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Peripheral venous thrombophlebitis during pregnancy
Peripheral Venous Thrombophlebitis
during Pregnancy NELSON GURLL, MD, Boston, Massachusetts ZOLMAN HELFAND, MD, Boston, Massachusetts EDWIN F. SALZMAN, MD, Boston, Massachusetts WILLIAM SILEN, MD, Boston, Massachusetts
Thrombophlebitis after delivery has been known and discussed for hundreds of years. The occurrence of this disease in the antepartum period, however, is so infrequent as to limit the experience of a single individual physician. Villasanta [1] in 1965 in a comprehensive review collected fewer than 300 cases of antepartum thrombophlebitis from the literature and reported the incidence in pregnancy to be between 0.013 and 0.15 per cent. Recent interest in the relationship of oral contraceptive agents to the development of thromboembolic disease has prompted a re-examination of the occurrence of this disease in pregnant as well as nonpregnant women. If one considers only clear-cut cases of deep thrombophlebitis, partially avoiding the problems of inadequate clinical diagnosis and under-reporting, then reported series of cases of antepartum thrombophlebitis from 1965 to the present show an incidence of 0.021 to 0.035 per cent [Z-.4]. No universal agreement exists ss to the treatment of choice because of the special problems of the use of anticoagulants in the pregnant state. Heparin may be inconvenient and often impractical for long-term therapy. Fetal abnormalities and death have been reported due to oral anticoagulants. Thrombectomy or venous ligation have been advocated by some but have not achieved general acceptance. The general inactivity concerning these matters has prompted the present review. Clinical Material
From January 1965 to June 1970 there were 13,500 live births at the Beth Israel Hospital, Boston. In this same period of time seven patients were treated for antepartum deep thromhophlebitis. All cases occurred in the third trimester of pregnancy. The diagnosis was made on the basis of tenderness and induration over the involved vein with edema and increased circumFrom the Department of Surgery, Beth Israel Hospital, Boston, Massachusetts. Presented at the Fifty-First Annual Meeting of the New England Surgical Society, West Herwich. Massachusetts, October l-3, 1970. Volume 121, April 1971
ference of the extremity distal to the site of venous involvement. Four of the patients had iliofemoral disease with swelling to the groin and tenderness at least as high as the thigh, Deep calf thrombophlebitis was diagnosed in three patients with calf tenderness and induration together with distal swelling. (Table I.) As has been previousIy reported Cl], there were more cases involving the left side than the right. Two patients gave a previous history of swelling of the legs in pregnancy without documented toxemia or phlebitis. Only one patient had a previous history of phlebitis or varicose veins, and she had both. Four of the seven patients had received diuretic agents during their pregnancy. Thrombophlebitis recurred before delivery in two patients. (Table II.) In one, the disease recurred twenty-four hours after discontinuation of a fifteen day course of heparin. The thrombophlebitis responded to resumption of heparin therapy, and the patient has not suffered a recurrence or pulmonary embolus since. In the other patient, heparin dosage was decreased to 4,000 units intravenously every four hours because of vaginal bleeding. Tenderness and swelling recurred in the affected limb but responded dramatically in twenty-four hours to an increase in the heparin dose to 6,000 units. This patient did not receive oral anticoagulants in the postpartum period ; she has suffered three episodes of thrombophlebitis in the ensuing three years. Two other patients who did not receive oral agents after delivery both had recurrences and nonfatal pulmonary emboli. All four patients treated with warfarin in the postpartum period after preparturn heparin therapy were clinically free of pulinonary embolism and recurrence of thrombophlebitis. After the aforementioned initial failures a standard therapeutic regimen has evolved and been adopted. All patients were hospitalized until term and were given 7,500 to 10,000 units of heparin every four hours by intermittent intravenous injection. This dose was in all cases reduced gradually to 4,000 units when the signs of acute inflammation and pain had subsided. The clotting time was determined three and a half hours after the previous dose. In some of the patients, heparin was adjusted to keep the clotting time at two to two and a half times normal. Heparin was discontinued with the onset of active labor and was resumed immediately after delivery. Warfarin 449
Gurll et al TABLE
Clinical Features in Seven Patients Antepartum Deep Thrombophlebitis
I
Number of patients Age range (yr) Site lliofemoral Calf Side Left Right Bilateral Previous venous disease Diuretics Week of gestation
VIII,
7 25-34 4 3 4 1 2 1 4 30-38
was
begun immediately after delivery without a loading dose. Since the anticoagulant effect of warfarin does not parallel the depression in prothrombin time until about the fifth day of warfarin therapy, heparin was continued for five to seven days after delivery. Warfarin was continued for three to six months. The patients were initially placed on strict bed rest with 6 inch elevation of the foot of the bed. They were allowed to ambulate but not to sit or stand still when the signs of inflammation had subsided. Active leg exercises were encouraged while they were at bed rest, and below-knee elastic stockings or Ace bandages were used thereafter. There were no fetal or maternal deaths. There were two minor episodes of vaginal bleeding, both of which responded to a decrease in the dosage of heparin. (Table III.) There were no hemorrhagic complications at delivery, and puerperal blood loss was not excessive. Two of the patients have persistent ankle edema without varicosities. Follow-up visits have ranged from two to fifty-three months (mean of twenty-nine months). Pathophysiology
Factors favoring the development of venous thrombosis in nonpregnant women also exist in pregnant women. These factors include obesity, anemia, increasing age and parity, varicose veins, trauma, systemic illness such as diabetes, and cardiovascular disease, such as toxemia, cardiac disease, or hypertension [5]. Alterations of the blood-clotting mechanism have also been docuTABLE
II
Results of Therapy Thrombophlebitis Heparin Therapy
Patient
AP*
Rii BC SB RT LC
4’12 wk 3wk 9wk 10 days 2wk
JM EC
1 wk 4wk
* AP = antepartum; 450
PP*
in Antepartum
Warfarin PP
Recurrence
lwk lwk 1 wk 5 days 0
+ 0 + + 0
+AP + pp 0 0 +AP
5 days 5 days
0 +
+++ + PP 0
PP = postpartum.
