Authors: Bhaskar Narayan
Categories: CME: Special Issue on Maternal Medicine, Pulmonary embolism, VTE, Pregnancy, Postpartum, Thrombolysis
Source: Clinical Medicine
Authors: Bhaskar Narayan
Pulmonary embolism (PE) is a significant cause of morbidity and mortality in pregnancy and the puerperium. In severe cases, it causes haemodynamic instability and can lead to cardiac arrest due to obstructive shock. Patients with acute PE can be risk stratified to guide their monitoring and treatment; this article focuses on intermediate- and high-risk PE. The criteria for defining high-risk PE can be used unmodified in pregnancy. Diagnostic imaging should not be delayed due to pregnancy. Low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) can be used during pregnancy and breastfeeding, and systemic thrombolysis can be used in obstetric patients, but there are significant bleeding risks and it should be reserved for high-risk PE with hypotension and shock. Although pregnancy and the puerperium are risk factors for PE, it is important to avoid early diagnostic closure, and to consider other causes for the patient’s presentation.
Key points 1.Patients with severe acute PE die of cardiovascular collapse rather than respiratory failure.2.CTPA and V/Q scans can both be performed during pregnancy where clinically indicated. Imaging should not be delayed in an acutely deteriorating patient and CTPA has some advantages in this context.3.Timely anticoagulation is essential – both LMWH and UFH can be used during pregnancy and while breastfeeding.4.Systemic thrombolysis can be used in life-threatening pregnancy-associated PE; risk-stratification and multidisciplinary input is important to determine the optimal management strategy.5.Consider other causes of deterioration, such as cardiac disease, sepsis and haemorrhage.
Pulmonary embolism (PE) is a leading cause of maternal mortality and morbidity.^1^ Venous thromboembolism (VTE) complicates approximately 1 in 1,000 pregnancies, and the risk of antenatal VTE is four- to fivefold higher in pregnant women than in non-pregnant women of the same age. It can occur at any stage of pregnancy, but the puerperium is the time of highest risk (relative risk as high as 20). The risk of VTE is particularly high in women with a history of thrombosis or additional risk factors such as active inflammatory disease, obesity or hyperemesis gravidarum.^2^
Acute PE affects both gas exchange and circulation. However, the circulatory dysfunction is the main cause of mortality and severe morbidity. There is an acute rise in pulmonary vascular resistance (PVR) due to occlusion of pulmonary vessels by thromboemboli, as well as pulmonary vasoconstriction mediated by serotonin and thromboxane A2.^3^ The sudden rise in PVR results in dilatation of the right ventricle (RV) due to pressure and volume overload. The RV has limited ability to compensate in the acute setting and the septum bows leftward, which in turn impairs left ventricle (LV) filling (‘ventricular interdependence’), reduces cardiac output and results in systemic hypotension and a downward spiral towards cardiovascular collapse (Fig. 1).^4^Fig. 1The ‘downward spiral’ of acute pulmonary hypertension, RV failure and obstructive shock.Fig 1
The clinical symptoms of PE include dyspnoea, pleuritic chest pain or haemoptysis. Pre-syncope or syncope can be a telltale sign of transient haemodynamic compromise in acute PE.^5^
These features are unchanged in pregnancy and the puerperium. While it is vital to have a high index of suspicion for PE in patients presenting with these symptoms, it is important to appreciate that other pathologies may also present in a similar manner. There is a risk of premature diagnostic closure if other diagnoses are overlooked because the patient is pregnant. Some of these conditions can have cardiovascular effects that may be misinterpreted as high-risk or intermediate/high-risk PE (Table 1).Table 1Differential diagnosis (other than PE) of chest pain with dyspnoea and haemodynamic changes in pregnancy.Table 1DiagnosisCommentsPneumoniaCan cause dyspnoea and pleuritic pain.Haemodynamic changes may be present in the context of sepsis.PneumothoraxCan cause dyspnoea and pleuritic pain.Haemodynamic compromise may be present in the context of tension pneumothoraxCardiac diseaseMyocardial ischaemia and cardiac failure can cause pain, dyspnoea and haemodynamic changes. Arrhythmia can cause dyspnoea and syncope.Aortic dissectionMore common in pregnancy, typically causes severe central/tearing chest pain.HaemorrhageMay be obstetric or non-obstetric and can be concealed (eg haemoperitoneum secondary to ectopic pregnancy or splenic artery aneurysm rupture). Can cause pain, tachypnoea and haemodynamic compromise.
