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Acute portal vein thrombosis complicating in vitro fertilization
Acute portal vein thrombosis complicating in vitro fertilization Natu Mmbaga, M.D.,a Saioa Torrealday, M.D.,a Shirley McCarthy, M.D., Ph.D.,b and Beth W. Rackow, M.D.c a Department of Obstetrics, Gynecology and Reproductive Sciences, and b Department of Radiology, Yale University School of Medicine, New Haven, Connecticut; and c Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, New York
Objective: To describe a case of acute portal vein thrombosis after IVF treatment. Design: Case report. Setting: University teaching hospital. Patient(s): A 39-year-old woman experienced worsening, right upper quadrant pain several days after oocyte retrieval; ET was withheld. Imaging studies revealed acute portal vein thrombosis with extension into the splenic and superior mesenteric veins. Intervention(s): Therapeutic anticoagulation; no ET was performed. Main Outcome Measure(s): Improvement in symptoms, accurate diagnosis of condition. Result(s): Decreased size of portal vein thrombosis and partial vessel recanalization. Conclusion(s): Thromboembolic events are a rare complication of assisted reproductive technology (ART). In women who present with upper abdominal pain during ART, portal vein thrombosis should be considered in the differential diagnosis. (Fertil SterilÒ 2012;98:1470–3. Ó2012 by American Society for Reproductive Use your smartphone Medicine.) to scan this QR code Key Words: Portal vein thrombosis, mesenteric vein thrombosis, thrombosis, in vitro and connect to the fertilization Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/mmbagan-portal-vein-thrombosis-ivf/
T
hromboembolic events are a rare, but potentially life-threatening, complication of assisted reproductive technology (ART). Venous thrombosis is more common than arterial thrombosis, and the majority of reported cases occur in the setting of ovarian hyperstimulation syndrome (1). At present, there is no published case of portal vein thrombosis after IVF.
MATERIALS AND METHODS A 39-year-old gravida 0 with tubal and male factor infertility, and body mass index (BMI) of 23.6 kg/m2, underwent her fifth cycle of IVF with intracytoplasmic sperm injection (ICSI). Cycle
day 3 basal ovarian reserve testing revealed an FSH level of 8.0 IU/L, LH level of 6.0 IU/L, and E2 level of 63 pg/mL. Thyroid stimulating hormone (TSH) and PRL levels were normal. A semen analysis identified asthenozoospermia (30% motility). Previous IVF cycles revealed an average of 16 oocytes retrieved, with a 52% fertilization rate with ICSI; however, there was poor embryo development after day 3. Her medical history was notable for group A streptococcus peritonitis that required an exploratory laparotomy, and uterine myomas. Three months before this IVF cycle, she underwent an abdominal myomectomy and bilateral salpingectomies; a single 10-cm fundal
Received January 18, 2012; revised June 18, 2012; accepted August 6, 2012; published online September 8, 2012. N.M. has nothing to disclose. S.T. has nothing to disclose. S.M. has nothing to disclose. B.W.R. has nothing to disclose. Reprint requests: Beth W. Rackow, M.D., Columbia University Medical Center, Center for Women's Reproductive Care, 1790 Broadway, New York, NY 10019 (E-mail: [email protected]). Fertility and Sterility® Vol. 98, No. 6, December 2012 0015-0282/$36.00 Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2012.08.010 1470
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
subserosal myoma and mild hydrosalpinges were removed. The patient had previously declined surgery. In the past, she took oral contraceptive (OC) pills for 9 years without any sequelae. She had no history of a deep venous thrombosis, thromboembolic event, or rheumatologic symptoms or disorder. There was no family history of coagulopathies or thromboembolic events. She denied any tobacco use, alcohol consumption, or illicit drug use. The IVF treatment protocol included luteal phase leuprolide acetate (LA; 1 mg/d), and when appropriately suppressed as determined by E2 level and ultrasound findings, controlled ovarian hyperstimulation (COH) was initiated with recombinant FSH (300 IU/d; Gonal-f, EMD Serono, Inc.). After 11 days of stimulation, eight follicles were at least 18 mm in average diameter, the E2 level was 2,490 pg/mL and hCG (250 mg; Ovidrel, EMD Serono, Inc.) was administered. Thirty-six hours later, an uncomplicated oocyte VOL. 98 NO. 6 / DECEMBER 2012
Fertility and Sterility® retrieval obtained 19 oocytes; 18 oocytes were metaphase II and ICSI was performed. Vaginal P supplementation was initiated. Due to multiple failed IVF/ICSI cycles, preimplantation genetic screening for aneuploidy was performed on 13 day 3 embryos using microarray analysis (Gene Security Network).
