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Internal jugular vein thrombosis after ovulation induction with gonadotropins
FERTILITY AND STERILITY Copyright e
Vol. 56, No.2, August
1991 The American Fertility Society
1991
Printed on acid-free paper in U.S.A.
Internal jugular vein thrombosis after ovulation induction with gonadotropins
Nicole Fournet, M.D.* Eric Surrey, M.D. John Kerin, M.D., Ph.D. Division of Reproductive Endocrinology, Cedars-Sinai Medical Center, University of California, Los Angeles, (UCLA) School of Medicine, Los Angeles, California
Despite advanced monitoring techniques, ovarian hyperstimulation syndrome remains a serious and poorly understood complication of ovulation induction with human menopausal gonadotropins (hMG). Using ultrasound (US) imaging in conjunction with serum estradiol (E 2 ) levels and clinical presentation, various degrees of ovarian hyperstimulation syndrome have been reported after hMG administration.1 Fortunately, most of the cases are mild to moderate and have no major clinical consequences. Severe hyperstimulation, however, is a rare but potentially lethal condition that requires prompt diagnosis and inpatient monitoring. The pathogenesis of this syndrome is unclear, but production of vasoactive substances results in increased local capillary permeability, stromal edema, and massively enlarged, multicystic ovaries. As a result, fluid escapes the intravascular compartment and may cause ascites, hypovolemia, oliguria, and hemoconcentration. In the most severe cases, the increased blood viscosity and alteration in coagulation factors may lead to thromboembolic events. 1 We report a case of severe ovarian hyperstimulation syndrome with extensive thrombosis of the right internal jugular vein extending into the superior vena cava after an unremarkable in vitro fertilizationembryo transfer (IVF-ET) cycle that resulted in a twin pregnancy.
Received January 28, 1991; revised and accepted April18, 1991.
* Reprint requests: Nicole Fournet, M.D., Division of Reproductive Endocrinology, Cedars-Sinai Medical Center, 444 South San Vicente Boulevard, Los Angeles, California 90048. 354
Fournet et al.
Communications-in-brief
CASE REPORT
A 37 -year-old nulligravida with primary infertility because of tubal disease was referred for IVF. Her first cycle, though unsuccessful, was uneventful. After a standard stimulation regimen as described below, the serum E 2 level rose to 1,225 pg/mL on the day of human chorionic gonadotropin (hCG, Profasi; Serono Laboratories, Randolph, MA) administration. After uncomplicated oocyte aspiration and IVF, five cleaved embryos were transferred. Pregnancy did not result. Three months later, a second IVF cycle was initiated. Leuprolide acetate (LA, Lupron; TAP Pharmaceuticals, North Chicago, IL) 1 mg/d was administered subcutaneously (SC) starting on day 21 of the menstrual cycle for 10 days. At this point, serum E 2 level was <20 pg/mL. The daily LA dose was decreased to 0.5 mg. Human menopausal gonadotropins (Pergonal; Serono Laboratories) 225 IU/day was then administered intramuscularly (IM) for 5 days after which the dose was individualized according to follicle size, number, and E 2 levels. A total of 30 ampules of hMG was given. After 10 days of hMG administration, 13 follicles measuring 15 to 19 mm in diameter and serum E 2 level of 1,405 pg/ mL were noted. Thirty-six hours after administration of hCG 10,000 IU, transvaginal follicular aspiration yielded 15 oocytes. Five cleaved embryos were transferred 48 hours later. Progesterone suppositories were given intravaginally twice daily for luteal phase support. Ten days later, the patient complained of abdominal distention and left-sided discomfort. Physical examination revealed stable vital signs and mild abFertility and Sterility
domina! distention without a fluid wave. The lung fields were clear. Transvaginal US examination revealed slightly enlarged ovaries and a small amount of free peritoneal fluid. Laboratory evaluation revealed hemoconcentration. Detailed clinical and laboratory findings are summarized in Table 1. The patient was treated with bed rest and oral hydration. Fourteen days after ET, conception was documented (serum ,8-hCG 724 miU/mL). The patient's condition remained stable, and the hematocrit returned rapidly to baseline (Table 1). Two weeks later, however, she presented with sudden onset of neck pain and dyspnea. Right supraclavicular induration was noted. The clinical suspicion of a right hydrothorax was confirmed radiologically. Ovarian size and the amount of ascites as assessed sonographically had further increased (Table 1). Therefore, the patient was admitted to the hospital. Vital signs remained stable. Laboratory parameters on admission are listed on Table 1. Thoracentesis yielded 1,000 cc of exudative fluid. Duplex ultrasonography of the neck revealed an acute thrombosis of the right jugular vein extending from the angle of the mandible to the clavicle and a segmental thrombosis of the right subclavian vein. Intravenous heparin anticoagulation was initiated. A 2-D echocardiogram revealed further extension of the thrombus into the superior vena cava and right atrium with reduced blood flow throughout these structures consistent with partial obstruction (Fig. 1). The patient had no history of deep venous thrombosis and had been taking birth control pills in the past without complications. Plasma levels of
Table 1
Figure 1 Echocardiographic appearance and diagrammatic representation of superior vena cava (SVC) thrombus. LV, left ventricle; RV, right ventricle; RA, right atrium; AO, aorta.
