Empowering Fertility - The Risk of Flying –  The Economy Class Syndrome 
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The Risk of Flying –  The Economy Class Syndrome 

By Paul Bergh, MD

On September 30th, 2000, a plane landed at London’s Heathrow airport following a 20-hour flight from Australia.  On that flight was 28-year-old Emma Christoffersen and her fiancé who were returning from an active, three week holiday that included white-water rafting and sky-diving.  Unfortunately, their trip took a tragic turn after landing.  Soon after disembarking from the plane, Emma suddenly collapsed in the airport and was pronounced dead.  An autopsy later revealed that Emma had died from a  massive pulmonary embolism (PE).  A clot that had developed in her calf during the flight  had broken off and travelled to her lung causing respiratory collapse.  Emma’s death brought worldwide attention to a syndrome that has been quietly described and discussed in the medical literature over the preceding 10 years.

It is well documented that decreased circulation, i.e. blood stasis and hemoconcentration lead to an increased risk of venous thrombosis (VT) formation. During quiet sitting, similar to what occurs in flight, an unbroken column of venous blood resides between the capillaries of the feet and the heart.  Under these circumstances, capillary pressure far exceeds plasma colloid osmotic pressure thus causing free fluid to leak from the capillaries into the surrounding tissue.  This results in lower extremity edema or swelling but also a risk  in local venous hematocrit and protein concentration.  In a study described by Moyses in the journal The Lancet, seven normal subjects were subject to having their venous blood simultaneously drawn from their feet and upper extremities while quietly sitting.  After an hour of sitting, the hematocrit in the blood from the feet rose to an average of 53.8% from a baseline of 42.1% .  Plasma protein concentration  in the lower extremities rose as well  in conjunction with decreased flow.

Certain medical conditions are well known to place patients at increased risk of a thromboembolic event.  These include recent major surgery, cancer, and an immobilized, casted limb.  Any situation that increases circulating estrogens such as oral contraceptives, hormone replacement therapy, controlled ovarian hyperstimulation related to infertility treatments,  pregnancy and recent pregnancy delivery also will increase this risk.  Also, some patients have a genetic predisposition to form blood clots.  These conditions are referred to as thrombophilias; Factor V Leiden is a more common genetic mutation.  These conditions coupled with reduced venous blood flow; i.e. venous stasis, are an especially high-risk situation.

Since the 1980’s there have been hundreds of reports of individuals suffering thrombotic events following air travel. First coined in 1998, the term “economy class syndrome” describes the risk of deep vein thrombosis (DVT) associated with prolonged immobility due to sitting in cramped economy class seating on flights of greater than 4 hours in duration.   In March of 2001, the World Health Organization (WHO) acknowledged that there is an increased risk of PE following long air flights (>5hrs) despite the absence of any pre-existing risk factors in most individuals affected. Prolonged sitting is not limited to air travel, and one would presume that the same risks exist for individuals undertaking long car or train rides.

A meta-analysis by Chandra et al. in 2009 looked at over 4000 cases of venous thrombosis. They found that any  travel, i.e. land or air, increased the risk of a venous thromboembolism (VTE) three fold.  They also found a dose-response relationship in that there was an 18% increased risk with every 2 hours travelled.  In 2007, Kuipers et al. performed a cohort study of over 8500 employees of large international companies exposed to frequent flying.  They established that the absolute risk of developing symptomatic VTE within eight weeks of a long haul flight (any flight greater than or equal to 4 hours) at 1 out of 4500 flights.  The risk increased with exposure to more flights within a given time frame and the duration of the flights.  The highest risk was within the first two weeks after travel.  Those individuals at an unusually high risk were employees under the age of 30 years old, women who used oral contraceptives, and travelers who were exceptionally tall, short or overweight. Other studies have identified window seating and economy class as having an increased risk compared to an aisle seat in business class respectively.  A follow-up study  by the same author in 2014 further analyzed this data to identify those subgroups of air travelers who were at an unusually high risk of developing VTE.  There was an astounding 20 fold increased risk of VTE for those individuals who had recently undergone surgery.  In addition, estrogen use increased the risk of VTE by over eight-fold.  Previous studies have reported a synergistic increase in the risk of VTE with the combination of air travel and oral contraceptive use.  Publications by  Martinelli in 2003 and Cannegueter in 2006 reported a 14 to 20 fold increased risk of VTE.