FIGURE 1
RESULTS The patient presented a few hours before the scheduled day 5 ET reporting a 3-day history of nonradiating right upper quadrant pain, nausea, anorexia, and generalized malaise. An office transvaginal ultrasound revealed a normal uterus with mildly enlarged cystic ovaries and the absence of free fluid. Due to her constellation of symptoms and right upper quadrant tenderness on examination, she was sent to the Emergency Department for further evaluation. Thereafter, the preimplantation genetic screening report was available and indicated that there were no genetically normal blastocysts. The ET was cancelled and P was discontinued. On admission to the Emergency Department, her vital signs were: temperature 97.6 F, heart rate 90 beats/min, blood pressure 113/78 mmHg, respiratory rate 16/min, and oxygen saturation 100% on room air. The only notable physical examination finding was epigastric tenderness. A repeat transvaginal ultrasound noted a normal-appearing uterus, no pelvic free fluid, and a 5.5 4.8 cm right ovary and a 3.2 4.9 cm left ovary, both with normal Doppler flow. Laboratory testing revealed elevated liver enzymes: aspartate aminotransferase 40 U/L (normal, 10–30 U/L) and alanine aminotransferase 59 U/L (normal, 6–40 U/L). The remainder of the laboratory tests was normal including a complete blood count, basic metabolic panel, and amylase and lipase. A right upper quadrant ultrasound visualized a heterogeneous, hypoechoic mass measuring 5.9 5.6 3.7 cm that appeared localized in the head of the pancreas, with a normal-appearing common bile duct. Subsequently, computed tomography (CT) with IV contrast identified that the ‘‘mass’’ involved the intrahepatic and extrahepatic portal vein, superior mesenteric vein, and splenic vein with multiple venous collaterals in the periesophageal region (Fig. 1). No ascites was appreciated. She was admitted to the hospital for further evaluation by the hematology service, and the gastroenterology service was consulted. Tumor markers (carcinoembryonic antigen, CA 19-9, and a-fetoprotein [AFP]) and a complete hepatitis panel were obtained and returned negative. Because the portal vein was markedly distended and heterogeneous on CT, thus making it difficult to exclude a mass/intravascular tumor, magnetic resonance imaging (MRI) with and without IV contrast was performed confirming the CT scan findings of an expanded portal vein and distal splenic and superior mesenteric veins. There was no intraluminal enhancement, diagnostic of an extensive portal vein bland thrombus with extension into the splenic and superior mesenteric veins (Fig. 2). Thereafter, anticoagulation commenced with low molecular weight heparin (LMWH) and warfarin; when the international normalized ratio level became therapeutic (between 2 and 3), LMWH was discontinued. The transaminitis was VOL. 98 NO. 6 / DECEMBER 2012
Computed tomography scan with IV contrast demonstrates a markedly distended and heterogeneous portal and splenic vein (arrow). Mmbaga. Acute portal vein thrombosis in IVF. Fertil Steril 2012.
thought to be secondary to thrombosis-induced mild hepatic ischemia. A hypercoagulability workup was performed, and revealed normal antithrombin activity, protein C and S levels, dilute Russell viper venom time, antiphospholipid antibodies, and homocysteine levels. Furthermore, no mutations in the Factor V Leiden, prothrombin, or Jak-2 genes were identified. During the 6 months after diagnosis, the patient remained anticoagulated without complication. Follow-up MRI studies revealed partial recanalization of the main and left portal veins and superior mesenteric vein, persistent occlusion of the right portal vein and splenic vein, and the presence of extensive collateral vasculature (Fig. 3). She decided to discontinue infertility treatment and is considering adoption.
