Acute Medicine 2013; 12(4): 239-245 239 Problem-Based Review Problem based review: pulmonary embolism in pregnancy F Neuberger & N Wennike Abstract Pulmonary embolism (PE) in pregnancy carries a significant mortality. Pregnant patients often present via the acute medical take with symptoms of possible PE and require timely assessment and investigation. The symptoms of PE are sometimes very difficult to differentiate from those of normal pregnancy and the vast majority of patients will require imaging. The radiation risks to mother and foetus from imaging may cause considerable anxiety (to both patients and healthcare providers) and need to be explained to patients in the context of a potentially life-threatening condition so they can be actively involved in decision-making on how best to proceed. When PE is diagnosed in pregnancy, there are obstetric considerations around the time of delivery and women should receive specialist follow-up. Keywords pulmonary embolism, pregnancy. Key Points • PE is a major cause of maternal death in the UK and carries a significant mortality if untreated. • Diagnosis or exclusion of PE based on symptoms or signs alone is very difficult in pregnancy making objective diagnosis essential. • Thrombophilia screens should not routinely be carried out on women presenting with PE while they are pregnant. • Novel Oral Anticoagulants (NOACs) are not licensed for use during pregnancy or by women who are breast-feeding. Introduction A pregnant patient with breathlessness is frequently encountered on the acute medical take, and can present a challenge to Acute Physicians. Venous thromboembolism (VTE) is up to ten times more common in pregnant women compared with nonpregnant women of the same age1 and is still a major cause of direct maternal death in the UK.2 Clinical assessment of pregnant women with suspected PE is challenging, as symptoms of PE can mimic those of normal pregnancy.3 There are a range of clinical scoring systems, laboratory and radiological investigations available to the clinician, many of which are not validated in pregnancy. Acute Physicians need to be aware of the limitations of clinical assessment in assessing pregnant women with suspected PE. They must also be knowledgeable about each of the investigations which may be proposed for a pregnant woman, to enable an informed decision to be made about how best to proceed. This review will focus on the assessment, investigation and treatment of pregnant women with suspected PE. What is the scale of the problem of PE in pregnancy? The Confidential Enquiry into Maternal and Child Health (CEMACH) report from 2007,4 identified thromboembolism as the major direct cause (i.e. condition attributed directly to the pregnancy itself) of maternal death in the UK. Treatment received © 2013 Rila Publications Ltd. by patients was considered substandard in the majority of cases of thromboembolism. The major deficiencies were poor risk assessment of patients, failure to recognise symptoms of thromboembolism, underinvestigation due to perceived risks of radiation exposure and failure to administer appropriate treatment. The incidence of PE in pregnancy is somewhere between 1 in 1000 and 1 in 10,000 pregnancies.3 It is a common misconception that the incidence of PE increases with each subsequent trimester; at least half of VTE in pregnancy occurs in the first twenty weeks.5 Hypercoagulability and venous stasis in pregnancy are the major risk factors; other factors e.g. dehydration secondary to hyperemesis gravidarum may also contribute. The incidence of PE rises further in the postpartum period6and remains elevated for up to six weeks after delivery. The mortality rate for untreated pulmonary embolism in pregnancy is up to 30%, making it important to rapidly identify and treat this condition.3 Case history A 26-year-old female teacher was referred by her GP to the Acute Medical Unit (AMU) with two weeks of progressive shortness of breath and retrosternal chest pain. She was 30 weeks pregnant. She had a past medical history of Polycystic Ovarian Syndrome (PCOS) and mild asthma. She took a salbutamol inhaler less than once per week and had no known drug allergies. She had never smoked, drank no Dr Francesca Neuberger MBChB MRCP (UK) Dr Nic Wennike BSc MBBS MRCP (UK) Consultant Acute Physician Musgrove Park Hospital Parkfield Drive Taunton Correspondence: Dr Francesca Neuberger StR 6 Acute and General Medicine Severn Deanery Email: [email protected] doctors.net.uk 240 