protein C, protein S, and antithrombin III were normal, thus excluding an intrinsic thrombogenic disorder. The patient was transferred to the intensive care unit (ICU) for close observation. After 5 days, she had remained hemodynamically stable and was transferred out of the ICU. Both subclavicular swelling and abdominal distention had resolved. After 10 days of adequate anticoagulation, a repeat echocardiogram confirmed stabilization of the thrombus. A transvaginal US showed a 6-week·twin gestation. The patient was discharged on full SC heparin anticoagulation. The remainder of her pregnancy was uneventful, and the patient underwent a normal spontaneous delivery of healthy twins at 36 weeks of gestation.
Clinical and Laboratory Parameters of the Patient Presented Date
No. of days postoocyte aspiration Weight (kg) Left ovaryb (mm X mm) Right ovaryb (mm X mm) Ascitesb Hematocrit(%) [37% to 47%]• WBC/UL [4,000 to 10,800] Platelets/UL [150,000 to 450,000] Prothrombin time (sec) Partial thromboplastin time (sec) [22 to 37] Na+ mmol/L [135 to 145] K+ mmol/L [3.5 to 5.0] • Date of admission. b Transvaginal US studies. Vol. 56, No.2, August 1991
8/29
9/6
9/9
9/16°
12 59 60 X 55 55 X 50 Small 52.7 27,000 608,000
20 59
23
41.8 16,000 630,000
60 X 50 60 X 50 Small 41.4 19,000 617,000
135 5.3
128 5.0
135 4.6
30 60.5 80 X 70 70 X 60 Moderate 39.4 19,800 523,000 Patient 10.1 Control 11.3 Ratio 0.9 26 135 4.2
• Values in brackets are normal values for nonpregnant adults.
Fournet et al.
Communications-in-brief
355
DISCUSSION
Vascular thrombosis is a rare but extremely serious complication of severe ovarian hyperstimulation syndrome. Two of seven reported cases involved occlusions localized to the head and neck area. In 1965, Mozes et al. 2 described a woman who developed a fatal left internal carotid artery thrombosis after hMG therapy. Recently, Rizk et al. 3 described a woman who developed a right middle cerebral artery occlusion after an exploratory laparotomy to rule out ovarian hyperstimulation syndrome-induced intra-abdominal hemorrhage. This patient recovered. To our knowledge, this is the first reported case of spontaneous internal jugular vein thrombosis associated with severe ovarian hyperstimulation syndrome. A rare event, internal jugular vein thrombosis resulted from severe head and neck infections in the preantibiotic era. Today, internal jugular vein thrombosis is usually associated with catheterization or intravenous (IV) drug abuse. Occasionally, internal jugular vein thrombosis may be caused by extrinsic tumor compression or a paraneoplastic phenomenon (Trousseau's syndrome). Interestingly, a case of position-induced internal jugular vein thrombosis has been recently described. 4 Because our patient admitted to reclining on her right side for prolonged time periods to relieve her left abdominal discomfort, position may have promoted right venous stasis. The etiology of ovarian hyperstimulation syndrome-associated thromboembolic disorders remains unclear. Hemoconcentration, as determined by the hematocrit on hospital admission, has been shown to correlate best with the severity of ovarian hyperstimulation syndrome. 1 This observation is of particular interest in this case because a transiently elevated hematocrit was the only ominous sign in an otherwise mild initial clinical presentation. Because alteration in blood viscosity promotes vascular stasis and, consequently thrombosis, close hemodynamic monitoring and IV volume replacement may be warranted in such patients on the basis of hematocrit alone. In selected cases, invasive monitoring with a Swan-Ganz catheter may be helpful in managing fluid balance. Coagulation factor abnormalities have been reported in this setting as well. Elevated factor V, fibrinogen, and profibrinolysin, as well as thrombocytosis, shortening of the partial thromboplastin time, and reduction in antithrombin III have been
356
Fournet et al.