FIGURE 2
Magnetic resonance imaging with IV contrast documents that the distended vessels exhibit no enhancement consistent with a large bland thrombus (arrow). Mmbaga. Acute portal vein thrombosis in IVF. Fertil Steril 2012.
1471
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
FIGURE 3
Follow-up magnetic resonance imaging demonstrates decreased distention and recanalization of the portal vein with minimal intraluminal thrombus remaining (arrow). Mmbaga. Acute portal vein thrombosis in IVF. Fertil Steril 2012.
DISCUSSION In 2009, ART accounted for about 1% of all infants born in the United States (2). Although the incidence of thromboembolic complications associated with ART remains low, there is growing literature detailing its occurrence. The incidence of venous thromboembolic events in women undergoing IVF is estimated to be 0.08%–0.11% per treatment cycle, a 10-fold increase in baseline risk compared to the general population of reproductive age women (3, 4). A review of thromboembolic complications associated with ART identified 71 episodes of thrombotic complications from 58 case reports or series (1). Thrombosis occurred after hCG administration in all but one patient; 69% (49/71) of women with thrombosis achieved pregnancy. Twenty-six of the cases involved arterial thrombosis, of which 54% (14/26) were cerebrovascular events and 23% (6/26) occurred in the extremities. Of the 45 cases of venous thrombosis, 78% (35/45) occurred in the neck and upper extremities. Ovarian hyperstimulation syndrome (OHSS) was a complicating factor in 95% (21/22) of women with arterial thrombosis and 70% (31/44) of women with venous thrombosis. Furthermore, in this compilation of case reports, inherited thrombophilias were identified in one-third (15/45) of the women tested (1). In ART, elevated endogenous estrogen (E) levels may predispose some women to alterations in coagulation and fibrinolytic systems, leading to hypercoagulability and possible thromboembolism. During COH, changes in coagulation factors include increased von Willibrand factor, Factors V and VIII and fibrinogen, increased activated protein C resistance, and decreased antithrombin III, proteins C and S activity. Additional fibrinoloytic changes include a reduction in tissue plasminogen activator and plasminogen activator inhibitor type 1. These changes in coagulation and fibrinolytic markers indicate that a prothrombotic environment is present during IVF (1, 5). However, before the administration of hCG to achieve final maturation of the oocytes, it is rare for 1472
a thromboembolic event to occur; marked prothrombotic changes are noted within a few days of hCG administration (6). Furthermore, OHSS increases the risk of venous thromboembolism, and this risk persists for several weeks after OHSS has clinically resolved. It can take several weeks for coagulation and fibrinolytic parameters to return to baseline (5, 6). Some degree of OHSS results in 2%–6% of ART cycles. The OHSS increases the risk of thrombosis from 0.1% baseline to 0.8%; this risk is most pronounced in the 1%–2% of OHSS cases with ascites, hypoalbuminemia, and hemoconcentration (7). Portal vein thrombosis (PVT) has not previously been reported as a complication of IVF. The PVT is associated with cirrhosis, abdominal inflammatory conditions (i.e., appendicitis, pancreatitis, cholecystitis), certain types of abdominal cancer, and thrombophilia (8). In patients with noncirrhotic PVT, more than 50% have one or more underlying prothrombotic conditions (9). In an acute presentation of PVT, symptoms are often subtle and present as abdominal pain without evidence of chronic portal hypertension. When the PVT is chronic, patients will often develop varices and splenomegaly, and may develop