in pregnancy. Fibrinogen and factors VII, and x increase during pregnancy, with factor VIII reaching twice normal values [6,7]. Fibrinolysis decreases during pregnancy ; this is an increased level of plasminogen and decreased urinary excretion of urokinase [ 71. Plasminogen and factors VII, VIII, and x decrease by 20 to 30 per cent after delivery [ 71. Fibrinolytic activity returns on the second postpartum day, and clotting tests show normal results some two to five months after delivery [ 71. Platelet adhesiveness has been shown to increase after delivery [S]. A progressive increase in venous distensibility during pregnancy has been demonstrated by plethysmography [9]. The velocity of blood flow is decreased in the legs in pregnant women, although the mean volume flow remains normal. Similar changes have been observed in women taking oral contraceptives [ 91. Previous varicosities and the pressure of the gravid uterus on the inferior vena cava are additional factors promoting stasis in pregnancy [ 10 1. Structural changes in the vessel wall have been described in pregnant rabbits. These consist of decreased smooth muscle, fragmented and decreased reticulum, and attenuated elastica with loss of corrugation [11]. Endothelial changes, probably more crucial in thrombogenesis, have not yet been demonstrated. mented
with
Deep
Pulmonary Embolus 0 + 0 0 0
PP + 0
IX,
Treatment
There are no convincing data to support or refute any of the conservative measures used, including bed rest, leg exercises, local heat, and ambulation with elastic stockings. These were employed chiefly to improve patients’ comfort by decreasing edema and perhaps accelerating the resolution of inflammation. In Villasanta’s collected series, there were 163 patients who were not treated with anticoagulants for antepartum thrombophlebitis [I]. In twentysix patients (15.9 per cent) pulmonary emboli developed, and twenty-one died (12.8 per cent). Twenty-six (19.4 per cent) of the 134 patients treated with anticoagulants had pulmonary emboli. In twenty-two, the emboli were present before treatment. In two, embolism occurred within forty-eight hours of initiation of treatment. In one patient a pulmonary embolus developed after treatment was stopped, and one embolism recurred when the prothrombin time was normal after a decrease in dosage. The maternal death rate from treatment was 0.7 per cent (l/134). Wingfield [12] reported one maternal death in forty-seven treated cases (0.2 per cent) as compared to seven deaths in sixteen untreated patients The American Journal of Surgery
Venous (43.7 per cent). Heparin has been shown experimentally to inhibit the propagation of thrombus [13,14]. Because of its large molecular size (MW 16,000)) high degree of ionization (pK, of 1.8)) and marked aqueous solubility, heparin does not cross the placenta [15]. There have been no reports of fetal abnormalities attributable to heparin [I]. Because of their smaller molecular size, oral anticoagulants have been shown to cross the placenta in experimental animals [16] and to cause fetal hemorrhage and death [17]. Two cases of hypoplasia of the nasal bones have been ascribed to oral agents [18,19]. By depressing the vitamin K-dependent clotting factors, they also decrease the progression of venous thrombosis. Prospective clinical evaluation has shown their effectiveness in decreasing the incidence of pulmonary emboli [20]. Comments
A striking and unexplained feature of antipartum thrombophlebitis is its relative rarity. The occurrence of deep thrombophlebitis is three to five times more common postpartum than antepartum [2-41. (Table IV.) Release of procoagulant placental products during delivery might account for this difference in incidence of thrombophlebitis. A puerperal increase in platelet adhesiveness might also play a role, although no direct relationship between platelet adhesiveness and the development of thromboembolic disease has been proved [21]. There appears to be a sixfold increase in thromboembolism during pregnancy and the puerperium compared to controls matched for age and parity, but the incidence of antepartum thrombophlebitis is not significantly different from that of nonpregnant, nonmedicated woman [22]. Yet women on oral contraceptives, with changes in the blood similar to those in pregnancy, have a risk of thromboembolic disease three times greater than that of control subjects [22]. It is difficult to explain the difference in incidence of thrombophlebitis between the pregnant state and the pseudopregnancy caused by oral contraceptives, which share many physiologic features. Therapy of the rare case of thrombophlebitis during pregnancy should aim to prevent pulmonary embolism and postphlebitic complications while minimizing hazards to mother and offspring. Heparin, at this time, appears to be the agent that best fits these requirements since the oral agents have been associated with fetal death and abnormalities. Anticoagulants have been shown not to increase puerperal blood loss when given postpartum [23]. Only one case of retroplacental Volume
121,
April
1971
TABLE
III
Mortality and Complications Deep Thrombophlebitis Mortality Maternal
Patient
Thrombophlebitis
in Pregnancy in Antepartum
Hemorrhage
Fetal
Maternal
Follow-up Study
Fetal
Varicosities
Swelling
RR
0
0
0
0
0
0
BC SB
0 0
0 0
0 +
0 0
0 0
+ 0
RT LC JM
0 0 0
0 0 0
0 + 0
0 0 0
0 0 0
+ 0 0
EC
0
0
0
0
+
+
hematoma causing separation has been attributed to heparin [I 1. Two cases of nasal bone hypoplasia have been ascribed to warfarin, although the mother of one of the infants had syphilis and the other received other drugs (digitalis and penicillin) as well as warfarin in the first trimester [18,19]. A difficulty in the use of heparin as described is the necessity for hospitalization until term. Since our patients were all treated after the thirtieth week of gestation, this was not a major problem. In the first trimester of pregnancy, the use of self-administered subcutaneous heparin might be more appropriate. Alternatively, the use of oral anticoagulants should be reconsidered. Hirsh, Cade, and O’Sullivan [24] recently reported treatment of fourteen patients in fifteen pregnancies with heparin and warfarin in ten patients when long-term anticoagulation was indicated. Heparin was substituted for warfarin at the thirty-seventh week of pregnancy. No maternal or fetal abnormalities were observed. Of the ten fetal deaths reported by Villasanta in thirty-seven patients treated before the thirty-sixth week of pregnancy, only two resulted from hemorrhage. In contrast, four of five fetal deaths were due to hemorrhage in thirteen pregnancies in which oral anticoagulants were given until term. Hirsh, Cade, and Gallus [25] administered warfarin to pregnant rabbits and observed the offspring for hemorrhagic complications. There were no complications if the delivery was by cesarian section or if the warfarin was stopped four days prior to vaginal delivery. However, all the fetuses were stillborn with disseminated hemorrhage when warfarin was given to term and vaginal delivery TABLE IV