Is there something unique to air travel that predisposes high-risk individuals to these complications?  Aside from stasis and dehydration that can occur with any form of travel, hypobaric hypoxia is a possible mechanism unique to air transport.  During commercial air travel,  cabin pressure can drop to an atmospheric pressure of 0.75 atm; an equivalent barometric pressure is found at an altitude of 1.5 miles above sea level.  As a result, oxygen saturation can drop to 90%-93% and as low as 80% in sleeping passengers.  These are levels that may induce acute mountain sickness  (symptoms include headache, fatigue, stomach illness, dizziness) in some individuals.  Several studies have suggested that either the relatively rapid decrease in cabin pressure or the sudden reversal of relative hypoxia on landing  may activate or up-regulate the coagulation system.  These reports, however, are somewhat mixed, and it remains hard to explain why an increase in VTE is not observed in airline pilots.

In 2011, the British Journal of Haematology published guidelines regarding travel-related venous thrombosis.  They suggest that interpreting the data on hormone use, in particular, may be misleading in view of the widespread use of the combined oral contraceptive pill and hormone replacement therapy.  They did make the following recommendations:

  • There is no evidence to support an association between dehydration and travel-associated VTE and so while maintaining proper hydration is unlikely to be harmful, it cannot be strongly recommended for prevention of thrombosis.
  • There is indirect evidence that maintaining mobility may prevent VTE and, in view of the likely pathogenesis of travel-related VTE, maintaining mobility is a reasonable precaution for all travelers on journeys over three hours.
  • Global use of compression stockings and anticoagulants for long distance travel is not indicated.
  • Assessment of risk should be made on an individual basis but it is likely that recent major surgery (within one month), active malignancy, previous unprovoked VTE, prior travel-related VTE with no associated temporary risk factor, or presence of more than one risk factor, identifies those travelers at highest thrombosis risk
  • Travelers at the highest risk of travel-related thrombosis undertaking journeys of > 3 hours should wear well-fitted below-knee compression hosiery.
  • Where pharmacological prophylaxis is considered appropriate, anticoagulants, as opposed to anti-platelet drugs, are recommended.  This recommendation is based on the observation that in other clinical scenarios,  anticoagulants provided more effective thromboprophylaxis. Usual contraindications to any form of thromboprophylaxis need to be considered.

This past month, in January of 2015 the Royal College of Obstetricians and Gynaecologists published recommendations for patients regarding air travel and pregnancy.  They state that due to prolonged sitting,  there is an increased risk of deep vein thrombosis (DVT) with flying and that this risk increases with the length of the flight.  In addition, a history of previous DVT or being overweight increases this risk factor.  Suggestions for actions to reduce the risk of DVT with flying include:

  • Wear loose clothing and comfortable shoes
  • Sit in an aisle seat and regularly walk around the plane
  • Perform in-seat exercises every 30 minutes or so
  • Remain hydrated and drink water at regular intervals throughout the flight
  • Reduce the number of drinks that contain alcohol or caffeine
  • Wear graduated elastic compression stockings

In summary, there is a large amount of data suggesting that any extended travel, but flying, in particular, increases the risk of a thrombotic event.  Fortunately, as these events are quite rare, the increased risk still results in a very low absolute risk of DVT due to flying.   There is no conclusive data to suggest that any particular action is of benefit; however, it makes sense for pregnant patients or those undergoing hormonal treatments for infertility, to minimize the venostasis related risk. Women should follow the recommendations of the Royal College of Obstetricians and Gynaecologists to prevent venous stasis.  While there is no specific data regarding the travel-related risk while undergoing fertility treatment, it stands to reason, that the combination of high estrogen and increased hemoconcetration observed in patients undergoing controlled ovarian hyperstimulation, may place them at a higher risk for DVT.  Prudent advice for these patients includes following the same recommendations for pregnant patients when travelling during or shortly after their treatment cycles.