jaundice and ascites. Liver function tests can be normal or mildly elevated due to thrombosis-induced mild hepatic ischemia, as the portal vein supplies approximately 70% of the blood supply to the liver (10). The determination of acute versus chronic PVT relies on the absence or presence of portal hypertension and portoportal collaterals. Treatment of acute PVT involves immediate anticoagulation with LMWH and subsequent transition to oral anticoagulation with warfarin (11). Chronic PVT treatment with anticoagulation depends on the benefits of therapy versus the risks of bleeding (11). When anticoagulation is initiated, it is usually continued until followup imaging confirms venous recanalization. In patients with acute portal or mesenteric vein thrombosis, anticoagulation for a minimum of 4 months achieved recanalization in 86% (25/29), with complete recanalization in 10 patients (10). Individualized assessment of risk of thrombotic complications should be performed in all women undergoing ART, and should include questions about personal or family history of thromboembolism or thrombophilias, concurrent medical conditions, increased age (>40 years), and obesity (6, 12). When possible, modifiable risk factors, such as medical conditions and obesity, should be optimized before ART (6). If a woman is determined to be high risk for venous thromboembolism during ART, prophylactic anticoagulation can be considered. The LMWH can be initiated when COH with gonadotropins begins, and the medication is briefly held around the time of oocyte retrieval (6). Alternatively, LMWH can be initiated 24 hours after oocyte retrieval to account for the increased thromboembolic risk after hCG administration (6). Continued anticoagulation use during pregnancy and for 6 weeks postpartum has also been proposed for high-risk women (6). With validated safety in pregnancy, women can be reassured that LMWH does not cross the placenta and is safe during pregnancy (13). In the present patient, the major surgical procedure performed 3 months before the index IVF cycle could have increased the thrombotic risk during IVF, although the long-term risk of thrombosis after major benign gynecologic VOL. 98 NO. 6 / DECEMBER 2012
Fertility and Sterility® surgery has not been established. During surgery and the postsurgical hospitalization, routine thrombosis prophylaxis with pneumatic compression boots occurred (14). However, in the absence of other risk for factors for thrombosis, thrombosis prophylaxis for a woman who had undergone an abdominal myomectomy 3 months before treatment would not have been recommended. In conclusion, thrombotic and thromboembolic events are a rare but serious complication of ART. This is the first reported case of portal vein thrombosis after IVF. As more couples turn to ART for infertility treatment, the number of thromboembolic events will likely continue to increase (1, 5). Therefore, providers should maintain a heightened level of suspicion, especially in women with OHSS, and be prepared to diagnose and treat these complications in an expeditious manner.
4.
5.
6. 7. 8. 9.
10.
11.
REFERENCES 1.
2.
3.
Chan WS, Dixon ME. The ‘‘ART’’ of thromboembolism: a review of assisted reproductive technology and thromboembolic complications. Thrombosis Research 2008;121:713–26. Centers for Disease Control and Prevention. 2009 Assisted Reproductive Technology Annual Success Rates Report. Available at: External link http: //www.cdc.gov/art/ARTreports.htm. Assessed November 22, 2011. Mara M, Koryntova D, Rezabek K, Kapral A, Drbohlav P, Jirsova S, et al. Thromboembolic complications inpatients undergoing in vitro fertilization: retrospective clinical study. Ceska Gynekol 2004;69:312–6.
VOL. 98 NO. 6 / DECEMBER 2012
12.
13.
14.