Etiologic Factors in Antepartum Postpartum Thrombophlebitis
1. Increased 2. Decreased 3. Increased 4. Increased 5. Decreased 6. Vessel wall
coagulation factor fibrinolysis platelet adhesiveness venous distensibility velocity of blood flow changes
and
postpartum
451
Gurll
et al
was performed. These reports underscore the importance of the trauma of delivery in the development of fetal hemorrhage, although they do not explain the reports of nonhemorrhagic fetal death attributed to oral anticoagulants [I]. Fogarty et al [26] have reported the use of thrombectomy followed by heparin in seven patients with antepartum iliofemoral venous thrombosis. Follow-up venograms showed patency in four of five cases. However, Karp and Wylie [273 found rethrombosis in eight of eight patients in whom venography wa.s performed after iliofemoral thrombectomy (not during pregnancy) despite the fact that all the patients were clinically improved. Mavor and Galloway [28] have reported an early rethrombosis rate of 32 per cent after thrombectomy. They believed that thrombectomy was not indicated without termination of the pregnancy because of the hazard of rethrombosis. Recourse to thrombectomy is probably justified only if the patient is faced with impending gangrene due to plegmasia cerulea dolens. In thirty-nine patients with iliofemoral venous thrombectomy, Lansing and Davis [29] reported two deaths from pulmonary embolism and observed venous insufficiency in sixteen of seventeen patients seen at follow-up study. It has been stated that anticoagulation decreases the occurrence of late sequelae including venous insufficiency, but few data are available [30]. McDevitt and Smith [S] reported a 60 per cent incidence of postphlebitic sequelae after antepartum thrombophlebitis but did not specify the therapy used. Venous ligation for thrombophlebitis is not without hazard in pregnancy. Extensive dilatation of collateral veins follows iliofemoral thrombosis or ligation [32] and collateral circulation through the vertebral veins to the azygous system is frequently seen during pregnancy [IO]. Pulmonary embolism through such collaterals have been reported [31]. Despite the risk of thrombosis above a ligature, femoral vein interruption for tibia1 phlebitis early in pregnancy would seem preferable to long-term hospitalization and perhaps to vena caval interruption. Inferior vena cava ligation might be expected to lead to pelvic venous hypertension and possibly to placental separation, although no fetal or placental abnormalities have been reported under these circumstances ,[32]. Dextran has been employed in uncontrolled trial in ten patients. No mortality or morbidity was observed [1,3,4]. Other modes of therapy have received even scantier trial ; we have found no reports of the use of streptokinase, urokinase, or Arvin. 452
Summary
The treatment of peripheral venous thrombosis during pregnancy presents difficult problems not encountered under usual circumstances. Since the coumarin derivatives are small molecules which readily traverse the placenta, hazards to the fetus have been considered a contraindication to the use of these drugs. Thrombectomy is usually followed by rethrombosis and is not recommended except for the massively swollen limb with impending gangrene. Femoral vein ligation seems suitable for the patient with calf thrombophlebitis seen early in pregnancy, in whom prolonged hospitalization for heparin therapy would be required. Nonoperative treatment with bed rest for five to seven days and intravenous administration of heparin, which does not cross the placenta, is based on sound pathophysiologic considerations. A four and a half year experience with this form of therapy is presented. Heparin is continued postpartum until oral anticoagulants, begun at the time of delivery, become effective. Vitamin K antagonists are then continued for three to six months. Thrombophlebitis during pregnancy is infrequent despite the similarities in physiology to other states with a much higher incidence of thromboembolic disease (puerperium and oral contraceptive agents). References 1. Villasanta U: Thromboembolic disease in pregnancy. Amer J Obstet Gynec 93: 142,1965. 2a. Aaro LA, Johnson TR, Juergens JL: Acute deep venous thrombosis associated with pregnancy. Obstet Gynec 28: 553, 1966. 2b. Aaro LA, Johnson TR, Juergens JL: Acute superficial venous thrombophlebitis associated with pregnancy. Amer J Obstet Gynec 97: 514, 1967. 3. Weekes LR, Deukmedjian AG: Thromboembolic disease in pregnancy. Amer J Obstet Gynec 107: 649, 1970. 4. Husni’ EA, Pena LI, Lenhert AE: Thrombophlebitis in oreenancv. Amer J Obstet Gvnec 97: 901. 1967. 5. M&e& E, Smith 6: Thrombophlebitis during pregnancy and in the puerperium, p 55. Thrombosis. (Sherry S, Brinkhous K, Genton E, and Stengle J, ed.) National Academy of Science Publication, Washington, DC, 1969. 6. Todd ME, Thompson JH, Bowie EJW, Owen CA: Changes in blood coagulation during pregnancy. Mayo C/in Proc 40: 370, 1965. 7. Nilsson I, Kullander S: Coagulation and fibrinolytic studies during pregnancy. Acta Obstet Gynec Stand 46: 273,1967. 8. Hellen AJ: Adhesiveness of human blood platelets in vitro. Stand J C/in Lab invest (Suppl 51): 1, 1960. 9. Goodrich SM. Wood JE: Peripheral venous distensibility and velochy of venous blood flow during pregnancy or during oral contraceptive therapy. Amer J Obstet Gynec 90: 740, 1964. 10. Kerr MG, Scott DB, Samuel E: Studies of the inferior vena cava in late pregnancy. Brit Med J 1: 532, 1964. 11. Danforth DN, Manalo-Estrella P, Buckingham JC: The effect of pregnancy and of Enovid on the rabbit vascuThe