Acute Medicine 2013; 12(4): 239-245 Problem based review: pulmonary embolism in pregnancy alcohol, and participated in triathlons in her spare time. She lived with her husband and healthy four year-old daughter. On initial assessment she had a pulse of 90 per minute, blood pressure of 140/80mmHg, temperature 36.5°C, respiratory rate-26 per minute and saturations of 98% on air. She was alert and orientated, with normal heart sounds and a clear chest on auscultation. Her calves were soft. How should a pregnant patient with suspected PE be assessed clinically? Clinical assessment alone has a low sensitivity and specificity in the diagnosis of VTE in pregnancy. Women with PE may not present with the classic symptoms of chest pain, dyspnoea, haemoptysis or collapse, and conversely, women may experience a degree of dyspnoea, leg swelling and tachycardia as part of a normal pregnancy. In a study of 38 pregnant women with confirmed PE, the four most common presenting complaints were dyspnoea (62%), pleuritic chest pain (55%), cough (24%) and sweating (18%).5 Of the ‘classic’ features of PE, there is no single feature that has a strong predictive value for PE in pregnancy. In a study of 304 women8 with suspected PE who were pregnant or postpartum, patients were assessed for six features: chest pain, dyspnoea, desaturation, tachycardia, increased A-a gradient and PaO2 <65mmHg. No association was found between an individual feature and diagnosis of PE or any cluster of features in this study. In non-pregnant patients, scoring systems such as the Well’s Score can help guide risk stratification and investigation of patients with suspected PE. Pregnant women were excluded from the analysis for validation of the Well’s Score9 and to date, no validated scoring system exists for pregnant women. In patients with suspected PE who go on to have imaging, the majority will have negative investigations. In a study of 120 consecutive women with suspected PE undergoing ventilation/ perfusion(V/Q) scanning, only 2 showed high probability of PE, and the majority were normal.10 This highlights the limitations of clinical assessment in this group of patients. Patients with suspected PE in pregnancy may present to medical or obstetric teams. Patients who are of advanced gestation with a viable foetus should be under the care of an obstetric team, with ready access to facilities and expertise for an emergency Caesarean Section (CS), should a patient’s clinical picture alter rapidly, for example with cardiopulmonary arrest secondary to PE. For women in early pregnancy, where the foetus is not viable, care under a medical team with input from obstetrics is preferable. Should a D-dimer be used in the assessment of PE in pregnant women? The physiological changes of normal pregnancy cause a progressive rise in D-dimer. A quarter of women will have a positive D-dimer in the second trimester and half of women in the third trimester. In the non-pregnant population, a negative D-dimer is useful in excluding VTE where the Well’s score indicates that VTE is ‘unlikely’. Pregnancy places a patient in a high risk category and thus D-dimer testing is not useful or indicated in pregnancy. This is endorsed by the Royal College of Obstetricians and Gynaecologists.11 If a D-dimer level is checked and is negative, it can be tempting to be falsely reassured. However, the diagnostic pathways for VTE that use D-dimer measurement have only been developed to exclude PE in low risk patients with a negative D-dimer, and should not be extrapolated to include high risk patients, such as those who are pregnant. What investigations should the pregnant patient with suspected PE undergo? The use of electrocardiography (ECG) and arterial blood gas analysis (ABG) are well-described in assessing patients with cardiorespiratory symptoms and should be performed in the vast majority of cases. It should be noted that while normal arterial blood gas values do not change significantly in pregnancy, the arterial oxygen tension drops by up to 2kPa when a pregnant woman lies flat, therefore the sample should be taken with the patient sitting.12 Hyperventilation and respiratory alkalosis may be a normal finding in the later stages of pregnancy (due to progesterone-mediated stimulation of the respiratory centre) and typical SI, QIII, TIII on an ECG may be a normal finding in pregnancy. An objective investigation to confirm or refute the diagnosis of PE is vital given the life-threatening nature of PE in