Communications-in-brief
associated with severe ovarian hyperstimulation syndrome.5 •6 High circulating estrogen levels have been shown to promote hypercoagulability, but their role in ovarian hyperstimulation syndrome-associated thromboembolic events remains unknown. Interestingly, the changes in coagulation factors do not seem to correlate with urinary steroid levels.5 This case illustrates once again that severe ovarian hyperstimulation syndrome may occur despite optimal monitoring with strict adherence to established guidelines. Health care providers should remain vigilant to allow prompt recognition and treatment of this life-threatening complication, which afflicts young and otherwise healthy women.
SUMMARY
An unusual case of ovarian hyperstimulation syndrome complicated by internal jugular vein and mediastinal thrombosis is presented. Hemoconcentration and perhaps immobilization appear to be the most probable causative factors. The patient was successfully treated with heparin anticoagulation. An uneventful twin pregnancy resulted from the stimulation cycle. Acknowledgments. We are indebted to Norman Lepore, M.D., Robert Wolfe, M.D., and Jeffrey Greenspoon, M.D., of CedarsSinai Medical Center, Los Angeles, California, for their expert assistance in the care of this patient. We wish to thank Morgan Chen, M.D., for providing the echocardiographic photographs and Mr. Ron Arzaga, B.A., for typing the manuscript.
REFERENCES 1. Pride SM, James CSJ, Ho Yuen B: The ovarian hyperstimulation syndrome. Semin Reprod Endocrinol8:247, 1990 2. Mozes M, Bogokowsky H, Antebi E, Lunenfeld B, Rabau E, David A, Serr DM, David A, Salomy M: Thromboembolic phenomena after ovarian stimulation with human gonadotropins. Lancet 2:1213, 1965 3. Rizk B, Meagher S, Fisher AM: Severe ovarian hyperstimulation syndrome and cerebrovascular accidents. Hum Reprod 5:697,1990 4. Weber RR, Shackelford HL, Bernhart WR: Position-induced internal jugular vein thrombosis. W V Med J 84:509, 1988 5. Philipps LL, Gladstone W, Vande Wiele R: Studies of the coagulation and fibrinolytic systems in hyperstimulation syndrome after administration of gonadotropins. J Reprod Med 14:138, 1975 6. Kaaja R, Siegberg R, Tiitinen A, Koskimies A: Severe ovarian hyperstimulation syndrome and deep venous thrombosis. Lancet 2:1043, 1989
Fertility and Sterility
Vol. 56, No.2, August
1991 The American Fertility Society
1991
Printed on acid-free paper in U.S.A.
Internal jugular vein thrombosis after ovulation induction with gonadotropins
Nicole Fournet, M.D.* Eric Surrey, M.D. John Kerin, M.D., Ph.D. Division of Reproductive Endocrinology, Cedars-Sinai Medical Center, University of California, Los Angeles, (UCLA) School of Medicine, Los Angeles, California
Despite advanced monitoring techniques, ovarian hyperstimulation syndrome remains a serious and poorly understood complication of ovulation induction with human menopausal gonadotropins (hMG). Using ultrasound (US) imaging in conjunction with serum estradiol (E 2 ) levels and clinical presentation, various degrees of ovarian hyperstimulation syndrome have been reported after hMG administration.1 Fortunately, most of the cases are mild to moderate and have no major clinical consequences. Severe hyperstimulation, however, is a rare but potentially lethal condition that requires prompt diagnosis and inpatient monitoring. The pathogenesis of this syndrome is unclear, but production of vasoactive substances results in increased local capillary permeability, stromal edema, and massively enlarged, multicystic ovaries. As a result, fluid escapes the intravascular compartment and may cause ascites, hypovolemia, oliguria, and hemoconcentration. In the most severe cases, the increased blood viscosity and alteration in coagulation factors may lead to thromboembolic events. 1 We report a case of severe ovarian hyperstimulation syndrome with extensive thrombosis of the right internal jugular vein extending into the superior vena cava after an unremarkable in vitro fertilizationembryo transfer (IVF-ET) cycle that resulted in a twin pregnancy.
Received January 28, 1991; revised and accepted April18, 1991.
* Reprint requests: Nicole Fournet, M.D., Division of Reproductive Endocrinology, Cedars-Sinai Medical Center, 444 South San Vicente Boulevard, Los Angeles, California 90048. 354
Fournet et al.