American
Journal
of
Surgery
Venous Thrombophlebitis lature. Amer J Obstet Gynec 88: 952, 1964. JG: Anticoagulation for antenatal thromboembolic disease. J Obstet Gynec Brit Comm 76: 518, 1969. Carey LC, Williams RD: Comparative effects of dicumarol, tromexan, and heparin on thrombus propagation. Ann Sorg 152: 919, 1960. Wessler S, Morris LE: Studies in intravascular coagulation: effect of heparin and dicumarol in serum-induced venous thrombosis. Circulation 12: 553, 1955. Villee CA: Placental transfer of drugs. Ann NY Acad Sci 123: 237, 1965. Qui,ck AJ: Experimentally induced changes in the prothrombin level of the blood: prothrombin concentration of newborn pups of a mother given dicumarol before parturition. J Biol Chem 164: 371, 1946. Kraus AP, Perlow A, Singer K, Danger of dicumarol therapy in pregnancy. JAMA 139: 758,1949. Kerber IJ, Warr OS, Richardson C: Pregnancy in a patient with a prosthetic mitral valve associated with a fetal anomaly attributed to warfarin sodium. JAMA 203: 223,196B. DiSaia PJ: Pregnancy and delivery of a patient with a Starr-Edwards mitral valve prosthesis. Obstet Gynec 28: 469, 1966. Barritt DW, Jordan SC: Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial. Lancet 1: 1309, 1960. Negus D, Pinto DJ, Brown N: Platelet adhesiveness in postoperative deep vein thrombosis. Lancet 1: 220, 1969. Committee on Safety of Drugs: Risk of thromboembolic disease in women taking oral contraceptives. Brit Med J 2: 355, 1967. Barnes AC, Ervin HK: The effect of anticoagulants and postpartum bleeding. Sorg Gynec Obstet 83: 528, 1946. Hirsh J, Cade JF, Sullivan EF: Clinical experience with anticoagulant therapy during pregnancy. Brit Med J 1: 270, 1970. Hirsh J, Cade JF, Gallus AS: Fetal effects of coumadin administered in pregnancy (In press.) Fonartv TJ. Wood JA. KriDDaehne WW. Dennis DL: Management of iliofemorai venous thrombosis in the antepartum state. Surg Gynec Obstet 128: 546, 1969. Karp RB, Wylie EJ: Recurrent thrombosis after iliofemoral venous thrombectomy. Surg Forum 17: 147, 1966. Mavor GE, Galloway JMD: lliofemoral venous thrombosis. Pathological considerations and surgical management. Brit J Surg 56: 45, 1969. Lansing AM, Davis WM: Five-year followup study of iliofemoral venous thrombectomy. Ann Surg 168: 620,
12. Wingfield 13. 14. 15. 16.
17. 18.
19. 20. 21. 22. 23. 24.
25. 26.
27. 28.
29.
1968. 30. Aggeler PM, Kosmin
31.
32.
M: Anticoagulant prophylaxis and treatment of venous thromboembolic disease, p 639. Thrombosis. (Sherry S, Brinkhous K, Genton E and Stengle J, ed.) National Academy of Science Publication 1706, Washington, DC, 1969. Gurewich V, Thomas DP, Rabinov KR: Pulmonary embolism after ligation of the inferior vena cava. New Engl J Med 274: 1350, 1966. Evans GL, Dalen JE, Dexter L: Pulmonary embolism during pregnancy. JAMA 206: 320,1968.
Discussion C. CRANE (Boston, Mass.) : This is a hard paper to discuss mostly because I do not have any great experience with phlebitis in pregnancy; however, we are very grateful to the authors for bringing this subject to our attention for it is not often discussed. We all
Volume 121. April 1971
in Pregnancy
occasionally encounter a case of deep vein thrombosis during pregnancy and managment is often a puzzle. Thrombophlebitis is well recognized as a treacherous disease, and since pregnancy itself is a somewhat treacherous condition, the combination makes for a formidable situation. I would agree with the authors on several points. In ileofemoral phlebitis, thrombectomy should almost never be performed. The famous southern series of twenty-five cases in which venograms were taken more than five years later demonstrated that twentyfour of the twenty-five veins were either closed or grossly incompetent. Thus, if the goal of thrombectomy is to obtain a patient and competent vein, the operation does not work. ileofemoral thrombosisHowever, in massive cerulea dolens-the operation is vital. Here the objective is not to get a permanently patent vein but to prevent pressure necrosis of muscle and nerve distal to the thrombus. The authors mentioned the use of venous ligation for phlebitis in the early months of pregnancy and this makes good sense. I think, moreover, that one can occasionally perform this ligation unilaterally and at the superficial femoral level in contrast to the situations in which the patient has had an embolus. If the patient has had an embolus and it is four or five months before delivery, we would place a clip on the inferior vena cava. I am most bothered by phlebitis in the prepartum stage since anticoagulants are generally considered to be contraindicated, especially during labor. With a calf vein thrombosis, one can tie the femoral veins. However, I do not known how one would proceed with an ileofemoral process. Since there is no good alternative treatment, I should think that an anticoagulation program, such as the one described by the authors, might be used. JOHN J. BYRNE (Boston, Mass) : I reviewed twentytwo cases of antepartum deep thrombosis at the Boston City Hospital and found this to be a benign process regardless of the method of therapy. Seven patients were treated by heat, leg elevation, and bed rest; eight had bilateral superficial vein division ; five received heparin for seven to ten days and two received dicumarol (one for twenty-two weeks). All had good results with no maternal or fetal mortality. Forty-two patients were treated in the postpartum period with various regimens as the previous group with no serious maternal or fetal sequelae. NELSON GURLL (Boston, Mass) : I want to thank Drs. Crane and Byrne for their comments. There have been 385 cases of antepartum thrombophlebitis reported in the literature with a 19 per cent incidence of pulmonary embolism and a mortality rate of 6.5 per cent. There was a difference in mortality between patients receiving anticoagulants (0.7 per cent) and those not receiving anticoagulants (13.7 per cent). Discrepancies between these data and those of Dr. Byrne may be due, in part, to underdiagnosis of thromboembolic disease.
