Cardiovascular diseases (CVDs) are a major cause of complications in pregnancy worldwide and the number of patients who develop cardiac problems during pregnancy is increasing. This review summarises recent literature on the aetiology and the underlying pathophysiology, diagnostic tools, risk stratification and prognosis in women who develop heart failure during pregnancy and in the peri-partum phase as well as in patients with pre-existing cardiomyopathies undergoing pregnancy. We specifically highlight peri-partum cardiomyopathy, valvular disease and Marfan’s syndrome. Furthermore, we provide overviews on established treatment concepts and novel therapeutic strategies for these different disease types, stressing the point that pregnancy-associated cardiac disease requires interdisciplinary concepts for diagnosis, management and treatment.
Introduction
At present, 0.2–4% of all pregnancies in Western industrialised countries are complicated by cardiovascular diseases (CVDs) and the number of the patients who develop cardiac problems during pregnancy is increasing . In the first part of this chapter, we focus on heart failure in previously healthy women during pregnancy and the peri-partum phase. In the second part, we summarise the current knowledge on pre-existing cardiomyopathies, specifically valvular disease and Marfan’s syndrome in women undergoing pregnancy.
In the first group, we mainly focus on peri-partum cardiomyopathy (PPCM), a disease that is considered rare but may be often overlooked and therefore may occur much more frequently. We summarise recent knowledge on aetiology, diagnosis and management as well as the newest insights into the underlying pathomechanisms. In addition, we highlight potential biomarkers for disease monitoring and risk stratification and novel, efficient therapy concepts.
For the second group, knowledge of the risks associated with CVD during pregnancy and their management are of pivotal importance for advising patients before pregnancy. In this regard, guidelines on disease management in pregnancy are of great relevance as they give special consideration to the fact that all measures concern not only the mother, but also the foetus, as therapies favourable for the mother can be harmful for the child (i.e., foetotoxic effects of angiotensin-converting enzyme (ACE) inhibitors). Conversely, therapies to protect the child may lead to a suboptimal outcome for the mother .
As outlined in the recent update of the European Society of Cardiology (ESC) guidelines on the management of CVDs during pregnancy , a major problem in the field of pregnancy-related heart failure is that prospective or randomised studies are lacking; with a few exceptions, recommendations are mainly based on evidence level C. Therefore, registries and prospective studies are urgently needed to improve the state of knowledge. Furthermore, differences in the presentation, diagnosis and management are suspected for the pregnancy-related diseases in the focus of this review between developed Western countries and developing countries, a feature that we also address. Finally, we stress the point that pregnancy-associated cardiac disease requires interdisciplinary concepts for diagnosis, management and treatment.
Cardiomyopathies developing spontaneously in or shortly after pregnancy in previously healthy women
PPCM is the major cause of pregnancy-induced heart failure and is associated with high morbidity and mortality . The true incidence of PPCM is unknown, as clinical presentation varies. Current estimates, ranging from 1:299 (Haiti), to 1:1000 (South Africa) to 1:5556 (USA), are primarily based on case series from single-centre or retrospective questionnaires . No data exist on the frequency of the disease in Europe. Our own experience suggests that PPCM occurs in 1 in 1500–2000 pregnancies in Germany (personal observation of Hilfiker-Kleiner).
The pathophysiology of the disease is still far from being understood and it is likely that multiple factors contribute to the induction and progression of PPCM. Nevertheless, decisive advances have been achieved in understanding some underlying molecular cascades that are deregulated in PPCM. Among those, elevated pro-inflammatory serum markers such as sFas/Apo1, C-reactive protein (CRP), interferon-γ (IFN-γ) and interleukin (IL)-6 point to pro-inflammatory processes (pathogen-induced or auto-immune response) involved in the induction and the progression of PPCM and may have an impact on the prognosis of patients . Indeed, positive effects of Pentoxifyllin in reducing the production of a number of inflammatory cytokines such as tumour necrosis factor (TNF)-α and IL-6 or immune globulin therapy have been reported . More recent work points to an angiogenic imbalance being responsible for PPCM, involving an angiostatic and pro-apoptotic 16 kDa prolactin fragment and the soluble vascular endothelial growth factor (VEGF) receptor 1 (sFlt1), which leads to massive endothelial damage and myocardial dysfunction , a notion that is further supported by observations showing that endothelial microparticles are increased in acute PPCM . Genetic factors may contribute to the susceptibility to PPCM in patients with a positive family history of cardiomyopathy, who typically have a more severe course of disease, and are therefore considered as risk factors . Additional risk factors associated with PPCM are listed in Table 1 , where pregnancy-induced hypertensive disorders such as pre-eclampsia, HELLP syndrome (where H stands for haemolysis, EL for elevated liver enzymes and LP for low platelet count) and twin pregnancy are especially prominent.