Chan WS, Ginsberg JS. A review of upper extremity deep vein thrombosis in pregnancy: unmasking the ‘‘ART’’ behind the clot. J Thromb Haemost 2006; 4:1673–7. Chan WS. The ‘‘ART’’of thrombosis: a review of arterial and venous thrombosis in assisted reproductive technology. Curr Opin Obstet Gynecol 2009; 21:207–18. Nelson SM. Prophylaxis of VTE in women—during assisted reproductive techniques. Thromb Res 2009;123(Suppl 3):S8–15. Whelan JG III, Vlahos NF. The ovarian hyperstimulation syndrome. Fertil Steril 2000;73:883–96. Valla D, Condat B. Portal vein thrombosis in adults: pathophysiology, pathogenesis and management. J Hepatol 2000;32:865–71. Plessier A, Darwish-Maurad S, Hernandez-Guerra M, Consigny Y, Fabris F, Trebicka J, et al. Acute portal vein thrombosis unrelated to cirrhosis: a prospective multicenter follow up study. Hepatology 2010;51: 210–8. Condat B, Pessione F, Helene Denninger M, Hillaire S, Villa D. Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy. Hepatology 2000;32:466–70. Deleve LD, Valla DC, Garcia-Tsao G. Vascular disorders of the liver. Hepatology 2009;49:1729–64. Dorais J, Jones K, Hammoud A, Gibson M, Johnstone E, Peterson CM. A superior mesenteric vein thrombosis associated with in vitro fertilization. Fertil Steril 2011;95:804.e11–3. Greer IA, Nelson-Piercy C. Low molecular weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005;106:401–7. Rahn DD, Mamik MM, Sanses TVD, Matteson KA, Aschkenazi SO, Washington BB, et al. Venous thromboembolism prophylaxis in gynecologic surgery: a systematic review. Obstet Gynecol 2011;118: 1111–25.
1473
Objective: To describe a case of acute portal vein thrombosis after IVF treatment. Design: Case report. Setting: University teaching hospital. Patient(s): A 39-year-old woman experienced worsening, right upper quadrant pain several days after oocyte retrieval; ET was withheld. Imaging studies revealed acute portal vein thrombosis with extension into the splenic and superior mesenteric veins. Intervention(s): Therapeutic anticoagulation; no ET was performed. Main Outcome Measure(s): Improvement in symptoms, accurate diagnosis of condition. Result(s): Decreased size of portal vein thrombosis and partial vessel recanalization. Conclusion(s): Thromboembolic events are a rare complication of assisted reproductive technology (ART). In women who present with upper abdominal pain during ART, portal vein thrombosis should be considered in the differential diagnosis. (Fertil SterilÒ 2012;98:1470–3. Ó2012 by American Society for Reproductive Use your smartphone Medicine.) to scan this QR code Key Words: Portal vein thrombosis, mesenteric vein thrombosis, thrombosis, in vitro and connect to the fertilization Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/mmbagan-portal-vein-thrombosis-ivf/
T
hromboembolic events are a rare, but potentially life-threatening, complication of assisted reproductive technology (ART). Venous thrombosis is more common than arterial thrombosis, and the majority of reported cases occur in the setting of ovarian hyperstimulation syndrome (1). At present, there is no published case of portal vein thrombosis after IVF.
MATERIALS AND METHODS A 39-year-old gravida 0 with tubal and male factor infertility, and body mass index (BMI) of 23.6 kg/m2, underwent her fifth cycle of IVF with intracytoplasmic sperm injection (ICSI). Cycle
day 3 basal ovarian reserve testing revealed an FSH level of 8.0 IU/L, LH level of 6.0 IU/L, and E2 level of 63 pg/mL. Thyroid stimulating hormone (TSH) and PRL levels were normal. A semen analysis identified asthenozoospermia (30% motility). Previous IVF cycles revealed an average of 16 oocytes retrieved, with a 52% fertilization rate with ICSI; however, there was poor embryo development after day 3. Her medical history was notable for group A streptococcus peritonitis that required an exploratory laparotomy, and uterine myomas. Three months before this IVF cycle, she underwent an abdominal myomectomy and bilateral salpingectomies; a single 10-cm fundal
Received January 18, 2012; revised June 18, 2012; accepted August 6, 2012; published online September 8, 2012. N.M. has nothing to disclose. S.T. has nothing to disclose. S.M. has nothing to disclose. B.W.R. has nothing to disclose. Reprint requests: Beth W. Rackow, M.D., Columbia University Medical Center, Center for Women's Reproductive Care, 1790 Broadway, New York, NY 10019 (E-mail: [email protected]). Fertility and Sterility® Vol. 98, No. 6, December 2012 0015-0282/$36.00 Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2012.08.010 1470