453
during Pregnancy NELSON GURLL, MD, Boston, Massachusetts ZOLMAN HELFAND, MD, Boston, Massachusetts EDWIN F. SALZMAN, MD, Boston, Massachusetts WILLIAM SILEN, MD, Boston, Massachusetts
Thrombophlebitis after delivery has been known and discussed for hundreds of years. The occurrence of this disease in the antepartum period, however, is so infrequent as to limit the experience of a single individual physician. Villasanta [1] in 1965 in a comprehensive review collected fewer than 300 cases of antepartum thrombophlebitis from the literature and reported the incidence in pregnancy to be between 0.013 and 0.15 per cent. Recent interest in the relationship of oral contraceptive agents to the development of thromboembolic disease has prompted a re-examination of the occurrence of this disease in pregnant as well as nonpregnant women. If one considers only clear-cut cases of deep thrombophlebitis, partially avoiding the problems of inadequate clinical diagnosis and under-reporting, then reported series of cases of antepartum thrombophlebitis from 1965 to the present show an incidence of 0.021 to 0.035 per cent [Z-.4]. No universal agreement exists ss to the treatment of choice because of the special problems of the use of anticoagulants in the pregnant state. Heparin may be inconvenient and often impractical for long-term therapy. Fetal abnormalities and death have been reported due to oral anticoagulants. Thrombectomy or venous ligation have been advocated by some but have not achieved general acceptance. The general inactivity concerning these matters has prompted the present review. Clinical Material
From January 1965 to June 1970 there were 13,500 live births at the Beth Israel Hospital, Boston. In this same period of time seven patients were treated for antepartum deep thromhophlebitis. All cases occurred in the third trimester of pregnancy. The diagnosis was made on the basis of tenderness and induration over the involved vein with edema and increased circumFrom the Department of Surgery, Beth Israel Hospital, Boston, Massachusetts. Presented at the Fifty-First Annual Meeting of the New England Surgical Society, West Herwich. Massachusetts, October l-3, 1970. Volume 121, April 1971
ference of the extremity distal to the site of venous involvement. Four of the patients had iliofemoral disease with swelling to the groin and tenderness at least as high as the thigh, Deep calf thrombophlebitis was diagnosed in three patients with calf tenderness and induration together with distal swelling. (Table I.) As has been previousIy reported Cl], there were more cases involving the left side than the right. Two patients gave a previous history of swelling of the legs in pregnancy without documented toxemia or phlebitis. Only one patient had a previous history of phlebitis or varicose veins, and she had both. Four of the seven patients had received diuretic agents during their pregnancy. Thrombophlebitis recurred before delivery in two patients. (Table II.) In one, the disease recurred twenty-four hours after discontinuation of a fifteen day course of heparin. The thrombophlebitis responded to resumption of heparin therapy, and the patient has not suffered a recurrence or pulmonary embolus since. In the other patient, heparin dosage was decreased to 4,000 units intravenously every four hours because of vaginal bleeding. Tenderness and swelling recurred in the affected limb but responded dramatically in twenty-four hours to an increase in the heparin dose to 6,000 units. This patient did not receive oral anticoagulants in the postpartum period ; she has suffered three episodes of thrombophlebitis in the ensuing three years. Two other patients who did not receive oral agents after delivery both had recurrences and nonfatal pulmonary emboli. All four patients treated with warfarin in the postpartum period after preparturn heparin therapy were clinically free of pulinonary embolism and recurrence of thrombophlebitis. After the aforementioned initial failures a standard therapeutic regimen has evolved and been adopted. All patients were hospitalized until term and were given 7,500 to 10,000 units of heparin every four hours by intermittent intravenous injection. This dose was in all cases reduced gradually to 4,000 units when the signs of acute inflammation and pain had subsided. The clotting time was determined three and a half hours after the previous dose. In some of the patients, heparin was adjusted to keep the clotting time at two to two and a half times normal. Heparin was discontinued with the onset of active labor and was resumed immediately after delivery. Warfarin 449
Gurll et al TABLE
Clinical Features in Seven Patients Antepartum Deep Thrombophlebitis
I
Number of patients Age range (yr) Site lliofemoral Calf Side Left Right Bilateral Previous venous disease Diuretics Week of gestation
VIII,
7 25-34 4 3 4 1 2 1 4 30-38
was
begun immediately after delivery without a loading dose. Since the anticoagulant effect of warfarin does not parallel the depression in prothrombin time until about the fifth day of warfarin therapy, heparin was continued for five to seven days after delivery. Warfarin was continued for three to six months. The patients were initially placed on strict bed rest with 6 inch elevation of the foot of the bed. They were allowed to ambulate but not to sit or stand still when the signs of inflammation had subsided. Active leg exercises were encouraged while they were at bed rest, and below-knee elastic stockings or Ace bandages were used thereafter. There were no fetal or maternal deaths. There were two minor episodes of vaginal bleeding, both of which responded to a decrease in the dosage of heparin. (Table III.) There were no hemorrhagic complications at delivery, and puerperal blood loss was not excessive. Two of the patients have persistent ankle edema without varicosities. Follow-up visits have ranged from two to fifty-three months (mean of twenty-nine months). Pathophysiology
Factors favoring the development of venous thrombosis in nonpregnant women also exist in pregnant women. These factors include obesity, anemia, increasing age and parity, varicose veins, trauma, systemic illness such as diabetes, and cardiovascular disease, such as toxemia, cardiac disease, or hypertension [5]. Alterations of the blood-clotting mechanism have also been docuTABLE
II
Results of Therapy Thrombophlebitis Heparin Therapy
Patient
AP*
Rii BC SB RT LC
4’12 wk 3wk 9wk 10 days 2wk
JM EC
1 wk 4wk
* AP = antepartum; 450
PP*
in Antepartum
Warfarin PP
Recurrence
lwk lwk 1 wk 5 days 0
+ 0 + + 0
+AP + pp 0 0 +AP
5 days 5 days
0 +
+++ + PP 0
PP = postpartum.
