Correspondence

Venous Thromboembolism during Pregnancy

N Engl J Med 1996; 335:1846-1847December 12, 1996

Article

To the Editor:

In their otherwise excellent review (July 11 issue),1 Toglia and Weg fail to mention an emerging type of venous thrombosis during pregnancy. We recently admitted a multiparous 37-year-old woman who was six weeks pregnant after induced ovulation and in vitro fertilization, during which a mild ovarian hyperstimulation syndrome had developed. She presented with pain and swelling of the right side of her neck. Doppler ultrasonography revealed thrombosis of the internal jugular vein that was confirmed by spiral computed tomography. Our patient was treated with intravenous heparin and subsequently with subcutaneous enoxaparin, and the use of a coumarin derivative for six weeks after delivery was recommended.

Thrombosis of the external or internal jugular, subclavian, or cerebral vein has now been well documented as a complication of the ovarian hyperstimulation syndrome.2-5 The reason for this propensity to upper-body thrombosis is not known. Perhaps hormones draining from the pituitary gland in response to the induction of ovulation cause a localized hypercoagulable state. The nephrotic syndrome presents an analogous situation, in which renal-vein thrombosis reflects a local loss of antithrombin III that is most prominent in the blood draining the kidneys. Since in vitro fertilization is increasingly common, these complications are likely to appear more frequently.

Oren Shibolet, M.D.
Mitchell J. Schwaber, M.D.
Mayer Brezis, M.D.
Hadassah University Hospital, Jerusalem 91120, Israel

5 References

1
Toglia MR, Weg JG. Venous thromboembolism during pregnancy. N Engl J Med 1996;335:108-114
Full Text | Web of Science | Medline

2
Waterstone JJ, Summers BA, Hoskins MC, Berry J, Parsons JH. Ovarian hyperstimulation syndrome and deep cerebral venous thrombosis. Br J Obstet Gynaecol 1992;99:439-440
CrossRef | Medline

3
Fournet N, Surrey E, Kerin J. Internal jugular vein thrombosis after ovulation induction with gonadotropins. Fertil Steril 1991;56:354-356
Web of Science | Medline

4
Ayhan A, Urman B, Gurgan T, Tuncer ZS, Deren O. Thrombosis of the internal jugular vein associated with severe ovarian hyperstimulation syndrome. Aust N Z J Obstet Gynaecol 1993;33:436-437
CrossRef | Web of Science | Medline

5
Rajah R, Boothroyd A, Lees WR. A pain in the neck! Br J Radiol 1991;64:867-868
CrossRef | Web of Science | Medline

To the Editor:

One important aspect of venous thromboembolic disease in pregnancy that was not covered by Toglia and Weg is how to advise women about long-term care of the affected leg. How can one minimize the risk of the post-thrombotic syndrome? Less than 15 percent of limbs return to normal on duplex scanning after deep-vein thrombosis. The remainder have either reflux, obstruction, or both,1 and the incidence of reflux increases throughout the first year.2 It is not possible to predict accurately who will have the post-thrombotic syndrome, although the presence of a normal venous system in the leg on duplex scanning after deep-vein thrombosis makes this complication unlikely. A logical plan is to advise all women who have deep-vein thrombosis during pregnancy to wear grade 2 graduated-compression hosiery (that is, hosiery with 18 to 24 mm Hg of pressure at the ankle 3) for a year. If duplex scanning after that time shows a normal venous system, the use of the hosiery may be discontinued. However, the presence of persistent reflux, obstruction, or both on the duplex scan should prompt the physician to advise the continued use of a stocking to minimize the risk of the post-thrombotic syndrome.

Andrew J.P. Sandison, F.R.C.S.
Yiannis P. Panayiotopoulos, M.D.
Peter R. Taylor, M.Chir.
Guy's Hospital, London SE1 9RT, United Kingdom

3 References

1
Johnson BF, Manzo RA, Bergelin RO, Strandness DE Jr. Relationship between changes in the deep venous system and the development of the postthrombotic syndrome after an acute episode of lower limb deep vein thrombosis: a one- to six-year follow-up. J Vasc Surg 1995;21:307-312
CrossRef | Web of Science | Medline

2
Markel A, Manzo RA, Bergelin RO, Strandness DE Jr. Häufigkeit und Zeitpunkt des Auftretens einer Klappeninsuffizienz nach tiefer Venenthrombose. Wien Med Wochenschr 1994;144:216-220
Medline

3
Keynes M. BS 6612. Specification for graduated compression hosiery. London: British Standards Institution, 1985.

To the Editor:

One of the recommendations of Toglia and Weg may be misinterpreted. In Table 4 they recommend that patients with the antiphospholipid-antibody syndrome who have not had thromboembolism should receive heparin ante partum and warfarin post partum.