| Pregnancy associated factors | General risk factors |
|---|---|
| Prolonged use of ß-agonists | Smoking |
| Pregnancy-induced hypertensive disorders | Diabetes |
| Caesarean section | Hypertension |
| Multiple childbirth, multiparity | Substance abuse |
| Teenage pregnancy | Obesity |
| Advanced age of mother | Malnutrition |
| Toxaemia | |
| Family history, ethnicity |
Symptoms in PPCM patients
The clinical presentation of patients with PPCM is similar to those with other forms of systolic heart failure secondary to cardiomyopathy but may be highly variable. Patients with only mild symptoms have been reported where PPCM becomes manifest in the last weeks of pregnancy up to 6 months following delivery in previously healthy women mainly through typical symptoms of cardiac failure such as dyspnoea on exertion, cough, orthopnoea and paroxysmal nocturnal dyspnoea . Additionally, less specific symptoms of cardiac congestion such as abdominal discomfort, pleuritic chest pain and palpitations can occur. However, such early signs and symptoms of heart failure can be mistaken for pregnancy- or peri-partum-associated physiological discomfort . For example, shortness of breath, leg oedema or fatigue are mild symptoms of heart failure but could also occur in normal pregnancy or early post-partum phase. This overlap in symptoms makes it difficult to sense heart failure, especially in previously healthy young women and may delay the diagnosis, which could explain why their first presentation is frequently with New York Heart Association (NYHA) III and IV classes. Such a late diagnosis is often associated with increased morbidity and mortality. Therefore, even in case of faint suspicion for PPCM, but especially in patients who have an elevated risk for the disease, an echocardiography should be performed to clarify the cardiac condition. In this regard, early biomarkers for the disease are warranted as discussed in the following paragraphs.
Diagnosis of PPCM: How to distinguish it from normal physiologic discomfort in the peri-partum phase
A redefinition of the diagnostic criteria for PPCM according to the most recent advances in clinical and experimental research has been published in a recent position paper from the Heart Failure Association of the European Society of Cardiology which says: 1) PPCM is an idiopathic cardiomyopathy presenting with heart failure secondary to left-ventricular (LV) systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause of heart failure is found and 2) it is a diagnosis of exclusion with a left-ventricular ejection fraction (LVEF) nearly always reduced below 45% but not always associated with LV dilatation.
Diagnostic tools useful for PPCM
Diagnosis of PPCM is based on exclusion criteria that include the absence of any identifiable cause for heart failure in women without known pre-existing cardiac disease and a strict time limit focussed on the last month of pregnancy and the first few months following delivery. These diagnostic criteria were intended to exclude congenital and acquired causes of heart failure that usually manifest by the second trimester due to physiological volume expansion . Physical examination should focus on signs of heart failure, such as hypoxia, third heart sound gallop rhythm, jugular venous distension, hepatomegaly and rales . The electrocardiography (ECG) presentation is quite variable: it may show normal ECG as in the majority of PPCM cases or prolongation of the PR or QRS intervals and evidence for LV hypertrophy and dysrhythmias .
Transthoracic echocardiography is the key tool for accurate diagnosis defined as an impairment of cardiac function manifest by a decrease in LVEF (EF <45%), fractional shortening (FS <30%) or both. Cardiac enlargement with an LV end-diastolic dimension >2.7 cm m −2 is also frequently evident, particularly in those women presenting late. However, some PPCM patients display normal ventricular dimensions suggesting that dilatation may not be specific for PPCM .
Recently, magnetic resonance imaging (MRI) has been used for the detection of myocardial damage in PPCM disease. Interestingly, many patients with PPCM do not exhibit a disease-specific cardiac MRI pattern. However, MRI is useful for the detection of inflammatory forms of PPCM or a thrombus formation . Echocardiography is sufficient for a functional analysis, especially in terms of disease progress.
In addition, as recommended by Sliwa et al. , a number of laboratory tests should be performed in patients with suspected PPCM: Full blood count, urea and electrolytes, CRP, blood glucose, D-dimer, creatine kinase-MB (CKMB) and cardiac troponin T (cTnT). In severe heart failure, international normalised ratio (INR) and arterial blood gas should also be performed. Transaminases, urinalysis and plasma B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) can be considered. Arterial blood gas analysis allows assessment of oxygenation (partial pressure of oxygen, pO 2 ), respiratory adequacy (partial pressure of carbon dioxide, pCO 2 ), acid–base balance (pH) and base deficit and should be performed in all patients with severe heart failure.
However, it should be noted that many of these classical markers normally associated with heart failure – elevation of CKMB, cTnT and CRP – may not be present in PPCM patients. In turn, a more specific serum marker profile including elevated NT-proBNP, oxidised low-density lipoprotein (oxLDL), prolactin and IFN-γ emerged in a more recent evaluation of PPCM patients with follow up . Furthermore, serum markers involved in the prolactin-cleaving pathway, such as activated Cathepsin D and 16-kDa prolactin , increased endothelial microparticles , and microRNA-146a associated with these microparticles may emerge as more specific diagnostic tools for PPCM.