in pregnancy. Fibrinogen and factors VII, and x increase during pregnancy, with factor VIII reaching twice normal values [6,7]. Fibrinolysis decreases during pregnancy ; this is an increased level of plasminogen and decreased urinary excretion of urokinase [ 71. Plasminogen and factors VII, VIII, and x decrease by 20 to 30 per cent after delivery [ 71. Fibrinolytic activity returns on the second postpartum day, and clotting tests show normal results some two to five months after delivery [ 71. Platelet adhesiveness has been shown to increase after delivery [S]. A progressive increase in venous distensibility during pregnancy has been demonstrated by plethysmography [9]. The velocity of blood flow is decreased in the legs in pregnant women, although the mean volume flow remains normal. Similar changes have been observed in women taking oral contraceptives [ 91. Previous varicosities and the pressure of the gravid uterus on the inferior vena cava are additional factors promoting stasis in pregnancy [ 10 1. Structural changes in the vessel wall have been described in pregnant rabbits. These consist of decreased smooth muscle, fragmented and decreased reticulum, and attenuated elastica with loss of corrugation [11]. Endothelial changes, probably more crucial in thrombogenesis, have not yet been demonstrated. mented
with
Deep
Pulmonary Embolus 0 + 0 0 0
PP + 0
IX,
Treatment
There are no convincing data to support or refute any of the conservative measures used, including bed rest, leg exercises, local heat, and ambulation with elastic stockings. These were employed chiefly to improve patients’ comfort by decreasing edema and perhaps accelerating the resolution of inflammation. In Villasanta’s collected series, there were 163 patients who were not treated with anticoagulants for antepartum thrombophlebitis [I]. In twentysix patients (15.9 per cent) pulmonary emboli developed, and twenty-one died (12.8 per cent). Twenty-six (19.4 per cent) of the 134 patients treated with anticoagulants had pulmonary emboli. In twenty-two, the emboli were present before treatment. In two, embolism occurred within forty-eight hours of initiation of treatment. In one patient a pulmonary embolus developed after treatment was stopped, and one embolism recurred when the prothrombin time was normal after a decrease in dosage. The maternal death rate from treatment was 0.7 per cent (l/134). Wingfield [12] reported one maternal death in forty-seven treated cases (0.2 per cent) as compared to seven deaths in sixteen untreated patients The American Journal of Surgery
Venous (43.7 per cent). Heparin has been shown experimentally to inhibit the propagation of thrombus [13,14]. Because of its large molecular size (MW 16,000)) high degree of ionization (pK, of 1.8)) and marked aqueous solubility, heparin does not cross the placenta [15]. There have been no reports of fetal abnormalities attributable to heparin [I]. Because of their smaller molecular size, oral anticoagulants have been shown to cross the placenta in experimental animals [16] and to cause fetal hemorrhage and death [17]. Two cases of hypoplasia of the nasal bones have been ascribed to oral agents [18,19]. By depressing the vitamin K-dependent clotting factors, they also decrease the progression of venous thrombosis. Prospective clinical evaluation has shown their effectiveness in decreasing the incidence of pulmonary emboli [20]. Comments
A striking and unexplained feature of antipartum thrombophlebitis is its relative rarity. The occurrence of deep thrombophlebitis is three to five times more common postpartum than antepartum [2-41. (Table IV.) Release of procoagulant placental products during delivery might account for this difference in incidence of thrombophlebitis. A puerperal increase in platelet adhesiveness might also play a role, although no direct relationship between platelet adhesiveness and the development of thromboembolic disease has been proved [21]. There appears to be a sixfold increase in thromboembolism during pregnancy and the puerperium compared to controls matched for age and parity, but the incidence of antepartum thrombophlebitis is not significantly different from that of nonpregnant, nonmedicated woman [22]. Yet women on oral contraceptives, with changes in the blood similar to those in pregnancy, have a risk of thromboembolic disease three times greater than that of control subjects [22]. It is difficult to explain the difference in incidence of thrombophlebitis between the pregnant state and the pseudopregnancy caused by oral contraceptives, which share many physiologic features. Therapy of the rare case of thrombophlebitis during pregnancy should aim to prevent pulmonary embolism and postphlebitic complications while minimizing hazards to mother and offspring. Heparin, at this time, appears to be the agent that best fits these requirements since the oral agents have been associated with fetal death and abnormalities. Anticoagulants have been shown not to increase puerperal blood loss when given postpartum [23]. Only one case of retroplacental Volume
121,
April
1971
TABLE
III
Mortality and Complications Deep Thrombophlebitis Mortality Maternal
Patient
Thrombophlebitis
in Pregnancy in Antepartum
Hemorrhage
Fetal
Maternal
Follow-up Study
Fetal
Varicosities
Swelling
RR
0
0
0
0
0
0
BC SB
0 0
0 0
0 +
0 0
0 0
+ 0
RT LC JM
0 0 0
0 0 0
0 + 0
0 0 0
0 0 0
+ 0 0
EC
0
0
0
0
+
+
hematoma causing separation has been attributed to heparin [I 1. Two cases of nasal bone hypoplasia have been ascribed to warfarin, although the mother of one of the infants had syphilis and the other received other drugs (digitalis and penicillin) as well as warfarin in the first trimester [18,19]. A difficulty in the use of heparin as described is the necessity for hospitalization until term. Since our patients were all treated after the thirtieth week of gestation, this was not a major problem. In the first trimester of pregnancy, the use of self-administered subcutaneous heparin might be more appropriate. Alternatively, the use of oral anticoagulants should be reconsidered. Hirsh, Cade, and O’Sullivan [24] recently reported treatment of fourteen patients in fifteen pregnancies with heparin and warfarin in ten patients when long-term anticoagulation was indicated. Heparin was substituted for warfarin at the thirty-seventh week of pregnancy. No maternal or fetal abnormalities were observed. Of the ten fetal deaths reported by Villasanta in thirty-seven patients treated before the thirty-sixth week of pregnancy, only two resulted from hemorrhage. In contrast, four of five fetal deaths were due to hemorrhage in thirteen pregnancies in which oral anticoagulants were given until term. Hirsh, Cade, and Gallus [25] administered warfarin to pregnant rabbits and observed the offspring for hemorrhagic complications. There were no complications if the delivery was by cesarian section or if the warfarin was stopped four days prior to vaginal delivery. However, all the fetuses were stillborn with disseminated hemorrhage when warfarin was given to term and vaginal delivery TABLE IV
