NIHR DC Discover

NIHR Signal Imaging is the only way to diagnose blood clots in pregnancy

Published on 13 March 2018

doi: 10.3310/signal-00569

No blood test can accurately tell if a pregnant or recently pregnant woman has a blood clot. All pregnant women with a suspected clot should continue to have imaging investigations as per current UK guidelines.

This NIHR-funded study recruited 328 pregnant or postpartum women with a suspected blood clot in the lung (pulmonary embolism) or leg (deep vein thrombosis). They had a blood test to measure the levels of 13 biomarkers, such as the D-dimer, to see if they could rule a blood clot in or out. It was hoped that this could reduce the number of women who would need confirmation from a scan, and so decrease their exposure to radiation.

None of the tests were accurate enough. The range of levels for each biomarker overlapped between women with and without a clot. 

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Why was this study needed?

Blood clots are the leading cause of death during pregnancy and after giving birth. Between 2012 and 2014 there were 20 maternal deaths due to blood clots in the UK. There are concerns about using CT scans to diagnose pulmonary embolism in pregnant women as only 5% of scans are positive. This could mean that women and their unborn baby are unnecessarily exposed to radiation.

A blood test called D-dimer is used to rule out a blood clot in people who are not pregnant. Those who test positive are then given an appropriate scan. The accuracy of the test is unclear for pregnant women as the level of D-dimer increases throughout pregnancy. This study aimed to see if the D-dimer or other blood tests could be used as a screening tool to reduce the number of women who need a scan.

What did this study do?

The Diagnosis of Pulmonary Embolism in Pregnancy (DiPEP) cohort study recruited 328 pregnant or postnatal women with a suspected blood clot from 11 hospitals in England. Most had clinically suspected pulmonary embolism while 18 had a diagnosed deep vein thrombosis. A blood sample was analysed for 13 biomarkers including D-dimer, prothrombin time, troponin and C-reactive protein.

The researchers followed women for 30 days through medical records, a questionnaire survey or the woman’s GP. The accuracy of blood tests was compared against a diagnosis of pulmonary embolism or deep vein thrombosis confirmed by two independent assessors. They were unaware of blood tests results and made the diagnosis by reviewing imaging results, adverse events and treatments given.

Most women had already been given the anticoagulant heparin before the blood test which may have affected the results. 

What did it find?

  • Thirty-six women had a clot: 18 with diagnosed deep vein thrombosis, 18 with pulmonary embolism confirmed by imaging and five with pulmonary embolism confirmed on clinical grounds. 
  • None of the biomarkers were able to accurately predict who did and did not have a clot.
  • Average levels of D-dimer tests, thrombin generation, Clauss fibrinogen and plasmin-antiplasmin were higher in women with a clot. However, the spread of levels overlapped across women with and without a clot, so some women with high levels did not have a clot. Setting a cut-off level that maximised sensitivity and ensured they missed as few cases as possible made specificity extremely poor. This meant most women without a blood clot would be wrongly indicated to have one on the basis of these tests.
  • Average levels of all other biomarkers tested did not differ between women with and without a clot.

What does current guidance say on this issue?

The 2015 Royal College of Obstetrics and Gynaecology guidelines recommend imaging for any pregnant woman who has symptoms of a pulmonary embolus or deep vein thrombosis. Anticoagulation with low molecular weight heparin should be started while waiting for the imaging results.

A compression ultrasound should be performed for suspected deep vein thrombosis. A chest X-Ray, ECG and either ventilation/perfusion lung scan or a CT pulmonary angiogram should be performed if pulmonary embolism is suspected.

Neither D-dimer nor any other blood test is recommended for screening purposes before imaging for pregnant women.

What are the implications?

The results of this trial do not change current guideline recommendations. However, it seems prudent that women of childbearing age who present with symptoms of a pulmonary embolism or deep vein thrombosis have a pregnancy test as part of the initial investigations in case they are at the early stages of pregnancy.

Citation and Funding

Hunt BJ, Parmar K, Horspool K, et al. The DiPEP (Diagnosis of PE in Pregnancy) biomarker study: An observational cohort study augmented with additional cases to determine the diagnostic utility of biomarkers for suspected venous thromboembolism during pregnancy and puerperium. Br J Haematol. 2018;180(5):694-704.

This project was funded by the National Institute for Health Research Health Technology Assessment programme.  

Why was this study needed?

Blood clots are the leading cause of death during pregnancy and after giving birth. Between 2012 and 2014 there were 20 maternal deaths due to blood clots in the UK. There are concerns about using CT scans to diagnose pulmonary embolism in pregnant women as only 5% of scans are positive. This could mean that women and their unborn baby are unnecessarily exposed to radiation.

A blood test called D-dimer is used to rule out a blood clot in people who are not pregnant. Those who test positive are then given an appropriate scan. The accuracy of the test is unclear for pregnant women as the level of D-dimer increases throughout pregnancy. This study aimed to see if the D-dimer or other blood tests could be used as a screening tool to reduce the number of women who need a scan.

What did this study do?

The Diagnosis of Pulmonary Embolism in Pregnancy (DiPEP) cohort study recruited 328 pregnant or postnatal women with a suspected blood clot from 11 hospitals in England. Most had clinically suspected pulmonary embolism while 18 had a diagnosed deep vein thrombosis. A blood sample was analysed for 13 biomarkers including D-dimer, prothrombin time, troponin and C-reactive protein.