In summary, due to the observations that early signs and symptoms of heart failure can be mistaken for pregnancy-/peri-partum-associated physiological discomfort, disease-specific biomarkers would be helpful for early diagnosis of PPCM. The diagnosis of PPCM defined as a systolic LV dysfunction can only be made by echocardiography or MRI.
Pathophysiology involved in PPCM
The pathophysiology of PPCM is not clear and it is likely that not one specific factor but rather the coincidental presence of multiple factors induce this disease in previously healthy women. Such factors include:
- a)
Inflammation: There is some evidence that pathogen- or auto-immune-related inflammation in the peri-partum phase may promote the development of PPCM. There were virus-positive myocardial biopsies reported in PPCM patients and experimental data suggest that viral infection of the heart may enhance the PPCM phenotype . Furthermore, there are reports that describe increased levels of auto-immune antibodies in the serum of PPCM patients . Interestingly, the serum marker profile suggested that inflammatory conditions are very frequent in PPCM patients from South Africa with increased serum levels of pro-inflammatory cytokines (IL-6, TNF-α and IFNγ) . In the same patient collective, the TNF-α inhibitor pentoxifyllin showed beneficial effects .
- b)
Oxidative stress and prolactin cleavage: Experimental results suggest that impaired anti-oxidative defence resulting in increased oxidative stress in the heart promotes PPCM. Such an enhanced oxidative stress seems to activate enzymes like Cathepsin D, which cleaves the nursing hormone prolactin into an N-terminal 16-kDa fragment . This 16-kDa form of prolactin injures endothelial cells and the capillary network. It promotes vasoconstriction and lowers metabolic activity and function of cardiomyocytes . Pharmacological treatment with bromocriptine, an inhibitor of prolactin secretion, prevents the development of PPCM in mice . Furthermore, first studies suggest that bromocriptine may have positive effects in patients with PPCM .
- c)
Impaired vasculature and pregnancy-associated hypertension: Patients with pregnancy-induced hypertension, pre-eclampsia and HELLP syndrome have an enhanced risk for PPCM. It is hypothesised that this is caused by systemic angiogenic imbalance. In humans, the placenta in late gestation secretes anti-angiogenic factors such as 16-kDa prolactin, vasopressin and VEGF inhibitors such as soluble FLT1 (sFLT1). Pre-eclampsia and multiple pregnancies seem to be associated with increased secretion of these factors . In turn, experimental data suggest that the heart needs to increase its expression of pro-angiogenic factors such as VEGF for protection against peripartal stress. This notion is supported by findings that mice which lack cardiac proliferator-activated receptor γ coactivator 1α (PGC-1α), a powerful positive regulator of VEGF, develop profound PPCM with massive loss of myocardial capillaries . The combination of prolactin blockade with bromocriptine and a VEGF analogue prevented PPCM in these mice and might therefore be a novel and more effective treatment option in PPCM .
- d)
Genetic background: A few studies report pregnancy-associated cardiomyopathy in patients with a family history of cardiomyopathy . It is likely that in some of these cases the elevated haemodynamic and/or hormonal stress during pregnancy unmask a sub-clinical cardiomyopathy.
- e)
Pregnancy-induced hypertension: About 5% of all pregnancies are complicated by hypertensive complications including pre-eclampsia and HELLP syndrome . These conditions are also risk factors for PPCM. In fact, a recent single-centre study in Ireland reported pre-eclampsia in nine out of 12 PPCM cases . Likewise, a study collective in Japan reported a high frequency of pre-eclampsia in PPCM patients as did the authors in their German PPCM registry (Hilfiker-Kleiner, personal observation). Since pre-eclampsia per se can induce heart failure , there is some controversy among experts whether patients with pregnancy-induced hypertension should be classified as PPCM (Bachelier-Walenta et al. Obstetric Medicine , in press). In fact, this may be difficult as there is overlap in the pathophysiology of both disease types with regard to impairment of the endothelium and it may indeed not be possible to clearly distinguish between pre-eclampsia/HELLP syndrome and PPCM, albeit most patients with pregnancy-induced hypertensive complications do not develop heart failure and it may need a second hit to induce the PPCM condition .
Treatment of PPCM
According to the newest guidelines of the ESC , PPCM patients should be treated with heart failure medication, mainly beta-blockers, ACE inhibitors (or angiotensin-receptor blockers, ARBs) and mineralocorticoid-receptor blockers (MRAs). Diuretics should only be used, if needed. It is important to note that PPCMs have increased the risk of thrombosis, especially if LV function is substantially decreased. Therefore, prophylactic or therapeutic anticoagulation should be used. This is of specific importance, if bromocriptine is used to stop nursing, or as therapeutic option because bromocriptine may enhance the risk of thrombosis.