Etiologic Factors in Antepartum Postpartum Thrombophlebitis
1. Increased 2. Decreased 3. Increased 4. Increased 5. Decreased 6. Vessel wall
coagulation factor fibrinolysis platelet adhesiveness venous distensibility velocity of blood flow changes
and
postpartum
451
Gurll
et al
was performed. These reports underscore the importance of the trauma of delivery in the development of fetal hemorrhage, although they do not explain the reports of nonhemorrhagic fetal death attributed to oral anticoagulants [I]. Fogarty et al [26] have reported the use of thrombectomy followed by heparin in seven patients with antepartum iliofemoral venous thrombosis. Follow-up venograms showed patency in four of five cases. However, Karp and Wylie [273 found rethrombosis in eight of eight patients in whom venography wa.s performed after iliofemoral thrombectomy (not during pregnancy) despite the fact that all the patients were clinically improved. Mavor and Galloway [28] have reported an early rethrombosis rate of 32 per cent after thrombectomy. They believed that thrombectomy was not indicated without termination of the pregnancy because of the hazard of rethrombosis. Recourse to thrombectomy is probably justified only if the patient is faced with impending gangrene due to plegmasia cerulea dolens. In thirty-nine patients with iliofemoral venous thrombectomy, Lansing and Davis [29] reported two deaths from pulmonary embolism and observed venous insufficiency in sixteen of seventeen patients seen at follow-up study. It has been stated that anticoagulation decreases the occurrence of late sequelae including venous insufficiency, but few data are available [30]. McDevitt and Smith [S] reported a 60 per cent incidence of postphlebitic sequelae after antepartum thrombophlebitis but did not specify the therapy used. Venous ligation for thrombophlebitis is not without hazard in pregnancy. Extensive dilatation of collateral veins follows iliofemoral thrombosis or ligation [32] and collateral circulation through the vertebral veins to the azygous system is frequently seen during pregnancy [IO]. Pulmonary embolism through such collaterals have been reported [31]. Despite the risk of thrombosis above a ligature, femoral vein interruption for tibia1 phlebitis early in pregnancy would seem preferable to long-term hospitalization and perhaps to vena caval interruption. Inferior vena cava ligation might be expected to lead to pelvic venous hypertension and possibly to placental separation, although no fetal or placental abnormalities have been reported under these circumstances ,[32]. Dextran has been employed in uncontrolled trial in ten patients. No mortality or morbidity was observed [1,3,4]. Other modes of therapy have received even scantier trial ; we have found no reports of the use of streptokinase, urokinase, or Arvin. 452
Summary
The treatment of peripheral venous thrombosis during pregnancy presents difficult problems not encountered under usual circumstances. Since the coumarin derivatives are small molecules which readily traverse the placenta, hazards to the fetus have been considered a contraindication to the use of these drugs. Thrombectomy is usually followed by rethrombosis and is not recommended except for the massively swollen limb with impending gangrene. Femoral vein ligation seems suitable for the patient with calf thrombophlebitis seen early in pregnancy, in whom prolonged hospitalization for heparin therapy would be required. Nonoperative treatment with bed rest for five to seven days and intravenous administration of heparin, which does not cross the placenta, is based on sound pathophysiologic considerations. A four and a half year experience with this form of therapy is presented. Heparin is continued postpartum until oral anticoagulants, begun at the time of delivery, become effective. Vitamin K antagonists are then continued for three to six months. Thrombophlebitis during pregnancy is infrequent despite the similarities in physiology to other states with a much higher incidence of thromboembolic disease (puerperium and oral contraceptive agents). References 1. Villasanta U: Thromboembolic disease in pregnancy. Amer J Obstet Gynec 93: 142,1965. 2a. Aaro LA, Johnson TR, Juergens JL: Acute deep venous thrombosis associated with pregnancy. Obstet Gynec 28: 553, 1966. 2b. Aaro LA, Johnson TR, Juergens JL: Acute superficial venous thrombophlebitis associated with pregnancy. Amer J Obstet Gynec 97: 514, 1967. 3. Weekes LR, Deukmedjian AG: Thromboembolic disease in pregnancy. Amer J Obstet Gynec 107: 649, 1970. 4. Husni’ EA, Pena LI, Lenhert AE: Thrombophlebitis in oreenancv. Amer J Obstet Gvnec 97: 901. 1967. 5. M&e& E, Smith 6: Thrombophlebitis during pregnancy and in the puerperium, p 55. Thrombosis. (Sherry S, Brinkhous K, Genton E, and Stengle J, ed.) National Academy of Science Publication, Washington, DC, 1969. 6. Todd ME, Thompson JH, Bowie EJW, Owen CA: Changes in blood coagulation during pregnancy. Mayo C/in Proc 40: 370, 1965. 7. Nilsson I, Kullander S: Coagulation and fibrinolytic studies during pregnancy. Acta Obstet Gynec Stand 46: 273,1967. 8. Hellen AJ: Adhesiveness of human blood platelets in vitro. Stand J C/in Lab invest (Suppl 51): 1, 1960. 9. Goodrich SM. Wood JE: Peripheral venous distensibility and velochy of venous blood flow during pregnancy or during oral contraceptive therapy. Amer J Obstet Gynec 90: 740, 1964. 10. Kerr MG, Scott DB, Samuel E: Studies of the inferior vena cava in late pregnancy. Brit Med J 1: 532, 1964. 11. Danforth DN, Manalo-Estrella P, Buckingham JC: The effect of pregnancy and of Enovid on the rabbit vascuThe