pregnancy and the limitations of clinical assessment and bedside testing. A reluctance to request basic imaging such as a chest X-ray has been implicated in the failures to accurately diagnose and manage these patients in the CEMACH report. A diagnosis of PE has implications for maternal and foetal health, and if these patients are underinvestigated, the implications can be catastrophic. Pregnant women with suspected PE need to be given accurate information regarding the risks and benefits of each investigation in a way they can understand, so they can actively be involved in the decisionmaking process. A chest X-ray is useful because it may identify alternative causes of symptoms such as a pneumothorax, lobar collapse or pneumonia. CXR carries a very low risk of radiation exposure in pregnancy (equivalent to 9 days of background radiation in the UK), is readily available and should be performed in all breathless pregnant patients. A normal chest X-ray does not exclude PE, but may encourage a clinician to choose VQ scanning in preference to CTPA as the subsequent investigation. Two studies of pregnant women with suspected PE have shown that the rate of diagnostic V/Q results (i.e. normal or high probability) is between 94% and 96% when the initial CXR was normal.13,14 © 2013 Rila Publications Ltd. Acute Medicine 2013; 12(4): 239-245 241 Problem based review: pulmonary embolism in pregnancy The radiation risk from imaging should be considered in terms of the radiation dose to the mother and radiation dose to the foetus. The risk to a foetus of prenatal death, abnormal mental development and malformations from radiation exposure is considered to be relevant above 50mGy15 (particularly in the very early stages of pregnancy), and requires specific discussion with the mother when it is greater than this.To put this in context, the foetal radiation dose from a single chest X-ray is approximately 0.002mGy.15 Should pregnant women with suspected PE have a Doppler US of both legs in the absence of any clinical signs of DVT? There is currently no direct evidence to support the use of bilateral Doppler ultrasound examination of the legs veins to diagnose PE in pregnancy.16 However, Doppler ultrasound does not involve ionising radiation, therefore if a patient presents with symptoms of a DVT, the diagnosis of venous thromboembolism can be reached without exposing the patient and foetus to ionising radiation. In the non-pregnant population, it is estimated that 70% of patients with PE have proximal DVT, but in pregnant women with PE, the proportion with DVT is unknown.17 Assessing pregnant women with suspected DVT can be difficult, as there is a higher incidence of iliac vein thrombosis which is not routinely assessed during Doppler US examinations. Furthermore, there is a not insignificant risk (approximately 3%) of a false positive Doppler US in pregnancy with attendant risks of unnecessary anticoagulation. Interestingly, 75-96% of DVTs in pregnant women affect the left leg rather that the right (compared with 55% in the non-pregnant population), which is thought to be due to compression of the left common iliac vein by the mass effect of the gravid uterus or by the crossing right iliac artery.3 In the general population with suspected PE, it has been calculated that 11 patients would need to have Doppler ultrasound of their legs to diagnose VTE, negating the need for further investigations.18 In pregnant women with suspected PE, the number of patients that would need to be tested would be several times higher due to the lower prevalence of PE within this group. In summary, if a patient has symptoms or clinical signs of a DVT, she should have a Doppler ultrasound examination of her legs as the next investigation. In the absence of clinical evidence of DVT, some patients and clinicians may choose Doppler ultrasound of the legs as the next investigation, accepting the risk that organising an extra test may delay definitive investigations and is very likely to be negative. The risks and benefits of bilateral Doppler ultrasound examination of the leg veins were explained to our patient. She was keen to avoid ionising radiation, and went on to have this investigation. The study was negative for DVT. What investigations should be performed next in the work-up of a pregnant patient with suspected PE? A CTPA or V/Q scan may both be considered as the next most appropriate investigation. V/Q scanning is not readily available in all hospitals, particularly out