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Three Part Question

In [pregnant women with symptoms of deep vein thrombosis], can [a single negative ultrasound] [exclude deep vein thrombosis?]

Clinical Scenario

A 29-year-old pregnant lady at 26 weeks of gestation, attends to the Emergency Department with painful swollen leg. An ultrasound evaluation showed no evidence of deep vein thrombosis, she was subsequently discharged with analgesics. She returned 5 days later with severe respiratory distress and an evaluation by CT PE showed bilateral pulmonary embolism

Search Strategy

Pubmed was searched on February 3rd ,2017 using the following advanced search:

(((("ultrasonography"[MeSH Terms]) OR (((((ultrasound[Text Word]) OR US[Text Word]) OR USS[Text Word]) OR ultrasonography[Text Word]) OR doppler[Text Word]))) AND (((pregnancy[Text Word]) OR pregnant[Text Word]) OR "pregnancy"[MeSH Terms])) AND ((((deep vein thrombosis[Text Word]) OR DVT[Text Word]) OR "venous thromboembolism"[MeSH Terms]) OR venous thrombosis[Text Word])

Search Outcome

402 papers were identified, of which 384 studies were excluded after title and abstract review. 10 papers were further excluded after full text review as they were not directly relevant to the three-part question. Finally, 2 studies were excluded during the data extraction phase due to overlap of study cohorts by the same author, leaving 6 studies that were directly relevant to the search. All the 6 studies were analyzed and incorporated in the given table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Gre´goire Le Gal December 5, 2005 France	162 pregnant or postpartum (80 pregnant, 82 postpartum) with suspicion of DVT between January 2002 and December 2004	Retrospective hospital based study	False negative rate of a single negative ultrasound	0/104 (0.0%, 95% confidence interval 0% to 3.6%)	- Retrospective study design - Eleven pregnant patients lost follow up, during which we have no knowledge whether they did develop VTE. The achieved follow up percentage is >82% - It was difficult to separate the pregnant from the postpartum women - Small sample size
Wee-Shian Chan July 21, 2009 Canada	194 pregnant women who presented to 1 of 5 Canadian centers from March 2000 to April 2007 with suspected lower extremity DVT	Observational cross sectional multicenter study	False negative rate of a single negative ultrasound	5/182 (2.74%)	- Small prevalence of DVT in the patient group ( only 8.8%) - Failure to do serial compression ultrasonography to all the pregnant women (done for only 83%), however the achieved follow up rate was 100% . - Absence of standardised method for follow up
A.Rafliu 2010 April-June Romania	87 consecutive pregnant women with clinical suspicion of DVT admitted in.Dr. D. Popescu. Maternity, Timisoara, between January 2007 and December 2009	Prospective Observational Cohort study	False negative rate of a single negative ultrasound	0/43 (0%)	- Small sample size - No calculated confidence intervals. - Prevalence of DVT was 34.48% which is considerably higher than other studies in the literature - Lack of standardised method for follow up - 12/55 pregnant women did not return for follow up which significantly affects the reliability of the results. the achieved follow up was only 78.2%
Grégoire Le Gal April 24, 2012 France	167 pregnant women with suspected lower extremity DVT presenting between January 2006 and June 2009	Prospective cohort outcome study	False negative rate of a single negative ultrasound	2/145 (1.4%, 0.4% to 4.9%)	- The study included pregnant women as well as postpartum women, but it was easy to subcategorise each group - Small sample size - 3/177 pregnant or postpartum (not specified) received anticoagulation for short duration for superficial thrombophlebitis and were kept in the analysis. It is unknown whether this small course of anticoagulation could have had any effect on the rate of thromboembolic events during the follow up period.
Wee-Shian Chan March 5, 2013 Canada	221 pregnant women recruited between August 2002 and September 2010 from 4 Canadian centers with dedicated thrombosis service	Multicenter Prospective cohort study	False negative rate of a single negative ultrasound	1/205 (0.49%) diagnosed with DVT and PE at the follow up period. This event took place 2 days after a miscarriage of the pregnancy	- low prevalence of DVT in the study (7.2%)
Emmanuelle Le Moigne July 2014 France	96 pregnant women with suspected lower extremity DVT recruited between November 2004-February 2006	Multicenter, prospective epidemiological observational cohort study	False negative rate of a single negative ultrasound	0/43 (0.0%, 95%CI 0.0 to 8.2%.)	- Sample size is small to draw any definitive conclusion - A random sample of pregnant women with an initial negative CUS was selected for the 3 month follow up. It is unknown whether the rest of the unfollowed pregnant women did develop thromboembolic events after initial negative scan.