The researchers followed women for 30 days through medical records, a questionnaire survey or the woman’s GP. The accuracy of blood tests was compared against a diagnosis of pulmonary embolism or deep vein thrombosis confirmed by two independent assessors. They were unaware of blood tests results and made the diagnosis by reviewing imaging results, adverse events and treatments given.

Most women had already been given the anticoagulant heparin before the blood test which may have affected the results. 

What did it find?

  • Thirty-six women had a clot: 18 with diagnosed deep vein thrombosis, 18 with pulmonary embolism confirmed by imaging and five with pulmonary embolism confirmed on clinical grounds. 
  • None of the biomarkers were able to accurately predict who did and did not have a clot.
  • Average levels of D-dimer tests, thrombin generation, Clauss fibrinogen and plasmin-antiplasmin were higher in women with a clot. However, the spread of levels overlapped across women with and without a clot, so some women with high levels did not have a clot. Setting a cut-off level that maximised sensitivity and ensured they missed as few cases as possible made specificity extremely poor. This meant most women without a blood clot would be wrongly indicated to have one on the basis of these tests.
  • Average levels of all other biomarkers tested did not differ between women with and without a clot.

What does current guidance say on this issue?

The 2015 Royal College of Obstetrics and Gynaecology guidelines recommend imaging for any pregnant woman who has symptoms of a pulmonary embolus or deep vein thrombosis. Anticoagulation with low molecular weight heparin should be started while waiting for the imaging results.

A compression ultrasound should be performed for suspected deep vein thrombosis. A chest X-Ray, ECG and either ventilation/perfusion lung scan or a CT pulmonary angiogram should be performed if pulmonary embolism is suspected.

Neither D-dimer nor any other blood test is recommended for screening purposes before imaging for pregnant women.

What are the implications?

The results of this trial do not change current guideline recommendations. However, it seems prudent that women of childbearing age who present with symptoms of a pulmonary embolism or deep vein thrombosis have a pregnancy test as part of the initial investigations in case they are at the early stages of pregnancy.

Citation and Funding

Hunt BJ, Parmar K, Horspool K, et al. The DiPEP (Diagnosis of PE in Pregnancy) biomarker study: An observational cohort study augmented with additional cases to determine the diagnostic utility of biomarkers for suspected venous thromboembolism during pregnancy and puerperium. Br J Haematol. 2018;180(5):694-704.

This project was funded by the National Institute for Health Research Health Technology Assessment programme.  

The DiPEP (Diagnosis of PE in Pregnancy) biomarker study: An observational cohort study augmented with additional cases to determine the diagnostic utility of biomarkers for suspected venous thromboembolism during pregnancy and puerperium.

Published on 1 March 2018

Hunt BJ, Parmar K, Horspool K, Shephard N, Nelson- Piercy C, Goodacre S, on behalf of the DiPEP research group. The

British Journal of Haematology Volume 180 Issue 5 , 2018

This study aimed to estimate the diagnostic utility of biomarkers for suspected venous thromboembolism (VTE) in pregnancy and the puerperium. Research nurses/midwives collected blood samples from 310 pregnant/postpartum women with suspected pulmonary emboli (PE) and 18 with diagnosed deep vein thrombosis (DVT). VTE was diagnosed using imaging, treatment and adverse outcome data. Primary analysis was limited to women with conclusive imaging (36 with VTE, 247 without). The area under the curve (AUC) for each biomarker was: activated partial thromboplastin time 0·669 (95% confidence interval 0·570–0·768), B-type natriuretic peptide 0·549 (0·453–0·645), C-reactive protein 0·542 (0·445–0·639), Clauss fibrinogen 0·589 (0·476–0·701), D-Dimer (by enzyme-linked immunosorbent assay) 0·668 (0·561–0·776), near-patient D-Dimer 0·651 (0·545–0·758), mid-regional pro-atrial natriuretic peptide 0·524 (0·418–0·630), prothrombin fragment 1 + 2 0·562 (0·462–0·661), plasmin-antiplasmin complexes 0·639 (0·536–0·742), prothombin time 0·613 (0·508–0·718), thrombin generation lag time 0·702 (0·598–0·806), thrombin generation endogenous potential 0·559 (0·437–0·681), thrombin generation peak 0·596 (0·478–0·715), thrombin generation time to peak 0·655 (0·541–0·769), soluble tissue factor 0·531 (0·424–0·638) and serum troponin 0·597 (0·499–0·695). No diagnostically useful threshold for diagnosing or ruling out VTE was identified. In pregnancy and the puerperium, conventional and candidate biomarkers have no utility either for their negative or positive predictive value in the diagnosis of VTE.

Quotes

Diagnosis of pulmonary embolism in pregnancy may be difficult as symptoms might mimic those of pregnancy. Outside of pregnancy, biomarkers such as D-dimer, the smallest breakdown product of blood clots, are useful for excluding pulmonary embolism. Combined with low probability clinical scores, a negative D-dimer test safely excludes clots without the need for imaging. In pregnancy, it is desirable to limit imaging because of risks of radiation exposure to mother and foetus. Unfortunately, D-dimers normally rise in pregnancy and are not considered useful to exclude pulmonary embolism. This study confirms the lack of utility of biomarkers, including D-dimer, for ruling out pulmonary embolism during pregnancy.

Roopen Arya, Professor of Thrombosis & Haemostasis, King’s College Hospital