of hours, and not all radiology departments will have expertise in interpreting results, making CTPA the preferred investigation in such circumstances. However, where V/Q scanning is available, it is often advocated as the next investigation of choice. V/Q scanning is a frequently used test for PE in the non-pregnant population, with reports being categorised as ‘high probability’, ‘normal’ or ‘indeterminate’. The implication of an indeterminate Investigation Pros Cons Doppler Ultrasound scan of leg veins - No radiation exposure - May give indirect evidence of PE - May delay definitive investigations for PE - A negative result is unhelpful - Labour intensive - Risk of false positives CXR - Readily available - Very low radiation dose - May pick up other pathology (e.g. pneumothorax, pneumonia) and/or highlight patients unsuitable for V/Q scanning - Doesn’t confirm or exclude PE CTPA - May pick up other pathology - Radiation to maternal breast/lung (and foetus) Perfusion scanning - Reduced overall radiation dose compared with CTPA - Risk of indeterminate scan result - Only suitable for patients with a normal CXR - May not be available locally - Radiation to foetus (and maternal breast/lung) Figure 1. Pros and cons of investigations for PE in pregnancy. © 2013 Rila Publications Ltd. 242 Acute Medicine 2013; 12(4): 239-245 Problem based review: pulmonary embolism in pregnancy Figure 2. Diagnostic algorithm for suspected PE in Pregnancy (American Thoracic Society 2011).16 maternal dose lung breast CTPA 39.5mGy 10-60mGy V/Q 5.7-13.5mGy 0.98-1.07mGy Figure 3. Maternal radiation doses associated with diagnostic tests for pulmonary embolism.26 scan result is that a further investigation (usually a CTPA) is required to confirm or exclude a diagnosis of PE. In the general hospital population, there is a high risk of indeterminate scans (up to 70%), which makes this test less popular among clinicians. In the pregnant population, the vast majority of patients are young with no respiratory comorbidities and normal CXRs, making the risk of an indeterminate scan far lower. In the pregnant population, 75% of patients have a normal scan and 5% have a ‘high probability’scan result, leaving only 20% of patients with‘indeterminate’ scan results.17 The radiation exposure from a V/Q scan is detailed in Figure 3 (the range of values results from a variety of imaging protocols and equipment being used). All radiation carries a potential but generally small risk, which must be balanced against the considerable risk of maternal and foetal death if there is a failure to diagnose and adequately treat PE. There is a lack of evidence regarding the effects of ionising radiation from investigations for PE in pregnancy and complications for mother and foetus. The foetal radiation dose from CTPA increases from 0.03mGy in early pregnancy to 0.66mGy in the third trimester. The corresponding values for V/Q scanning are between 0.32mGy and 0.74mGy for V/Q according to the American Thoracic Society.16 The maximal dose of radiation to the foetus from either investigation falls well below the 50mGy threshold that is associated with increased risk of prenatal death, malformations and abnormal mental development. The average foetal radiation doses from V/Q scanning are slightly higher than from CTPA. To minimise the radiation dose associated with V/Q scanning, it is possible to perform a half-dose perfusion scan, and only proceeding to ventilation imaging if a defect is identified on the perfusion scan.19 The radiation dose to the mother from CTPA and V/Q scanning is also of concern to both clinicians and patients. The radiation doses to the lung and breast from each investigation are outlined in figure 3. It has been calculated that the lifetime risk of breast cancer from 20mGy radiation is 1/1200 women at age 20, 1/2000 women at age 30, 1/3500 women at age 40. The lifetime risk of breast cancer is 1/820 and the overall excess lifetime relative risk following a CTPA is only 1.004. The issue of radiation to maternal breast and lung and associated increased risk of malignancies again needs to be considered in the context of a life-threatening illness, and the radiation risk balanced against the morbidity and mortality associated with undiagnosed and untreated PE. Radiologists should be aware of the higher rate of sub-optimal CTPA studies on pregnant women when compared with an age-matched non-pregnant controlled group.21 Pregnant women have significantly decreased pulmonary