Therapies involving catecholamines (inotropic substances or vasopressors) should be avoided and may lead to progression of the disease in a therapy-resistant situation. In turn, our experience suggests that even in patients with severely reduced cardiac function a well-dosed and well-supervised beta-blocker therapy appears to be beneficial. However, therapy should be induced and closely monitored by a cardiologist.
In cases of therapy-resistant patients extracorporal life support (ECLS) may help to stabilise a patient and a left-ventricular assist device (LVAD) may be used as a ‘bridge to recovery’ or ‘bridge to transplantation’. It is important to note that the majority of patients, even with severely reduced cardiac function, recover under optimal therapy and therefore invasive therapy options should only be used as a last resort.
Mortality due to PPCM is caused by heart failure, thrombo-embolism and ventricular fibrillation. Patients with persistent poor LV function 6 months after diagnosis need an implantable cardioverter–defibrillator (ICD). Wearable portable defibrillators should be indicated in patients with highly reduced LV function or high risk of sudden death.
Newer, more specific therapy options derive from experimental research where, for example, a pathophysiologic effect could be assigned to the cleaved 16-kDa prolactin fragment. The first pilot trials and healing attempts in PPCM patients in South Africa and Germany using bromocriptine to block prolactin yielded positive effects . While the treatment is now used regularly in South Africa, further clinical evidence for the efficacy of this therapy is needed and a larger multicentre randomised trial is currently underway in Germany (ClinicalTrials.gov, NCT00998556).
Prognosis
Very little is known about the incidence of PPCM. Prospective, population-based, epidemiologic studies have not been performed in Europe and the US. The number of patients with a benign course of the disease is unknown.
End-stage heart failure (transplantation and death) due to PPCM is seen in 10–23% of patients, while recovery of an LVEF over 50% is reported in about 50% of the patients. Predictors of therapy failure seem to be poor LV function (LV-EF <30% or fractional shortening <20%), an LV end-diastolic diameter >6 cm and an elevated Troponin T .
Nevertheless, while it seems that both poor LV function at the time of diagnosis and dilated LV have a higher chance for an adverse outcome, it should be noted that many patients with poor baseline conditions recover as well. In fact, improvement of LV function during treatment has been observed even years after diagnosis . In turn, we observe that in some patients with normalised LV function worsening of heart failure occurs after discontinuing medication. A reason could be a sub-clinical irreversible injury of the myocardium or vascular system in PPCM. Therefore, careful evaluation of whether a recovered PPC patient is really stable without heart failure medication is required.
Interdisciplinary management
When PPCM occurs in pregnancy, the situation is life threatening for the foetus. The heart failure condition in PPCM and the heart failure treatment may cause placental insufficiency, leading to intrauterine foetal death or premature birth. Therefore, interdisciplinary management is required to treat a pregnant woman with heart failure, requiring a team of cardiologists, obstetricians, neonatologists, anaesthetists and, if necessary, cardiac surgeons who have to confer among each other and manage the situation together. The guidelines of the ESC for the management of CVD in pregnancy are helpful instructions .
As mentioned above, the unborn child has also to be carefully monitored as the cardiac recompensation therapy in the mother could be followed by placental insufficiency causing the death of the foetus. Therefore, decisions have to be taken which help to rescue the mother’s and, if possible, also the foetus’ life, by considering a premature delivery with a timely use of corticosteroids for foetal lung maturation.
The mode of delivery should be adapted to the condition of the mother considering the ESC guidelines, also with regard to anaesthesia in severe heart failure .
Subsequent pregnancy
After recovery from PPCM, there is an elevated risk of heart failure in a subsequent pregnancy. In general, the severity of PPCM in a subsequent pregnancy increases . Patients with persistent reduced LV function before subsequent pregnancy have an especially high risk of a recurrence of PPCM . A pilot study in South Africa and case reports from Germany indicate that patients with subsequent pregnancy after PPCM appear to profit from an early treatment with bromocriptine starting right after delivery and induction of heart failure medication as soon as haemodynamic stability is reached .
Therefore, all patients have to be informed about the relatively high risk of a relapse of PPCM in a subsequent pregnancy. If the LV function has not recovered to a normal range, patients should be advised not to get pregnant again. If a patient becomes pregnant again, a continuous obstetrics- and cardiology-based care during pregnancy is necessary. Physicians experienced in treating PPCM should counsel patients with subsequent pregnancies. For example, it is important to note that PPCM may not be prevented by an early termination of pregnancy because the trigger for the disease seems to be associated with the peri-partum physiology and because we have cases where PPCM started after a miscarriage in the first trimester.
The ESC guidelines on the management of CVD during pregnancy point out the importance of pregnancy status for treatment of chronic heart failure as foetotoxic treatment, such as ACE inhibitors and ARBs ( Table 1 ), has to be stopped in pregnant women, while the treatment with β-blockers could be continued .