Although combined treatment with heparin and aspirin is accepted for women with recurrent fetal loss associated with the antiphospholipid-antibody syndrome (who do not have thromboembolism), that therapy is directed to the health of the fetus, not the mother. Women whose only manifestation of the antiphospholipid-antibody syndrome is fetal loss may not be at increased risk for thromboembolism. Since many women decline to use heparin for fetal protection, it may be inappropriate to cite the risk of thromboembolism in order to persuade a reluctant woman to accept anticoagulant therapy.

There is no consensus among rheumatologists and hematologists about therapy for patients with complex conditions that include the antiphospholipid-antibody syndrome.1 Any treatment recommendation should therefore be considered tentative. Low titers of antiphospholipid antibody (as opposed to the antiphospholipid-antibody syndrome) are very common in normal pregnant women and have doubtful import.2 Drs. Toglia and Weg make this distinction carefully but do not specifically state that asymptomatic, seropositive women should not be treated. Physicians treating pregnant women who are positive for antiphospholipid antibody and who have no history of thromboembolism should be conservative in their treatment decisions.

Michael D. Lockshin, M.D.
National Institutes of Health, Bethesda, MD 20892

2 References

1
McCrae KR. Antiphospholipid antibody associated thrombosis: a consensus for treatment. Lupus (in press).

2
Silver RM, Porter TF, van Leeuween I, Jeng G, Scott JR, Branch DW. Anticardiolipin antibodies: clinical consequences of “low titers.“ Obstet Gynecol 1996;87:494-500
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Author/Editor Response

The authors reply:

To the Editor: We agree with Dr. Lockshin that recommendations for prophylaxis against thrombosis in women with the antiphospholipid-antibody syndrome but no history of thrombosis remain controversial, because the incidence of thrombosis in such women during pregnancy remains unknown and no large clinical trials of therapy have been performed. However, there are reports that women with this syndrome are at increased risk for thrombosis during pregnancy or oral-contraceptive use.

Silver et al.1 described 130 women with antiphospholipid antibodies and related disease, among whom 42 percent had thrombosis, 49 percent of them in association with pregnancy or the use of oral contraceptives. Thirty-four new thrombotic events occurred during the study, 24 percent of them associated with pregnancy.

These authors have suggested 1,2 that women with the antiphospholipid-antibody syndrome receive heparin throughout pregnancy as prophylaxis against thrombosis. The fourth Consensus Conference on Antithrombotic Therapy of the American College of Chest Physicians also suggests that these women be either treated with heparin prophylaxis or followed by clinical surveillance combined with venous compressive ultrasonography or impedance plethysmography.3 As Dr. Lockshin states, the meaning of low titers of antiphospholipid antibodies in otherwise normal pregnant women is unknown. It is likely that such women do not require prophylaxis against thrombosis during pregnancy.4

Although we share the concern of Sandison and colleagues about the development of the post-thrombotic syndrome and believe that using compression stockings sounds reasonable, we are unaware of prospective randomized trials that support their use. We thank Dr. Shibolet et al. for bringing to our attention the association between the use of gonadotropins and the development of internal-jugular-vein thrombosis.

Marc R. Toglia, M.D.
Graduate Hospital, Philadelphia, PA 19146

John G. Weg, M.D.
University of Michigan Medical Center, Ann Arbor, MI 48106

4 References

1
Silver RM, Draper ML, Scott JR, Lyon JL, Reading J, Branch DW. Clinical consequences of antiphospholipid antibodies: an historic cohort study. Obstet Gynecol 1994;83:372-377
Web of Science | Medline

2
Branch DW, Silver RM, Blackwell JL, Reading JC, Scott JR. Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obstet Gynecol 1992;80:614-620
Web of Science | Medline

3
Ginsberg JS, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 1995;108:Suppl:305S-311S
CrossRef | Web of Science | Medline

4
Silver RM, Porter TF, van Leeuween I, Jeng G, Scott JR, Branch DW. Anticardiolipin antibodies: clinical consequences of “low titers.“ Obstet Gynecol 1996;87:494-500
CrossRef | Web of Science | Medline

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