Comment(s)

Venous compression ultrasonography (CUS) has become the diagnostic imaging of choice for deep vein thrombosis (DVT) in the lower extremities of non pregnant patients. Compression ultrasonography is highly sensitive and specific in detecting proximal DVTs, and a single negative CUS is safe to rule out DVT in non pregnant patients. The diagnosis of deep vein thrombosis in pregnant women however is still a challenge due to; the absence of a validated structured clinical decision rule, challenging anatomical distribution of DVT in pregnancy being more common in proximal veins, differences in clinical presentation, and un-reliable standard d-dimer testing. The diagnostic accuracy of single CUS has not been established yet in pregnant women, and therefore serial testing with CUS and follow up is recommended. During the period of data extraction, we came across 4 papers that were published by Chan, where the study groups and time of recruitment seemed to overlap, we contacted the author and she confirmed the overlap, therefore we chose 2 papers that represent the highest percentage of pregnant patients during the recruitment period. We noticed that the sample size in all of the included papers is relatively small due to the difficulty of recruiting pregnant patients with DVTs despite the huge effort of involving multiple centers over several years. We reviewed the enrolled studies in our systematic review in detail, and found that the false negative rate of a single negative ultrasound in detecting DVT in the pregnant population was 0% in three papers, 0.49%, 1.4%, and 2.74% in each separate study. The achieved follow up period for all pregnant women with initial negative ultrasound was 100% in 4 studies, 88.2% and 78.2% in other two studies which highlights a low rate of missed data, giving reliable strength to the provided results. The false negative rate of single negative CUS in the pregnant population appears to be similar to the non pregnant population. Therefore, it is probably safe to discharge patients with negative initial ultrasonography with appropriate return instructions if needed, as a missed DVT in a patient whether pregnant or not is unlikely to remain asymptomatic.

Clinical Bottom Line

The data shows that a single complete negative ultrasonography of the lower extremity is safe to rule out deep vein thrombosis in symptomatic pregnant women. The false negative rate in pregnant patients appears to be similar to the non pregnant population. Further studies are necessary to investigate diagnostic strategies to incorporate a clinical prediction rule with an adjusted d-dimer level in addition to a single compression ultrasound.

References

1. Gre´goire Le Gal Diagnostic value of a negative single complete compression ultrasound of the lower limbs to exclude the diagnosis of deep venous thrombosis in pregnant or postpartum women: A retrospective hospital-ba Thrombosis Research December 5, 2005. 7 pages
2. Wee-Shian Chan Predicting deep venous thrombosis in pregnancy: Out in the “left” field Annals of Internal Medicine July 21, 2009, 9 pages
3. A.Rafliu Diagnostic value of a negative single color duplex ultrasound in deep vein thrombosis suspicion during pregnancy 2010 April-June
4. Grégoire Le Gal Diagnostic value of single complete compression ultrasonography in pregnant and postpartum women with suspected deep vein thrombosis: prospective study British Medical Journal April 24, 2012. 9 Pages.
5. Wee-Shian Chan Safety of withholding anticoagulation in pregnant women with suspected deep vein thrombosis following negative serial compression ultrasound and iliac vein imaging Canadian Medical Association Journal CMAJ March 5, 2013, 7 pages
6. Emmanuelle Le Moigne Validation of the LEFt score, a newly proposed diagnostic tool for deep vein thrombosis in pregnant women Thrombosis Research July 2014. 4 pages