Differential Diagnosis of PPCM
PPCM is a diagnosis of exclusion. It is, by definition, a disease that occurs in the last month of pregnancy and the months following delivery. Maternal heart failure that appears before that last trimester may therefore have other causes. For example, pre-existing congenital or acquired cardiac diseases that were unmasked under a growing haemodynamic workload, or hypertensive heart disease caused by untreated hypertension or pregnancy-induced hypertension may be a reason for these types of heart failures.
Notably, patients after chemotherapy often develop heart failure in pregnancy. In patients with chemotherapy-induced cardiomyopathy, the worsening under a pregnancy does not fulfil the definition of PPCM. In turn, patients who do not develop cardiomyopathy after chemotherapy but who develop heart failure peri-partum may be considered PPCM.
Thus, chemotherapy has to be considered a risk factor for peri-partum heart failure. As both patient types seem to benefit from an early heart failure treatment, we advise cardiologic assessments before, during and after pregnancy to these patients.
Peri-partum myocardial infarction is a rare complication. Its pathophysiology, diagnosis, treatment and prognosis is reviewed by El-Deeb and co-workers .
Another differential diagnosis is a pulmonary embolism. Thrombo-embolic complications have also been observed in patients with PPCM caused by lowered cardiac output .
Cardiomyopathies developing spontaneously in or shortly after pregnancy in previously healthy women
PPCM is the major cause of pregnancy-induced heart failure and is associated with high morbidity and mortality . The true incidence of PPCM is unknown, as clinical presentation varies. Current estimates, ranging from 1:299 (Haiti), to 1:1000 (South Africa) to 1:5556 (USA), are primarily based on case series from single-centre or retrospective questionnaires . No data exist on the frequency of the disease in Europe. Our own experience suggests that PPCM occurs in 1 in 1500–2000 pregnancies in Germany (personal observation of Hilfiker-Kleiner).
The pathophysiology of the disease is still far from being understood and it is likely that multiple factors contribute to the induction and progression of PPCM. Nevertheless, decisive advances have been achieved in understanding some underlying molecular cascades that are deregulated in PPCM. Among those, elevated pro-inflammatory serum markers such as sFas/Apo1, C-reactive protein (CRP), interferon-γ (IFN-γ) and interleukin (IL)-6 point to pro-inflammatory processes (pathogen-induced or auto-immune response) involved in the induction and the progression of PPCM and may have an impact on the prognosis of patients . Indeed, positive effects of Pentoxifyllin in reducing the production of a number of inflammatory cytokines such as tumour necrosis factor (TNF)-α and IL-6 or immune globulin therapy have been reported . More recent work points to an angiogenic imbalance being responsible for PPCM, involving an angiostatic and pro-apoptotic 16 kDa prolactin fragment and the soluble vascular endothelial growth factor (VEGF) receptor 1 (sFlt1), which leads to massive endothelial damage and myocardial dysfunction , a notion that is further supported by observations showing that endothelial microparticles are increased in acute PPCM . Genetic factors may contribute to the susceptibility to PPCM in patients with a positive family history of cardiomyopathy, who typically have a more severe course of disease, and are therefore considered as risk factors . Additional risk factors associated with PPCM are listed in Table 1 , where pregnancy-induced hypertensive disorders such as pre-eclampsia, HELLP syndrome (where H stands for haemolysis, EL for elevated liver enzymes and LP for low platelet count) and twin pregnancy are especially prominent.
| Pregnancy associated factors | General risk factors |
|---|---|
| Prolonged use of ß-agonists | Smoking |
| Pregnancy-induced hypertensive disorders | Diabetes |
| Caesarean section | Hypertension |
| Multiple childbirth, multiparity | Substance abuse |
| Teenage pregnancy | Obesity |
| Advanced age of mother | Malnutrition |
| Toxaemia | |
| Family history, ethnicity |
Symptoms in PPCM patients
The clinical presentation of patients with PPCM is similar to those with other forms of systolic heart failure secondary to cardiomyopathy but may be highly variable. Patients with only mild symptoms have been reported where PPCM becomes manifest in the last weeks of pregnancy up to 6 months following delivery in previously healthy women mainly through typical symptoms of cardiac failure such as dyspnoea on exertion, cough, orthopnoea and paroxysmal nocturnal dyspnoea . Additionally, less specific symptoms of cardiac congestion such as abdominal discomfort, pleuritic chest pain and palpitations can occur. However, such early signs and symptoms of heart failure can be mistaken for pregnancy- or peri-partum-associated physiological discomfort . For example, shortness of breath, leg oedema or fatigue are mild symptoms of heart failure but could also occur in normal pregnancy or early post-partum phase. This overlap in symptoms makes it difficult to sense heart failure, especially in previously healthy young women and may delay the diagnosis, which could explain why their first presentation is frequently with New York Heart Association (NYHA) III and IV classes. Such a late diagnosis is often associated with increased morbidity and mortality. Therefore, even in case of faint suspicion for PPCM, but especially in patients who have an elevated risk for the disease, an echocardiography should be performed to clarify the cardiac condition. In this regard, early biomarkers for the disease are warranted as discussed in the following paragraphs.