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
subserosal myoma and mild hydrosalpinges were removed. The patient had previously declined surgery. In the past, she took oral contraceptive (OC) pills for 9 years without any sequelae. She had no history of a deep venous thrombosis, thromboembolic event, or rheumatologic symptoms or disorder. There was no family history of coagulopathies or thromboembolic events. She denied any tobacco use, alcohol consumption, or illicit drug use. The IVF treatment protocol included luteal phase leuprolide acetate (LA; 1 mg/d), and when appropriately suppressed as determined by E2 level and ultrasound findings, controlled ovarian hyperstimulation (COH) was initiated with recombinant FSH (300 IU/d; Gonal-f, EMD Serono, Inc.). After 11 days of stimulation, eight follicles were at least 18 mm in average diameter, the E2 level was 2,490 pg/mL and hCG (250 mg; Ovidrel, EMD Serono, Inc.) was administered. Thirty-six hours later, an uncomplicated oocyte VOL. 98 NO. 6 / DECEMBER 2012
Fertility and Sterility® retrieval obtained 19 oocytes; 18 oocytes were metaphase II and ICSI was performed. Vaginal P supplementation was initiated. Due to multiple failed IVF/ICSI cycles, preimplantation genetic screening for aneuploidy was performed on 13 day 3 embryos using microarray analysis (Gene Security Network).
FIGURE 1
RESULTS The patient presented a few hours before the scheduled day 5 ET reporting a 3-day history of nonradiating right upper quadrant pain, nausea, anorexia, and generalized malaise. An office transvaginal ultrasound revealed a normal uterus with mildly enlarged cystic ovaries and the absence of free fluid. Due to her constellation of symptoms and right upper quadrant tenderness on examination, she was sent to the Emergency Department for further evaluation. Thereafter, the preimplantation genetic screening report was available and indicated that there were no genetically normal blastocysts. The ET was cancelled and P was discontinued. On admission to the Emergency Department, her vital signs were: temperature 97.6 F, heart rate 90 beats/min, blood pressure 113/78 mmHg, respiratory rate 16/min, and oxygen saturation 100% on room air. The only notable physical examination finding was epigastric tenderness. A repeat transvaginal ultrasound noted a normal-appearing uterus, no pelvic free fluid, and a 5.5 4.8 cm right ovary and a 3.2 4.9 cm left ovary, both with normal Doppler flow. Laboratory testing revealed elevated liver enzymes: aspartate aminotransferase 40 U/L (normal, 10–30 U/L) and alanine aminotransferase 59 U/L (normal, 6–40 U/L). The remainder of the laboratory tests was normal including a complete blood count, basic metabolic panel, and amylase and lipase. A right upper quadrant ultrasound visualized a heterogeneous, hypoechoic mass measuring 5.9 5.6 3.7 cm that appeared localized in the head of the pancreas, with a normal-appearing common bile duct. Subsequently, computed tomography (CT) with IV contrast identified that the ‘‘mass’’ involved the intrahepatic and extrahepatic portal vein, superior mesenteric vein, and splenic vein with multiple venous collaterals in the periesophageal region (Fig. 1). No ascites was appreciated. She was admitted to the hospital for further evaluation by the hematology service, and the gastroenterology service was consulted. Tumor markers (carcinoembryonic antigen, CA 19-9, and a-fetoprotein [AFP]) and a complete hepatitis panel were obtained and returned negative. Because the portal vein was markedly distended and heterogeneous on CT, thus making it difficult to exclude a mass/intravascular tumor, magnetic resonance imaging (MRI) with and without IV contrast was performed confirming the CT scan findings of an expanded portal vein and distal splenic and superior mesenteric veins. There was no intraluminal enhancement, diagnostic of an extensive portal vein bland thrombus with extension into the splenic and superior mesenteric veins (Fig. 2). Thereafter, anticoagulation commenced with low molecular weight heparin (LMWH) and warfarin; when the international normalized ratio level became therapeutic (between 2 and 3), LMWH was discontinued. The transaminitis was VOL. 98 NO. 6 / DECEMBER 2012
Computed tomography scan with IV contrast demonstrates a markedly distended and heterogeneous portal and splenic vein (arrow). Mmbaga. Acute portal vein thrombosis in IVF. Fertil Steril 2012.
