D-Dimer in Pregnancy: Limiting Radiation with Pre-test Probability

Background: Pulmonary embolism is the leading cause of death in pregnancy and the puerperium – accounting for nearly 20% of maternal deaths in the United States – making rapid and accurate diagnosis critically important for emergency physicians, OB/GYNs, and all who take care of these women on a regular basis. Diagnosis is made more difficult by the frequency of concerning and suggestive signs and symptoms in this population, particularly dyspnea (a common symptom in pregnancy related to an increase in progesterone levels) and tachycardia (as resting heart rate is typically expected to increase by up to 25% in normal pregnancy).

While the use of the D-dimer in conjunction with a low pre-test probability for pulmonary embolism is well-established for ruling out PE in the non-pregnant population, pregnant women were excluded from studies that derived and validated models assessing pretest clinical probability of PE, and no specific tool to assess pretest probability is available in this setting. This lack of a pretest probability assessment tool and the lack of prospective data confirming the safety of ruling out PE on the basis of a negative D-dimer result have limited the adoption of the D-dimer test in pregnant patients. Indeed, the American Thoracic Society guidelines [1] recommend specifically against the use of D-dimer to exclude PE in pregnancy. The DiPEP study, published in the British Journal of Haematology, attempted to add to this literature base [2], and was reviewed here on REBEL EM. The DiPEP authors’ conclusion, that D-dimer should not be recommended for use in the diagnostic work-up of PE in pregnancy, was echoed in our review, however this study was likely fundamentally flawed in that it did not risk stratify patients prior to application of D-dimer testing, a critical step in all validated applications.

Recently, a group of French and Swiss authors published a prospective diagnostic management outcome study for diagnosis of PE in pregnant women that sought to better define the role of D-dimer when paired with pre-test risk stratification. [3]

What They Did:

• Multicenter, multinational, prospective diagnostic management outcome study of outpatient pregnant women presenting with clinically suspected PE.

• 11 centers in France and Switzerland
• Pretest probability of PE was determined using the revised Geneva score. [4]

• Pulmonary embolism was excluded in women who had low or intermediate pretest probability and a negative high-sensitivity, quantitative D-dimer result (<500 μg/L).

• Women who had a high pre-test probability proceeded to bilateral compression ultrasonography (CUS) of the lower legs. When proximal DVT was found, PE was considered to be confirmed and no further testing done.
• Women with a negative result on CUS underwent CTPA.
• Patients with negative work-ups were followed for 3 months and all subsequent suspected VTE events adjudicated by blinded consensus.

Table 1. Revised Geneva Score [5]

Outcomes:

• Primary: Risk for adjudicated VTE events during the 3-month follow-up in women who did not receive anticoagulant therapy on the basis of negative results on the initial work-up.

Inclusion:

• Pregnant women with clinically suspected PE in emergency departments, defined as acute onset of new or worsening shortness of breath or chest pain without another obvious cause.

Exclusion:

• Age <18 years
• Allergy to iodinated contrast agent
• Impaired renal function (CrCl <30 mL/min)
• Diagnosis before presentation
• Indication for or current receipt of full-dose anticoagulation
• Inaccessibility for follow-up

Results:

• 395 women with suspected PE recruited from 11 sites.

• • 17 were receiving prophylactic anticoagulation at inclusion, mainly for a previous VTE
  • Pre-test probabilities:
    • Low—192 (48.6%)
    • Intermediate—200 (50.6%)
    • High—3 (0.8%)

• 392 women underwent D-dimer testing.
• • 46 (11.7%) had a negative D-dimer result.
  • 341 (87%) had a positive result
  • 5 (1.3%) had no D-dimer testing.
  • 21% of patients were in their 1^st trimester, 43% 2^nd trimester, and 35.9% 3^rd trimester
  • Mean Heart Rate (SD) bpm = 91 (17)
  • Mean SaO2 (SD) % = 98.0 (1.8)
• The proportion of negative D-dimer results decreased with increasing gestational age
  • 21/83 (25.3%) during the first trimester
  • 19/170 (11.1%) during the second trimester
  • 6/142 (4.2%) during the third trimester
• 11 women underwent CTPA despite a negative D-dimer (none were diagnosed with PE)
• 349 women underwent imaging testing.
  • 7 (2.0%) had positive CUS
  • 21 (6.0%) had positive CTPA or V/Q lung scan
  • Overall, PE was diagnosed in 28 (7.1%) of women.
• Zero deaths occurred during follow-up, regardless if the patient received or did not receive anticoagulation.
• None of the patients with negative D-dimer testing were diagnosed with PE at 3-month follow-up.