Diagnosis of PPCM: How to distinguish it from normal physiologic discomfort in the peri-partum phase
A redefinition of the diagnostic criteria for PPCM according to the most recent advances in clinical and experimental research has been published in a recent position paper from the Heart Failure Association of the European Society of Cardiology which says: 1) PPCM is an idiopathic cardiomyopathy presenting with heart failure secondary to left-ventricular (LV) systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause of heart failure is found and 2) it is a diagnosis of exclusion with a left-ventricular ejection fraction (LVEF) nearly always reduced below 45% but not always associated with LV dilatation.
Diagnostic tools useful for PPCM
Diagnosis of PPCM is based on exclusion criteria that include the absence of any identifiable cause for heart failure in women without known pre-existing cardiac disease and a strict time limit focussed on the last month of pregnancy and the first few months following delivery. These diagnostic criteria were intended to exclude congenital and acquired causes of heart failure that usually manifest by the second trimester due to physiological volume expansion . Physical examination should focus on signs of heart failure, such as hypoxia, third heart sound gallop rhythm, jugular venous distension, hepatomegaly and rales . The electrocardiography (ECG) presentation is quite variable: it may show normal ECG as in the majority of PPCM cases or prolongation of the PR or QRS intervals and evidence for LV hypertrophy and dysrhythmias .
Transthoracic echocardiography is the key tool for accurate diagnosis defined as an impairment of cardiac function manifest by a decrease in LVEF (EF <45%), fractional shortening (FS <30%) or both. Cardiac enlargement with an LV end-diastolic dimension >2.7 cm m −2 is also frequently evident, particularly in those women presenting late. However, some PPCM patients display normal ventricular dimensions suggesting that dilatation may not be specific for PPCM .
Recently, magnetic resonance imaging (MRI) has been used for the detection of myocardial damage in PPCM disease. Interestingly, many patients with PPCM do not exhibit a disease-specific cardiac MRI pattern. However, MRI is useful for the detection of inflammatory forms of PPCM or a thrombus formation . Echocardiography is sufficient for a functional analysis, especially in terms of disease progress.
In addition, as recommended by Sliwa et al. , a number of laboratory tests should be performed in patients with suspected PPCM: Full blood count, urea and electrolytes, CRP, blood glucose, D-dimer, creatine kinase-MB (CKMB) and cardiac troponin T (cTnT). In severe heart failure, international normalised ratio (INR) and arterial blood gas should also be performed. Transaminases, urinalysis and plasma B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) can be considered. Arterial blood gas analysis allows assessment of oxygenation (partial pressure of oxygen, pO 2 ), respiratory adequacy (partial pressure of carbon dioxide, pCO 2 ), acid–base balance (pH) and base deficit and should be performed in all patients with severe heart failure.
However, it should be noted that many of these classical markers normally associated with heart failure – elevation of CKMB, cTnT and CRP – may not be present in PPCM patients. In turn, a more specific serum marker profile including elevated NT-proBNP, oxidised low-density lipoprotein (oxLDL), prolactin and IFN-γ emerged in a more recent evaluation of PPCM patients with follow up . Furthermore, serum markers involved in the prolactin-cleaving pathway, such as activated Cathepsin D and 16-kDa prolactin , increased endothelial microparticles , and microRNA-146a associated with these microparticles may emerge as more specific diagnostic tools for PPCM.
In summary, due to the observations that early signs and symptoms of heart failure can be mistaken for pregnancy-/peri-partum-associated physiological discomfort, disease-specific biomarkers would be helpful for early diagnosis of PPCM. The diagnosis of PPCM defined as a systolic LV dysfunction can only be made by echocardiography or MRI.
Pathophysiology involved in PPCM
The pathophysiology of PPCM is not clear and it is likely that not one specific factor but rather the coincidental presence of multiple factors induce this disease in previously healthy women. Such factors include:
- a)
Inflammation: There is some evidence that pathogen- or auto-immune-related inflammation in the peri-partum phase may promote the development of PPCM. There were virus-positive myocardial biopsies reported in PPCM patients and experimental data suggest that viral infection of the heart may enhance the PPCM phenotype . Furthermore, there are reports that describe increased levels of auto-immune antibodies in the serum of PPCM patients . Interestingly, the serum marker profile suggested that inflammatory conditions are very frequent in PPCM patients from South Africa with increased serum levels of pro-inflammatory cytokines (IL-6, TNF-α and IFNγ) . In the same patient collective, the TNF-α inhibitor pentoxifyllin showed beneficial effects .