The complete diagnostic work-up of pregnancy-associated PE is beyond the scope of this article, which focuses on intermediate/high- and high-risk PE in pregnancy. It is important to obtain a thorough history and examination. Point of care ultrasonography is a valuable adjunct to the clinical examination and is increasingly utilised in the acute care setting. This could include cardiac, thoracic, abdominal and lower limb ultrasound, which may identify alternative pathologies and/or help risk stratify the patient.
The diagnosis of PE is confirmed by either nuclear medicine ventilation/perfusion (V/Q) scanning or computerised tomography pulmonary angiogram (CTPA). These should not be denied or delayed if clinically indicated in pregnancy; Royal College of Obstetricians and Gynaecologists (RCOG) guidelines^2^ support the use of either modality and state that ‘compared with CTPA, V/Q scanning may carry a slightly increased risk of childhood cancer but is associated with a lower risk of maternal breast cancer; in both situations, the absolute risk is very small’. However, CTPA has several advantages as outlined in Box 1, and therefore should be considered first-line in the acutely unwell pregnant or postpartum patient with suspected PE.
Box 1Advantages of CTPA over V/Q scanning in the acutely unwell patient •More likely to be available and reported rapidly ‘out of hours’ (ie nights and weekends)•Assessment of RV size for risk stratification•Detailed information about clot burden and anatomy, to guide catheter-directed treatment if indicated•Identification of cardiac/aortic pathology Alt-text: Unlabelled box
Echocardiography is a useful additional investigation to identify RV dilatation or dysfunction. A dilated RV on CTPA may provide sufficient information for the purposes of risk stratification, but serial echocardiography can provide more dynamic information. The other key investigations are the cardiac biomarkers (serum troponin and/or BNP).
High-risk (previously known as ‘massive’) PE is defined by cardiac arrest or haemodynamic instability. ESC criteria^4^ for haemodynamic instability are a systolic blood pressure (SBP) <90 mmHg, a drop of SBP ≥40 mmHg without another cause, or obstructive shock with end-organ hypoperfusion. This is seen in approximately 7% of cases of pregnancy-associated PE,^6^ which is similar to the prevalence outside pregnancy. Mortality in high-risk PE is 15–30%^7^ and therefore urgent reperfusion treatment is required to relieve the obstructive shock.
Haemodynamically stable patients are considered intermediate risk if there is RV dilation, elevated troponin or elevated B-type natriuretic peptide (BNP). The presence of both RV dilatation and elevated cardiac biomarkers is a marker of intermediate/high-risk PE, which has previously been called labelled ‘submassive’ PE, which is associated with a 3–15% mortality.^8^ These patients need close monitoring, as they may acutely deteriorate and develop haemodynamic instability.
Although there are some physiological changes in pregnancy, it is reasonable to use the same criteria as in the general population for risk stratification of PE in pregnancy. Blood pressure falls slightly in the first trimester (due to vasodilatation), but a large contemporary prospective study (4P Study)^9^ showed only a small decrease from 12 weeks’ gestation, before rising back to normal towards the end of pregnancy. However, hypotension is rare; in the 4P study population, less than 3% had systolic blood pressure (sBP) <95 mmHg during the first and second trimester. This study informed the development of the UK national Maternal Early Warning Score,^10^ which uses sBP ≤93 mmHg as the threshold for significant hypotension. All of this supports the use of the standard thresholds for hypotension (sBP <90 mmHg) when assessing and managing PE in pregnancy.
There is a slight increase in the size of all heart chambers during pregnancy, but the LV/RV ratio remains unchanged^11^ and significant RV dilatation should not be attributed to pregnancy alone. Serum troponin and BNP should remain within the normal range,^12^ and can therefore still be used for risk stratification during pregnancy (Fig. 2).Fig. 2PE risk stratification – derived from Konstantinides et al.^4^Fig 2
Parenteral anticoagulation is the core treatment for pregnancy-associated intermediate/high- and high-risk PE. Both unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) can be used in pregnancy and during breastfeeding.^2^ If diagnostic imaging is not immediately available, and PE is the suspected diagnosis, the first dose should be given while awaiting confirmation by imaging.
Intravenous UFH is used in high-risk PE, where immediate reperfusion therapy (see below) is required. Its use in intermediate/high-risk PE has been largely superseded by subcutaneous LMWH, which has more predictable pharmacokinetics and therapeutic effect. Higher doses may be required in pregnancy (due to increased clearance).^2^
In the obstetric setting, the reversibility and shorter duration of effect of UFH may be preferred in certain circumstances (eg to facilitate neuraxial anaesthesia, or if there is very high bleeding risk). However, these perceived advantages need to be balanced against the difficulty in achieving safe and effective anticoagulation with this agent. A recent study found that the majority of patients with acute PE treated with UFH spend most of their first 48 hours outside the target range for anticoagulation.^13^
Direct oral anticoagulants (eg apixaban, rivaroxaban) should not be used during pregnancy. There are inadequate safety data and these drugs (unlike LMWH) cross the placenta, with the potential to cause bleeding in the fetus. There is also an association with reproductive toxicity in animal studies.