Communications-in-brief
CASE REPORT
A 37 -year-old nulligravida with primary infertility because of tubal disease was referred for IVF. Her first cycle, though unsuccessful, was uneventful. After a standard stimulation regimen as described below, the serum E 2 level rose to 1,225 pg/mL on the day of human chorionic gonadotropin (hCG, Profasi; Serono Laboratories, Randolph, MA) administration. After uncomplicated oocyte aspiration and IVF, five cleaved embryos were transferred. Pregnancy did not result. Three months later, a second IVF cycle was initiated. Leuprolide acetate (LA, Lupron; TAP Pharmaceuticals, North Chicago, IL) 1 mg/d was administered subcutaneously (SC) starting on day 21 of the menstrual cycle for 10 days. At this point, serum E 2 level was <20 pg/mL. The daily LA dose was decreased to 0.5 mg. Human menopausal gonadotropins (Pergonal; Serono Laboratories) 225 IU/day was then administered intramuscularly (IM) for 5 days after which the dose was individualized according to follicle size, number, and E 2 levels. A total of 30 ampules of hMG was given. After 10 days of hMG administration, 13 follicles measuring 15 to 19 mm in diameter and serum E 2 level of 1,405 pg/ mL were noted. Thirty-six hours after administration of hCG 10,000 IU, transvaginal follicular aspiration yielded 15 oocytes. Five cleaved embryos were transferred 48 hours later. Progesterone suppositories were given intravaginally twice daily for luteal phase support. Ten days later, the patient complained of abdominal distention and left-sided discomfort. Physical examination revealed stable vital signs and mild abFertility and Sterility
domina! distention without a fluid wave. The lung fields were clear. Transvaginal US examination revealed slightly enlarged ovaries and a small amount of free peritoneal fluid. Laboratory evaluation revealed hemoconcentration. Detailed clinical and laboratory findings are summarized in Table 1. The patient was treated with bed rest and oral hydration. Fourteen days after ET, conception was documented (serum ,8-hCG 724 miU/mL). The patient's condition remained stable, and the hematocrit returned rapidly to baseline (Table 1). Two weeks later, however, she presented with sudden onset of neck pain and dyspnea. Right supraclavicular induration was noted. The clinical suspicion of a right hydrothorax was confirmed radiologically. Ovarian size and the amount of ascites as assessed sonographically had further increased (Table 1). Therefore, the patient was admitted to the hospital. Vital signs remained stable. Laboratory parameters on admission are listed on Table 1. Thoracentesis yielded 1,000 cc of exudative fluid. Duplex ultrasonography of the neck revealed an acute thrombosis of the right jugular vein extending from the angle of the mandible to the clavicle and a segmental thrombosis of the right subclavian vein. Intravenous heparin anticoagulation was initiated. A 2-D echocardiogram revealed further extension of the thrombus into the superior vena cava and right atrium with reduced blood flow throughout these structures consistent with partial obstruction (Fig. 1). The patient had no history of deep venous thrombosis and had been taking birth control pills in the past without complications. Plasma levels of
Table 1
Figure 1 Echocardiographic appearance and diagrammatic representation of superior vena cava (SVC) thrombus. LV, left ventricle; RV, right ventricle; RA, right atrium; AO, aorta.
protein C, protein S, and antithrombin III were normal, thus excluding an intrinsic thrombogenic disorder. The patient was transferred to the intensive care unit (ICU) for close observation. After 5 days, she had remained hemodynamically stable and was transferred out of the ICU. Both subclavicular swelling and abdominal distention had resolved. After 10 days of adequate anticoagulation, a repeat echocardiogram confirmed stabilization of the thrombus. A transvaginal US showed a 6-week·twin gestation. The patient was discharged on full SC heparin anticoagulation. The remainder of her pregnancy was uneventful, and the patient underwent a normal spontaneous delivery of healthy twins at 36 weeks of gestation.
Clinical and Laboratory Parameters of the Patient Presented Date
No. of days postoocyte aspiration Weight (kg) Left ovaryb (mm X mm) Right ovaryb (mm X mm) Ascitesb Hematocrit(%) [37% to 47%]• WBC/UL [4,000 to 10,800] Platelets/UL [150,000 to 450,000] Prothrombin time (sec) Partial thromboplastin time (sec) [22 to 37] Na+ mmol/L [135 to 145] K+ mmol/L [3.5 to 5.0] • Date of admission. b Transvaginal US studies. Vol. 56, No.2, August 1991
8/29
9/6
9/9
9/16°
12 59 60 X 55 55 X 50 Small 52.7 27,000 608,000
20 59
23
41.8 16,000 630,000
60 X 50 60 X 50 Small 41.4 19,000 617,000
135 5.3
128 5.0
135 4.6
30 60.5 80 X 70 70 X 60 Moderate 39.4 19,800 523,000 Patient 10.1 Control 11.3 Ratio 0.9 26 135 4.2
• Values in brackets are normal values for nonpregnant adults.