thought to be secondary to thrombosis-induced mild hepatic ischemia. A hypercoagulability workup was performed, and revealed normal antithrombin activity, protein C and S levels, dilute Russell viper venom time, antiphospholipid antibodies, and homocysteine levels. Furthermore, no mutations in the Factor V Leiden, prothrombin, or Jak-2 genes were identified. During the 6 months after diagnosis, the patient remained anticoagulated without complication. Follow-up MRI studies revealed partial recanalization of the main and left portal veins and superior mesenteric vein, persistent occlusion of the right portal vein and splenic vein, and the presence of extensive collateral vasculature (Fig. 3). She decided to discontinue infertility treatment and is considering adoption.
FIGURE 2
Magnetic resonance imaging with IV contrast documents that the distended vessels exhibit no enhancement consistent with a large bland thrombus (arrow). Mmbaga. Acute portal vein thrombosis in IVF. Fertil Steril 2012.
1471
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
FIGURE 3
Follow-up magnetic resonance imaging demonstrates decreased distention and recanalization of the portal vein with minimal intraluminal thrombus remaining (arrow). Mmbaga. Acute portal vein thrombosis in IVF. Fertil Steril 2012.
DISCUSSION In 2009, ART accounted for about 1% of all infants born in the United States (2). Although the incidence of thromboembolic complications associated with ART remains low, there is growing literature detailing its occurrence. The incidence of venous thromboembolic events in women undergoing IVF is estimated to be 0.08%–0.11% per treatment cycle, a 10-fold increase in baseline risk compared to the general population of reproductive age women (3, 4). A review of thromboembolic complications associated with ART identified 71 episodes of thrombotic complications from 58 case reports or series (1). Thrombosis occurred after hCG administration in all but one patient; 69% (49/71) of women with thrombosis achieved pregnancy. Twenty-six of the cases involved arterial thrombosis, of which 54% (14/26) were cerebrovascular events and 23% (6/26) occurred in the extremities. Of the 45 cases of venous thrombosis, 78% (35/45) occurred in the neck and upper extremities. Ovarian hyperstimulation syndrome (OHSS) was a complicating factor in 95% (21/22) of women with arterial thrombosis and 70% (31/44) of women with venous thrombosis. Furthermore, in this compilation of case reports, inherited thrombophilias were identified in one-third (15/45) of the women tested (1). In ART, elevated endogenous estrogen (E) levels may predispose some women to alterations in coagulation and fibrinolytic systems, leading to hypercoagulability and possible thromboembolism. During COH, changes in coagulation factors include increased von Willibrand factor, Factors V and VIII and fibrinogen, increased activated protein C resistance, and decreased antithrombin III, proteins C and S activity. Additional fibrinoloytic changes include a reduction in tissue plasminogen activator and plasminogen activator inhibitor type 1. These changes in coagulation and fibrinolytic markers indicate that a prothrombotic environment is present during IVF (1, 5). However, before the administration of hCG to achieve final maturation of the oocytes, it is rare for 1472
a thromboembolic event to occur; marked prothrombotic changes are noted within a few days of hCG administration (6). Furthermore, OHSS increases the risk of venous thromboembolism, and this risk persists for several weeks after OHSS has clinically resolved. It can take several weeks for coagulation and fibrinolytic parameters to return to baseline (5, 6). Some degree of OHSS results in 2%–6% of ART cycles. The OHSS increases the risk of thrombosis from 0.1% baseline to 0.8%; this risk is most pronounced in the 1%–2% of OHSS cases with ascites, hypoalbuminemia, and hemoconcentration (7). Portal vein thrombosis (PVT) has not previously been reported as a complication of IVF. The PVT is associated with cirrhosis, abdominal inflammatory conditions (i.e., appendicitis, pancreatitis, cholecystitis), certain types of abdominal cancer, and