- b)
Oxidative stress and prolactin cleavage: Experimental results suggest that impaired anti-oxidative defence resulting in increased oxidative stress in the heart promotes PPCM. Such an enhanced oxidative stress seems to activate enzymes like Cathepsin D, which cleaves the nursing hormone prolactin into an N-terminal 16-kDa fragment . This 16-kDa form of prolactin injures endothelial cells and the capillary network. It promotes vasoconstriction and lowers metabolic activity and function of cardiomyocytes . Pharmacological treatment with bromocriptine, an inhibitor of prolactin secretion, prevents the development of PPCM in mice . Furthermore, first studies suggest that bromocriptine may have positive effects in patients with PPCM .
- c)
Impaired vasculature and pregnancy-associated hypertension: Patients with pregnancy-induced hypertension, pre-eclampsia and HELLP syndrome have an enhanced risk for PPCM. It is hypothesised that this is caused by systemic angiogenic imbalance. In humans, the placenta in late gestation secretes anti-angiogenic factors such as 16-kDa prolactin, vasopressin and VEGF inhibitors such as soluble FLT1 (sFLT1). Pre-eclampsia and multiple pregnancies seem to be associated with increased secretion of these factors . In turn, experimental data suggest that the heart needs to increase its expression of pro-angiogenic factors such as VEGF for protection against peripartal stress. This notion is supported by findings that mice which lack cardiac proliferator-activated receptor γ coactivator 1α (PGC-1α), a powerful positive regulator of VEGF, develop profound PPCM with massive loss of myocardial capillaries . The combination of prolactin blockade with bromocriptine and a VEGF analogue prevented PPCM in these mice and might therefore be a novel and more effective treatment option in PPCM .
- d)
Genetic background: A few studies report pregnancy-associated cardiomyopathy in patients with a family history of cardiomyopathy . It is likely that in some of these cases the elevated haemodynamic and/or hormonal stress during pregnancy unmask a sub-clinical cardiomyopathy.
- e)
Pregnancy-induced hypertension: About 5% of all pregnancies are complicated by hypertensive complications including pre-eclampsia and HELLP syndrome . These conditions are also risk factors for PPCM. In fact, a recent single-centre study in Ireland reported pre-eclampsia in nine out of 12 PPCM cases . Likewise, a study collective in Japan reported a high frequency of pre-eclampsia in PPCM patients as did the authors in their German PPCM registry (Hilfiker-Kleiner, personal observation). Since pre-eclampsia per se can induce heart failure , there is some controversy among experts whether patients with pregnancy-induced hypertension should be classified as PPCM (Bachelier-Walenta et al. Obstetric Medicine , in press). In fact, this may be difficult as there is overlap in the pathophysiology of both disease types with regard to impairment of the endothelium and it may indeed not be possible to clearly distinguish between pre-eclampsia/HELLP syndrome and PPCM, albeit most patients with pregnancy-induced hypertensive complications do not develop heart failure and it may need a second hit to induce the PPCM condition .
Treatment of PPCM
According to the newest guidelines of the ESC , PPCM patients should be treated with heart failure medication, mainly beta-blockers, ACE inhibitors (or angiotensin-receptor blockers, ARBs) and mineralocorticoid-receptor blockers (MRAs). Diuretics should only be used, if needed. It is important to note that PPCMs have increased the risk of thrombosis, especially if LV function is substantially decreased. Therefore, prophylactic or therapeutic anticoagulation should be used. This is of specific importance, if bromocriptine is used to stop nursing, or as therapeutic option because bromocriptine may enhance the risk of thrombosis.
Therapies involving catecholamines (inotropic substances or vasopressors) should be avoided and may lead to progression of the disease in a therapy-resistant situation. In turn, our experience suggests that even in patients with severely reduced cardiac function a well-dosed and well-supervised beta-blocker therapy appears to be beneficial. However, therapy should be induced and closely monitored by a cardiologist.
In cases of therapy-resistant patients extracorporal life support (ECLS) may help to stabilise a patient and a left-ventricular assist device (LVAD) may be used as a ‘bridge to recovery’ or ‘bridge to transplantation’. It is important to note that the majority of patients, even with severely reduced cardiac function, recover under optimal therapy and therefore invasive therapy options should only be used as a last resort.
Mortality due to PPCM is caused by heart failure, thrombo-embolism and ventricular fibrillation. Patients with persistent poor LV function 6 months after diagnosis need an implantable cardioverter–defibrillator (ICD). Wearable portable defibrillators should be indicated in patients with highly reduced LV function or high risk of sudden death.
Newer, more specific therapy options derive from experimental research where, for example, a pathophysiologic effect could be assigned to the cleaved 16-kDa prolactin fragment. The first pilot trials and healing attempts in PPCM patients in South Africa and Germany using bromocriptine to block prolactin yielded positive effects . While the treatment is now used regularly in South Africa, further clinical evidence for the efficacy of this therapy is needed and a larger multicentre randomised trial is currently underway in Germany (ClinicalTrials.gov, NCT00998556).