American
Journal
of
Surgery
Venous Thrombophlebitis lature. Amer J Obstet Gynec 88: 952, 1964. JG: Anticoagulation for antenatal thromboembolic disease. J Obstet Gynec Brit Comm 76: 518, 1969. Carey LC, Williams RD: Comparative effects of dicumarol, tromexan, and heparin on thrombus propagation. Ann Sorg 152: 919, 1960. Wessler S, Morris LE: Studies in intravascular coagulation: effect of heparin and dicumarol in serum-induced venous thrombosis. Circulation 12: 553, 1955. Villee CA: Placental transfer of drugs. Ann NY Acad Sci 123: 237, 1965. Qui,ck AJ: Experimentally induced changes in the prothrombin level of the blood: prothrombin concentration of newborn pups of a mother given dicumarol before parturition. J Biol Chem 164: 371, 1946. Kraus AP, Perlow A, Singer K, Danger of dicumarol therapy in pregnancy. JAMA 139: 758,1949. Kerber IJ, Warr OS, Richardson C: Pregnancy in a patient with a prosthetic mitral valve associated with a fetal anomaly attributed to warfarin sodium. JAMA 203: 223,196B. DiSaia PJ: Pregnancy and delivery of a patient with a Starr-Edwards mitral valve prosthesis. Obstet Gynec 28: 469, 1966. Barritt DW, Jordan SC: Anticoagulant drugs in the treatment of pulmonary embolism: a controlled trial. Lancet 1: 1309, 1960. Negus D, Pinto DJ, Brown N: Platelet adhesiveness in postoperative deep vein thrombosis. Lancet 1: 220, 1969. Committee on Safety of Drugs: Risk of thromboembolic disease in women taking oral contraceptives. Brit Med J 2: 355, 1967. Barnes AC, Ervin HK: The effect of anticoagulants and postpartum bleeding. Sorg Gynec Obstet 83: 528, 1946. Hirsh J, Cade JF, Sullivan EF: Clinical experience with anticoagulant therapy during pregnancy. Brit Med J 1: 270, 1970. Hirsh J, Cade JF, Gallus AS: Fetal effects of coumadin administered in pregnancy (In press.) Fonartv TJ. Wood JA. KriDDaehne WW. Dennis DL: Management of iliofemorai venous thrombosis in the antepartum state. Surg Gynec Obstet 128: 546, 1969. Karp RB, Wylie EJ: Recurrent thrombosis after iliofemoral venous thrombectomy. Surg Forum 17: 147, 1966. Mavor GE, Galloway JMD: lliofemoral venous thrombosis. Pathological considerations and surgical management. Brit J Surg 56: 45, 1969. Lansing AM, Davis WM: Five-year followup study of iliofemoral venous thrombectomy. Ann Surg 168: 620,
12. Wingfield 13. 14. 15. 16.
17. 18.
19. 20. 21. 22. 23. 24.
25. 26.
27. 28.
29.
1968. 30. Aggeler PM, Kosmin
31.
32.
M: Anticoagulant prophylaxis and treatment of venous thromboembolic disease, p 639. Thrombosis. (Sherry S, Brinkhous K, Genton E and Stengle J, ed.) National Academy of Science Publication 1706, Washington, DC, 1969. Gurewich V, Thomas DP, Rabinov KR: Pulmonary embolism after ligation of the inferior vena cava. New Engl J Med 274: 1350, 1966. Evans GL, Dalen JE, Dexter L: Pulmonary embolism during pregnancy. JAMA 206: 320,1968.
Discussion C. CRANE (Boston, Mass.) : This is a hard paper to discuss mostly because I do not have any great experience with phlebitis in pregnancy; however, we are very grateful to the authors for bringing this subject to our attention for it is not often discussed. We all
Volume 121. April 1971
in Pregnancy
occasionally encounter a case of deep vein thrombosis during pregnancy and managment is often a puzzle. Thrombophlebitis is well recognized as a treacherous disease, and since pregnancy itself is a somewhat treacherous condition, the combination makes for a formidable situation. I would agree with the authors on several points. In ileofemoral phlebitis, thrombectomy should almost never be performed. The famous southern series of twenty-five cases in which venograms were taken more than five years later demonstrated that twentyfour of the twenty-five veins were either closed or grossly incompetent. Thus, if the goal of thrombectomy is to obtain a patient and competent vein, the operation does not work. ileofemoral thrombosisHowever, in massive cerulea dolens-the operation is vital. Here the objective is not to get a permanently patent vein but to prevent pressure necrosis of muscle and nerve distal to the thrombus. The authors mentioned the use of venous ligation for phlebitis in the early months of pregnancy and this makes good sense. I think, moreover, that one can occasionally perform this ligation unilaterally and at the superficial femoral level in contrast to the situations in which the patient has had an embolus. If the patient has had an embolus and it is four or five months before delivery, we would place a clip on the inferior vena cava. I am most bothered by phlebitis in the prepartum stage since anticoagulants are generally considered to be contraindicated, especially during labor. With a calf vein thrombosis, one can tie the femoral veins. However, I do not known how one would proceed with an ileofemoral process. Since there is no good alternative treatment, I should think that an anticoagulation program, such as the one described by the authors, might be used. JOHN J. BYRNE (Boston, Mass) : I reviewed twentytwo cases of antepartum deep thrombosis at the Boston City Hospital and found this to be a benign process regardless of the method of therapy. Seven patients were treated by heat, leg elevation, and bed rest; eight had bilateral superficial vein division ; five received heparin for seven to ten days and two received dicumarol (one for twenty-two weeks). All had good results with no maternal or fetal mortality. Forty-two patients were treated in the postpartum period with various regimens as the previous group with no serious maternal or fetal sequelae. NELSON GURLL (Boston, Mass) : I want to thank Drs. Crane and Byrne for their comments. There have been 385 cases of antepartum thrombophlebitis reported in the literature with a 19 per cent incidence of pulmonary embolism and a mortality rate of 6.5 per cent. There was a difference in mortality between patients receiving anticoagulants (0.7 per cent) and those not receiving anticoagulants (13.7 per cent). Discrepancies between these data and those of Dr. Byrne may be due, in part, to underdiagnosis of thromboembolic disease.
453