Links:

http://www.telegraph.co.uk/news/health/1371389/Bride-to-be-killed-by-blood-clot-after-20-hour-flight.html

https://www.rcog.org.uk/globalassets/documents/patients/patient-information-leaflets/pregnancy/air-travel-pregnancy.pdf

References:

Economy class syndrome. Lancet 2(8619), 1077. 11-5-1988.

Cruickshank, J. M., Gorlin, R., and Jennett, B. Air travel and thrombotic episodes: the economy class syndrome. Lancet 2(8609), 497-498. 8-27-1988.

Kuipers, Saskia, Venemans, Annemarie, Middeldorp, Saskia, B++ller, Harry R., Cannegieter, Suzanne C., and Rosendaal, Frits R. The risk of venous thrombosis after air travel: contribution of clinical risk factors. British Journal of Haematology 165(3), 412-413. 5-1-2014

Chandra, D., Parisini, E., and Mozaffarian, D. Meta-analysis: travel and risk for venous thromboembolism. Ann.Intern.Med 151(3), 180-190. 8-4-2009.

Kuipers, S., Cannegieter, S. C., Middeldorp, S., Robyn, L., Buller, H. R., and Rosendaal, F. R. The absolute risk of venous thrombosis after air travel: a cohort study of 8,755 employees of international organisations. PLoS.Med 4(9), e290. 2007

Martinelli, I., Taioli, E., Battaglioli, T., Podda, G. M., Passamonti, S. M., Pedotti, P., and Mannucci, P. M. Risk of venous thromboembolism after air travel: interaction with thrombophilia and oral contraceptives. Arch Intern Med 163(22), 2771-2774. 2003.

Cannegieter, S. C., Doggen, C. J., van Houwelingen, H. C., and Rosendaal, F. R. Travel-related venous thrombosis: results from a large population-based case control study (MEGA study). PLoS.Med 3(8), e307. 2006

Kuipers, S., Cannegieter, S. C., Doggen, C. J., and Rosendaal, F. R. Effect of elevated levels of coagulation factors on the risk of venous thrombosis in long-distance travelers. Blood 113(9), 2064-2069. 2-26-2009.

Schreijer, A. J., Cannegieter, S. C., Doggen, C. J., and Rosendaal, F. R. The effect of flight-related behaviour on the risk of venous thrombosis after air travel. Br.J Haematol. 144(3), 425-429. 2009.

Schreijer, A. J. M., Hoylaerts, M. F., Meijers, J. C. M., LIJNEN, H. R., Middeldorp, S., B+£LLER, H. R., Reitsma, P. H., Rosendaal, F. R., and Cannegieter, S. C. Explanations for coagulation activation after air travel. Journal of Thrombosis and Haemostasis 8(5), 971-978. 5-1-2010.

Bendz, B., Rostrup, M., Sevre, K., Andersen, T. O., and Sandset, P. M. Association between acute hypobaric hypoxia and activation of coagulation in human beings. Lancet 356(9242), 1657-1658. 11-11-2000.

Brill, A., Suidan, G. L., and Wagner, D. D. Hypoxia, such as encountered at high altitude, promotes deep vein thrombosis in mice. Journal of Thrombosis and Haemostasis 11(9), 1773-1775. 9-1-2013.

Venemans-Jellema, A., Schreijer, A. J., Le, Cessie S., Emmerich, J., Rosendaal, F. R., and Cannegieter, S. C. No effect of isolated long-term supine immobilization or profound prolonged hypoxia on blood coagulation. J Thromb.Haemost. 12(6), 902-909. 2014

Kuipers, S., Venemans-Jellema, A., Cannegieter, S. C., van, Haften M., Middeldorp, S., Buller, H. R., and Rosendaal, F. R. The incidence of venous thromboembolism in commercial airline pilots: a cohort study of 2630 pilots. J Thromb.Haemost. 12(8), 1260-1265. 2014.

Hitos, K., Cannon, M., Cannon, S., Garth, S., and Fletcher, J. P. Effect of leg exercises on popliteal venous blood flow during prolonged immobility of seated subjects: implications for prevention of travel-related deep vein thrombosis. Journal of Thrombosis and Haemostasis 5(9), 1890-1895. 9-1-2007.

Empowering Fertility: An educational blog for patients & healthcare professionals that empowers individuals to take charge of their fertility. Visit us at http://empoweringfertility.com.

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