in pregnancy are increasing with high risk of mortality and significant morbidity. ...
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