Prognosis
Very little is known about the incidence of PPCM. Prospective, population-based, epidemiologic studies have not been performed in Europe and the US. The number of patients with a benign course of the disease is unknown.
End-stage heart failure (transplantation and death) due to PPCM is seen in 10–23% of patients, while recovery of an LVEF over 50% is reported in about 50% of the patients. Predictors of therapy failure seem to be poor LV function (LV-EF <30% or fractional shortening <20%), an LV end-diastolic diameter >6 cm and an elevated Troponin T .
Nevertheless, while it seems that both poor LV function at the time of diagnosis and dilated LV have a higher chance for an adverse outcome, it should be noted that many patients with poor baseline conditions recover as well. In fact, improvement of LV function during treatment has been observed even years after diagnosis . In turn, we observe that in some patients with normalised LV function worsening of heart failure occurs after discontinuing medication. A reason could be a sub-clinical irreversible injury of the myocardium or vascular system in PPCM. Therefore, careful evaluation of whether a recovered PPC patient is really stable without heart failure medication is required.
Interdisciplinary management
When PPCM occurs in pregnancy, the situation is life threatening for the foetus. The heart failure condition in PPCM and the heart failure treatment may cause placental insufficiency, leading to intrauterine foetal death or premature birth. Therefore, interdisciplinary management is required to treat a pregnant woman with heart failure, requiring a team of cardiologists, obstetricians, neonatologists, anaesthetists and, if necessary, cardiac surgeons who have to confer among each other and manage the situation together. The guidelines of the ESC for the management of CVD in pregnancy are helpful instructions .
As mentioned above, the unborn child has also to be carefully monitored as the cardiac recompensation therapy in the mother could be followed by placental insufficiency causing the death of the foetus. Therefore, decisions have to be taken which help to rescue the mother’s and, if possible, also the foetus’ life, by considering a premature delivery with a timely use of corticosteroids for foetal lung maturation.
The mode of delivery should be adapted to the condition of the mother considering the ESC guidelines, also with regard to anaesthesia in severe heart failure .
Subsequent pregnancy
After recovery from PPCM, there is an elevated risk of heart failure in a subsequent pregnancy. In general, the severity of PPCM in a subsequent pregnancy increases . Patients with persistent reduced LV function before subsequent pregnancy have an especially high risk of a recurrence of PPCM . A pilot study in South Africa and case reports from Germany indicate that patients with subsequent pregnancy after PPCM appear to profit from an early treatment with bromocriptine starting right after delivery and induction of heart failure medication as soon as haemodynamic stability is reached .
Therefore, all patients have to be informed about the relatively high risk of a relapse of PPCM in a subsequent pregnancy. If the LV function has not recovered to a normal range, patients should be advised not to get pregnant again. If a patient becomes pregnant again, a continuous obstetrics- and cardiology-based care during pregnancy is necessary. Physicians experienced in treating PPCM should counsel patients with subsequent pregnancies. For example, it is important to note that PPCM may not be prevented by an early termination of pregnancy because the trigger for the disease seems to be associated with the peri-partum physiology and because we have cases where PPCM started after a miscarriage in the first trimester.
The ESC guidelines on the management of CVD during pregnancy point out the importance of pregnancy status for treatment of chronic heart failure as foetotoxic treatment, such as ACE inhibitors and ARBs ( Table 1 ), has to be stopped in pregnant women, while the treatment with β-blockers could be continued .
Differential Diagnosis of PPCM
PPCM is a diagnosis of exclusion. It is, by definition, a disease that occurs in the last month of pregnancy and the months following delivery. Maternal heart failure that appears before that last trimester may therefore have other causes. For example, pre-existing congenital or acquired cardiac diseases that were unmasked under a growing haemodynamic workload, or hypertensive heart disease caused by untreated hypertension or pregnancy-induced hypertension may be a reason for these types of heart failures.
Notably, patients after chemotherapy often develop heart failure in pregnancy. In patients with chemotherapy-induced cardiomyopathy, the worsening under a pregnancy does not fulfil the definition of PPCM. In turn, patients who do not develop cardiomyopathy after chemotherapy but who develop heart failure peri-partum may be considered PPCM.
Thus, chemotherapy has to be considered a risk factor for peri-partum heart failure. As both patient types seem to benefit from an early heart failure treatment, we advise cardiologic assessments before, during and after pregnancy to these patients.
Peri-partum myocardial infarction is a rare complication. Its pathophysiology, diagnosis, treatment and prognosis is reviewed by El-Deeb and co-workers .
Another differential diagnosis is a pulmonary embolism. Thrombo-embolic complications have also been observed in patients with PPCM caused by lowered cardiac output .
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