thrombophilia (8). In patients with noncirrhotic PVT, more than 50% have one or more underlying prothrombotic conditions (9). In an acute presentation of PVT, symptoms are often subtle and present as abdominal pain without evidence of chronic portal hypertension. When the PVT is chronic, patients will often develop varices and splenomegaly, and may develop jaundice and ascites. Liver function tests can be normal or mildly elevated due to thrombosis-induced mild hepatic ischemia, as the portal vein supplies approximately 70% of the blood supply to the liver (10). The determination of acute versus chronic PVT relies on the absence or presence of portal hypertension and portoportal collaterals. Treatment of acute PVT involves immediate anticoagulation with LMWH and subsequent transition to oral anticoagulation with warfarin (11). Chronic PVT treatment with anticoagulation depends on the benefits of therapy versus the risks of bleeding (11). When anticoagulation is initiated, it is usually continued until followup imaging confirms venous recanalization. In patients with acute portal or mesenteric vein thrombosis, anticoagulation for a minimum of 4 months achieved recanalization in 86% (25/29), with complete recanalization in 10 patients (10). Individualized assessment of risk of thrombotic complications should be performed in all women undergoing ART, and should include questions about personal or family history of thromboembolism or thrombophilias, concurrent medical conditions, increased age (>40 years), and obesity (6, 12). When possible, modifiable risk factors, such as medical conditions and obesity, should be optimized before ART (6). If a woman is determined to be high risk for venous thromboembolism during ART, prophylactic anticoagulation can be considered. The LMWH can be initiated when COH with gonadotropins begins, and the medication is briefly held around the time of oocyte retrieval (6). Alternatively, LMWH can be initiated 24 hours after oocyte retrieval to account for the increased thromboembolic risk after hCG administration (6). Continued anticoagulation use during pregnancy and for 6 weeks postpartum has also been proposed for high-risk women (6). With validated safety in pregnancy, women can be reassured that LMWH does not cross the placenta and is safe during pregnancy (13). In the present patient, the major surgical procedure performed 3 months before the index IVF cycle could have increased the thrombotic risk during IVF, although the long-term risk of thrombosis after major benign gynecologic VOL. 98 NO. 6 / DECEMBER 2012
Fertility and Sterility® surgery has not been established. During surgery and the postsurgical hospitalization, routine thrombosis prophylaxis with pneumatic compression boots occurred (14). However, in the absence of other risk for factors for thrombosis, thrombosis prophylaxis for a woman who had undergone an abdominal myomectomy 3 months before treatment would not have been recommended. In conclusion, thrombotic and thromboembolic events are a rare but serious complication of ART. This is the first reported case of portal vein thrombosis after IVF. As more couples turn to ART for infertility treatment, the number of thromboembolic events will likely continue to increase (1, 5). Therefore, providers should maintain a heightened level of suspicion, especially in women with OHSS, and be prepared to diagnose and treat these complications in an expeditious manner.
4.
5.
6. 7. 8. 9.
10.
11.
REFERENCES 1.
2.
3.
Chan WS, Dixon ME. The ‘‘ART’’ of thromboembolism: a review of assisted reproductive technology and thromboembolic complications. Thrombosis Research 2008;121:713–26. Centers for Disease Control and Prevention. 2009 Assisted Reproductive Technology Annual Success Rates Report. Available at: External link http: //www.cdc.gov/art/ARTreports.htm. Assessed November 22, 2011. Mara M, Koryntova D, Rezabek K, Kapral A, Drbohlav P, Jirsova S, et al. Thromboembolic complications inpatients undergoing in vitro fertilization: retrospective clinical study. Ceska Gynekol 2004;69:312–6.
VOL. 98 NO. 6 / DECEMBER 2012
12.
13.
14.
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