The acute mortality associated with PE is largely due to obstructive shock and haemodynamic collapse. Reperfusion therapies aim to rapidly break down the occlusive thrombus and relieve the obstruction.
Systemic intravenous administration of a fibrinolytic agent (thrombolysis) is recommended as the first-line treatment in high-risk PE.^4^ There is good evidence of benefit in haemodynamically unstable non-pregnant patients,^14^ but the evidence in pregnancy is limited to pre-clinical data and case reports/series.
First-generation agents (streptokinase and urokinase) have now been superseded by alteplase, which is a recombinant protein with a more favourable bleeding risk profile. None of these drugs cross the placenta in any significant quantity at therapeutic doses, and animal studies do not suggest any teratogenic effects.^15^
In a systematic review of more than 100 pregnant women with high-risk PE, of whom 83 received systemic thrombolysis, survival was 94%^16^ although this favourable rate may reflect reporting bias. The risk of major bleeding was 17.5% during pregnancy and 58.3% in the postpartum period. About half of severe postpartum PEs occurred within 24 h of delivery. There was a 12% rate of fetal death,^17^ possibly related to PE or its treatment.
Despite the bleeding risks, the high risk of deterioration and death mean that systemic thrombolysis is still recommended for life-threatening PE in pregnancy, in the context of severe hypotension, shock or cardiac arrest.^18^ However, it should not be used as initial therapy in haemodynamically stable intermediate/high-risk pregnancy-associated PE, as the bleeding risks outweigh the potential benefits. These patients should be anticoagulated and monitored closely, and thrombolysis considered if they deteriorate.
Percutaneous catheter-directed reperfusion therapies are an alternative to systemic thrombolysis and techniques include suction thrombectomy and catheter-directed low-dose thrombolysis. These treatments have been suggested as a way to achieve reperfusion with lower bleeding risk than systemic thrombolysis. Early safety and efficacy data are promising, but there is currently insufficient evidence on short- and long-term outcomes to support their routine use.^4^ Recent national guidance in the UK recommended that these treatments are only considered as part of a research trial or registry, or in patients ‘who cannot have thrombolysis, or when there are no other suitable treatment options or alternative treatments have failed’.^19^ There may therefore be a role for such treatments in pregnancy-associated high-risk or intermediate/high-risk PE, particularly in the peripartum period of greatest bleeding risk. However this should be on a case-by-case basis, following expert guidance.
Any pregnant or postpartum patient with haemodynamically significant PE should be discussed with the critical care team and considered for close monitoring in a high-dependency setting. IV fluid should be given in limited volumes to avoid overdistension of the decompensating RV. In the deteriorating patient, induction of anaesthesia, intubation and ventilation should be undertaken with great caution by experienced clinicians, as these patients are vulnerable to rapid cardiovascular collapse. Systemic vasopressors (eg noradrenaline) can be used if required. ‘Inodilator’ agents such as milrinone, dobutamine and levosimendan improve RV contractility and reduce pulmonary vascular resistance; they have a potential role in treating acute RV failure due to PE, but most of the literature and experience in pregnant/postpartum patients is in the treatment of cardiogenic shock secondary to chronic pulmonary hypertension^20^ or peripartum cardiomyopathy.^21^ For refractory shock, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been successfully used in this patient group.^11^
There is an increasing role for multidisciplinary ‘PE Response Teams’ (PERT) or ‘pregnancy heart teams’ to share expertise in the management of these complex, critically ill patients.^4^
Acute PE is a significant cause of morbidity and mortality in pregnancy and the puerperium. In severe cases, it causes haemodynamic instability and can lead to cardiac arrest due to obstructive shock. It is therefore important to risk stratify patients with acute PE, to guide their monitoring and treatment; the risk stratification criteria can be used unmodified during and after pregnancy. Diagnostic imaging should not be delayed due to pregnancy, and LMWH and UFH can be used during pregnancy and breastfeeding. Anticoagulation should be promptly initiated in suspected or confirmed PE; systemic thrombolysis can be used in obstetric patients, but there are significant bleeding risks and it should be reserved for high-risk PE with hypotension and shock. Catheter-directed treatments are available, but their precise role is yet to be determined. Although pregnancy and the puerperium are risk factors for PE, it is important to avoid early diagnostic closure, and to consider other causes for the patient's presentation.
No funding sources to declare.
Bhaskar Narayan: Writing – review & editing, Writing – original draft, Conceptualization.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.