Strengths:

• Study specifically addresses D-dimer’s utility in a practical bedside application.
• No patients lost to follow-up.
• A 3-member independent adjudication committee reviewed all suspected VTE events, with blinding to the initial diagnostic workup
• To confirm VTE there had to be unanimous consensus of the adjudication committee.
• Funding source had no role in the study design, interpretation of data, writing of the manuscript, or decision to submit the manuscript for publication.
• Small study, but powered appropriately to assess the diagnostic safety of the proposed algorithm—determined a priori that the upper limit of the 95% CI around the estimate of 3-month VTE risk should not be higher than 3.0%.
• Higher PE prevalence (7.1%) than previous retrospective studies reporting a 2% prevalence of PE among pregnant women.
• This is the first full data release, prospective design on diagnostic workup of PE in pregnancy to be published.

Limitations:

• 10% of patients had protocol deviations.
• 6% of patients were receiving thromboprophylaxis during follow-up which may (though unlikely) have affected results.
• Not addressed in the study is the safety and performance of using CTPA vs V/Q scan in pregnancy.
• Use of therapeutic anticoagulation was an exclusion criterion of the study, but women receiving prophylactic anticoagulation were not excluded, and could, although not likely, affect the results of the study.

Figure 1. Diagnostic Algorithm

Discussion:

• While at first glance difficult to reconcile with the conclusions of the DiPEP trial, this study reinforces D-dimer’s role in a population stratified into low/intermediate and high-risk groups.

• The authors utilized the revised Geneva Score (which they created) instead of the Well’s Score, though it is likely reasonable to extrapolate their findings to any validated risk stratification instrument.
• 92% of women had negative results on CUS—while non-invasive and free of radiation, CUS is clearly a low-yield test in this population.
• The proportion of patients with confirmed PE (7.1%) was lower than that in nonpregnant population in Europe (Currently around 15 – 20%)

• The proportion of women in whom PE could be ruled out on the basis of a negative D-dimer result was clinically significant (11.6%).

• • Although, negative d-dimer results decreased with increasing gestational age, these results were still clinically useful in the 1^st and 2^nd trimesters (25% and 11% respectively)

Authors’ Conclusion:

In pregnant women with suspected PE, a diagnostic strategy involving assessment of pretest clinical probability, D-dimer measurement, bilateral leg CUS, and CTPA can safely rule out the disease, with a 3-month thromboembolic rate of 0.0% (95% CI, 0.0% to 1.0%).

Clinical Take Home Point: Among pregnant women presenting with concern for pulmonary embolism in pregnancy, who have a low or medium pre-test probability of PE, a negative D-dimer can safely rule out the disease, though will only be helpful in a small proportion of patients.

References:

1. Leung AN, Bull TM, Jaeschke R, Lockwood CJ, Boiselle PM. Evaluation of Suspected Pulmonary Embolism in Pregnancy. American Journal of Respiratory Critical Care Medicine 2011; 184: 1200-1208. PMID: 22086989
2. Hunt, Beverley J., 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.” British journal of haematology(2018). PMID: 29359796
3. Righini M, et al. Diagnosis of Pulmonary Embolism During Pregnancy: A Multicenter Prospective Management Outcome Study. Ann Intern Med. 2018; ePub Ahead of Print.
4. Le Gal G, Righini M, Roy PM, Sanchez O, Aujesky D, Bou- nameaux H, et al. Prediction of pulmonary embolism in the emer- gency department: the revised Geneva score. Ann Intern Med. 2006; 144:165-71. PMID: 16461960
5. Le Gal, Grégoire, et al. “Prediction of pulmonary embolism in the emergency department: the revised Geneva score.” Annals of internal medicine3 (2006): 165-171. PMID: 16461960

For More on This Topic Checkout:

Ryan Radecki at EM Lit of Note: The Swiss, Ruling Out PE in Pregnancy

Post Peer Reviewed By: Salim Rezaie, MD (Twitter: @srrezaie)