arterial enhancement compared to non-pregnant patients, probably due to the increase in cardiac output in pregnancy.22 This should be taken into consideration when choosing an imaging protocol. Clinicians should gain informed consent from their patient in this situation for imaging involving ionising radiation. The risks and benefits of any imaging proposed should be explained to the patient in a way she can understand, and the patient should be given the opportunity to ask questions. The explanation should focus on the risk of undiagnosed PE to the mother and foetus balanced against the potential risk of radiation exposure to mother and foetus. The patient can be reassured that the radiation exposure from a chest X-ray is not significant, and while there is little direct evidence regarding the safety © 2013 Rila Publications Ltd. Acute Medicine 2013; 12(4): 239-245 243 Problem based review: pulmonary embolism in pregnancy Subcutaneous dose Early pregnancy weight (Kg) <50 50-69 70-89 >90 Enoxaparin 40mg bd 60mg bd 80mg bd 100mg bd Dalteparin 5,000iu bd 6,000iu bd 8,000iu bd 10,000iu bd Tinzaparin 175 units/Kg once daily (all weights) Figure 4. Calculation of heparin dose during pregnancy.11 of CTPA and V/Q scanning in pregnancy, the risk of undiagnosed PE to mother and foetus is clear and significant. Unstable patients require urgent imaging to be arranged if they present out of hours. A bedside echocardiogram is the initial investigation of choice for patients who are too unstable for transfer, followed by a CTPA as the definitive investigation. For women with a viable foetus, where possible, it is preferable Image 1. Perfusion scan showing multiple perfusion defects © 2013 Rila Publications Ltd. to obtain diagnostic imaging to confirm or exclude the diagnosis of PE as prior use of anticoagulation significantly increases the risk of haemorrhage during urgent delivery. Case Continued Following a normal CXR our patient went on to have a halfdose Q scan, which showed multiple perfusion defects that were unmatched on ventilation scanning (see image 1). 244 Acute Medicine 2013; 12(4): 239-245 Problem based review: pulmonary embolism in pregnancy What is the treatment for PE in pregnancy? Patients with PE require anticoagulation, which has special considerations in pregnancy. Vitamin K antagonists, such as Warfarin, are associated with teratogenesis and risk of haemorrhage, particularly at the time of delivery, and are not recommended during pregnancy. The Royal College of Obstetricians and Gynaecologists recommend low molecular weight heparin (LWMH) in preference to unfractionated heparin. LWMH does not cross the placenta and has fewer side effects such as osteoporosis, allergic reactions and heparin-induced thrombocytopaenia than unfractionated heparin. Dosing of LMWH is often different during pregnancy, is weight-based and should be calculated from the patient’s early pregnancy weight e.g. for enoxaparin, the dose during pregnancy is 1mg/kg BD rather than the standard treatment dose of 1.5mg/kg OD recommended outside of pregnancy. Patients may prefer treatment with tinzaparin, because it can be given once daily, though there is less published outcome data for this option. (figure 4) Before starting anticoagulants, patients should have blood taken for a full blood count, coagulation screen, urea and electrolytes and liver function tests as a minimum. Performing a thrombophilia screen prior to therapy is not routinely recommended according to the RCOG guidelines, as it will not affect the immediate management and results can be difficult to interpret. The physiological effects of pregnancy can interfere with clotting screen results. For example the levels of protein S fall, making the diagnosis of protein S deficiency difficult. The presence of extensive thrombus may also affect coagulation screen testing, as antithrombin levels are reduced when extensive thrombus is present, which makes results misleading. The advice from the RCOG is that results of thrombophilia screens taken in this situation should be interpreted by clinicians with expertise in this area, usually haematologists. Patients with PE should be anticoagulated with LMWH for the remainder of the pregnancy but this should be stopped for a minimum of 24 hours prior to planned delivery, or as soon as a patient has symptoms of labour. There should be a minimum of 24 hours without anticoagulation before any spinal anaesthetic or analgesic attempts are made. Decisions regarding the