Fournet et al.
Communications-in-brief
355
DISCUSSION
Vascular thrombosis is a rare but extremely serious complication of severe ovarian hyperstimulation syndrome. Two of seven reported cases involved occlusions localized to the head and neck area. In 1965, Mozes et al. 2 described a woman who developed a fatal left internal carotid artery thrombosis after hMG therapy. Recently, Rizk et al. 3 described a woman who developed a right middle cerebral artery occlusion after an exploratory laparotomy to rule out ovarian hyperstimulation syndrome-induced intra-abdominal hemorrhage. This patient recovered. To our knowledge, this is the first reported case of spontaneous internal jugular vein thrombosis associated with severe ovarian hyperstimulation syndrome. A rare event, internal jugular vein thrombosis resulted from severe head and neck infections in the preantibiotic era. Today, internal jugular vein thrombosis is usually associated with catheterization or intravenous (IV) drug abuse. Occasionally, internal jugular vein thrombosis may be caused by extrinsic tumor compression or a paraneoplastic phenomenon (Trousseau's syndrome). Interestingly, a case of position-induced internal jugular vein thrombosis has been recently described. 4 Because our patient admitted to reclining on her right side for prolonged time periods to relieve her left abdominal discomfort, position may have promoted right venous stasis. The etiology of ovarian hyperstimulation syndrome-associated thromboembolic disorders remains unclear. Hemoconcentration, as determined by the hematocrit on hospital admission, has been shown to correlate best with the severity of ovarian hyperstimulation syndrome. 1 This observation is of particular interest in this case because a transiently elevated hematocrit was the only ominous sign in an otherwise mild initial clinical presentation. Because alteration in blood viscosity promotes vascular stasis and, consequently thrombosis, close hemodynamic monitoring and IV volume replacement may be warranted in such patients on the basis of hematocrit alone. In selected cases, invasive monitoring with a Swan-Ganz catheter may be helpful in managing fluid balance. Coagulation factor abnormalities have been reported in this setting as well. Elevated factor V, fibrinogen, and profibrinolysin, as well as thrombocytosis, shortening of the partial thromboplastin time, and reduction in antithrombin III have been
356
Fournet et al.
Communications-in-brief
associated with severe ovarian hyperstimulation syndrome.5 •6 High circulating estrogen levels have been shown to promote hypercoagulability, but their role in ovarian hyperstimulation syndrome-associated thromboembolic events remains unknown. Interestingly, the changes in coagulation factors do not seem to correlate with urinary steroid levels.5 This case illustrates once again that severe ovarian hyperstimulation syndrome may occur despite optimal monitoring with strict adherence to established guidelines. Health care providers should remain vigilant to allow prompt recognition and treatment of this life-threatening complication, which afflicts young and otherwise healthy women.
SUMMARY
An unusual case of ovarian hyperstimulation syndrome complicated by internal jugular vein and mediastinal thrombosis is presented. Hemoconcentration and perhaps immobilization appear to be the most probable causative factors. The patient was successfully treated with heparin anticoagulation. An uneventful twin pregnancy resulted from the stimulation cycle. Acknowledgments. We are indebted to Norman Lepore, M.D., Robert Wolfe, M.D., and Jeffrey Greenspoon, M.D., of CedarsSinai Medical Center, Los Angeles, California, for their expert assistance in the care of this patient. We wish to thank Morgan Chen, M.D., for providing the echocardiographic photographs and Mr. Ron Arzaga, B.A., for typing the manuscript.
REFERENCES 1. Pride SM, James CSJ, Ho Yuen B: The ovarian hyperstimulation syndrome. Semin Reprod Endocrinol8:247, 1990 2. Mozes M, Bogokowsky H, Antebi E, Lunenfeld B, Rabau E, David A, Serr DM, David A, Salomy M: Thromboembolic phenomena after ovarian stimulation with human gonadotropins. Lancet 2:1213, 1965 3. Rizk B, Meagher S, Fisher AM: Severe ovarian hyperstimulation syndrome and cerebrovascular accidents. Hum Reprod 5:697,1990 4. Weber RR, Shackelford HL, Bernhart WR: Position-induced internal jugular vein thrombosis. W V Med J 84:509, 1988 5. Philipps LL, Gladstone W, Vande Wiele R: Studies of the coagulation and fibrinolytic systems in hyperstimulation syndrome after administration of gonadotropins. J Reprod Med 14:138, 1975 6. Kaaja R, Siegberg R, Tiitinen A, Koskimies A: Severe ovarian hyperstimulation syndrome and deep venous thrombosis. Lancet 2:1043, 1989
Fertility and Sterility