most appropriate management for a patient with PE in pregnancy need to be made on an individual basis, with the best available evidence. The NICE clinical guideline 14424 gives detailed guidance in the assessment and management of patients with VTE, but does not include pregnant women. What is the treatment for massive lifethreatening PE? Management of massive life-threatening PE in pregnancy is a medical and obstetric emergency and requires multidisciplinary management including experienced physicians, obstetricians, intensivists and radiologists. Obstetric teams looking after such patients are advised to call the medical team immediately and an urgent portable echocardiogram or CTPA should be arranged within one hour of presentation.11 Therapeutic options for massive life-threatening PE in pregnancy include intravenous unfractionated heparin, thrombolytic therapy, catheter-directed thrombolytic therapy or thoracotomy and surgical embolectomy. At present, the data regarding the treatments options are limited. Intravenous unfractionated heparin is the preferred treatment for massive PE in pregnancy11 due to its rapid onset of action and extensive experience of use in this situation. Intravenous thrombolysis should be considered if there is haemodynamic compromise associated with massive PE. This should be followed by an intravenous infusion of unfractionated heparin. From a review of 172 patients, intravenous thrombolysis was associated with maternal haemorrhage rate of 1% to 6%, which is comparable with non-pregnant patients receiving thrombolytics. Out of 172 patients, there were three foetal deaths and two maternal deaths. The maternal deaths were not secondary to haemorrhage, and no maternal intracranial haemorrhages were reported.23 The data for catheter-directed thrombolytic therapy and surgical embolectomy for PE in pregnancy are very sparse, but these treatments should be considered in patients with haemodynamic compromise who are not suitable for thrombolysis, depending on the local availability. For very unstable patients, the risk of transfer to a tertiary centre is likely to exceed potential benefits. What further treatment should be provided following discharge from hospital? Patients should be anticoagulated for at least six weeks postnatally11 and a minimum of three months anticoagulation should be given in total. The decision regarding the length of period of anticoagulation will be based on personal and family history of VTE, results of any thrombophilia tests and any other risk factors. Women should be advised that both heparin and warfarin are acceptable forms of anticoagulation during breastfeeding, and women can choose between them based on their perception of the acceptability of frequent blood tests for patients on warfarin and regular subcutaneous injections for those receiving heparin. The novel oral anticoagulants (NOACs), such as rivoroxaban, apixaban and dabigatran, are not currently licensed for use during pregnancy or by women who are breastfeeding. Women who have co-existing DVT alongside PE, should be advised to wear graduated elastic compression stockings on the affected leg for at least two year to reduce the risk of post-thrombotic syndrome. Women who have VTE during pregnancy should have expert follow up, at an obstetric medicine © 2013 Rila Publications Ltd. Acute Medicine 2013; 12(4): 239-245 245 Problem based review: pulmonary embolism in pregnancy or joint obstetric haematology clinic where possible. At this stage, thrombophilia testing can be considered and recommendations made for future pregnancies depending on an individual’s risk of future events. Patients should also have an echocardiogram and respiratory follow-up, to assess for pulmonary hypertension, which may precede the development of chronic thromboembolic hypertension (CTEPH).25 Case Conclusion Our patient was given enoxaparin sodium 1mg/kg SC BD for the remainder of her pregnancy. She had labour induced at 38 weeks gestation with anticoagulation up until 24 hours prior to induction. She had a healthy female infant via normal vaginal delivery weighing 6 pounds and 7 ounces. She recommenced LMWH with once daily dosing following delivery and was followed up by haematology, obstetrics and respiratory medicine. Conflict of interest This study was funded entirely by the authors and they have no conflict of interest with any third party. References 1.Romero A, Alonso C, Rincon M, et al. 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