http://informahealthcare.com/gye ISSN: 0951-3590 (print), 1473-0766 (electronic) Gynecol Endocrinol, Early Online: 1–5 ! 2014 Informa UK Ltd. DOI: 10.3109/09513590.2014.927858
REVIEW ARTICLE
Thrombosis following ovarian hyperstimulation syndrome Miro Kasum1, Damir Danolic´2, Slavko Oresˇkovic´1, Davor Jezˇek3, Lidija Beketic´-Oresˇkovic´4, and Marijeta Pekez5 1
Department of Obstetrics and Gynaecology, University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia, Department of Gynecologic Oncology, University Hospital Centre Sestre Milosrdnice, University Hospital for Tumors, Zagreb, Croatia, 3Department of Histology, School of Medicine, University of Zagreb, Zagreb, Croatia, 4Department of Oncology, Clinical Hospital Centre Sestre Milosrdnice, School of Medicine, University of Zagreb, Zagreb, Croatia, and 5Clinical Hospital Centre Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia
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Abstract
Keywords
The aim of this review is to analyse the pathophysiology and complications of thrombosis in conjuction with ovarian hyperstimulation syndrome (OHSS) following ovulation induction and to suggest practical guidelines usefull for the prevention and treatment. Although the incidence of thrombosis varies from 0.2% among in vitro fertilization (IVF) cycles and up to 10% for severe cases of the syndrome, it represents the most dangerous complication of OHSS. Different changes in haemostatic markers have been found to create a state of hypercoagulability, but no single standard test is available to estimate the state of thrombosis. The role of markers for thrombophilia is controversial. Thromboses are mostly venous (67–75%) involving upper limbs and neck, then arterial (25–33%) which are mainly intracerebral. The predominant sites of venous thromboembolism in the upper part of the body may be explained by higher concentrations of estrogens drained through lymphatic ducts from ascites and by compression of rudimentary branchyal cysts. Once early diagnosis is established, it is crucial to use an anticoagulant treatment with heparin proceeded with thromboprophylaxis. However, identification of patients at risk and preventive measures of OHSS are the best means in reducing the risk of thrombosis after ovarian stimulation.
Ovarian hyperstimulation syndrome, pathophysiology, prevention and treatment, thrombosis
Introduction Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of ovulation induction with gonadotrophins of infertile women in in-vitro fertilization (IVF) program. It is characterized by bilateral, multiple follicular and theca-lutein cysts and an acute vascular hyperpermeability resulting in ascites and pleural effusion, electrolyte imbalance, hypovolemia, liver dysfunction, oliguria, haemoconcentration and thrombosis. The overall incidence of OHSS is estimated at 0.6–14% of all ovarian stimulation cycles and severe OHSS accounts for 0.5–5% of all cases of the syndrome [1]. Thromboembolic disease has been reported in many sites of the body, including internal jugular, subclavian, axillary, ulnar, popliteal, cortical, mesenteric, coronary, and cerebral vessels. Vascular thrombosis is an uncommon, yet potentially fatal complication of assisted reproductive technology (ART) and represents the most serious complication of OHSS with an incidence ranging from 0.2% among IVF cycles up to 10% for severe cases of the syndrome [2]. Although OHSS may be an important factor in the pathogenesis of thrombosis, it does not precede all cases because one in 128 women with severe OHSS develops thromboembolic disease [3]. Cerebrovascular thromboembolism is perhaps the most dangerous thrombosis with fatal cases of OHSS with cerebral infarction having been reported [4]. In an earlier review between 1964 and 1997 of 54 cases with Address for correspondence: Prof. Miro Kasum, Department of Obstetrics and Gynaecology, School of Medicine, University Hospital Centre, Petrova 13, 10 000 Zagreb, Croatia. Tel: (+385) 1 4604646. Fax: (+385) 1 2376267. E-mail: [email protected]
History Received 28 February 2014 Revised 29 April 2014 Accepted 21 May 2014 Published online 11 July 2014
thromboembolic phenomena associated with ovulation induction, it was found that 66% of these cases were in conjuction with OHSS and 84% were during pregnancy. In addition, 75% of the cases were venous in origin (60% in the upper limbs, neck area and head) while 25% were arterial thromboses (mostly intracerebral) [5]. Similar findings were confirmed in a later review by including an additional 43 cases of thromboembolism associated with ovulation induction between 1997 and 2003. Among the 97 cases, 74% of cases were associated with OHSS and 77% were during pregnancy. Sixty-seven of the reported cases were venous in origin (71% involved the upper limb, neck and head) while 33% were arterial thromboses [6]. Although thromboembolic phenomena are not frequently encountered in the course of OHSS associated with ART, they may be potentially serious with dangerous sequellae in a proportion of affected patients. The aim of this review would be to report an update of our knowledge regarding the pathogenesis and complications of thrombotic events and to suggest practical guidelines which would be usefull for the prevention and treatment of ART-associated thromboses.
Pathophysiology of thrombosis Although the exact mechanism of thrombosis has not yet been elucidated entirely, it has been surmised that the hypercoagulable state is created due to haemoconcentration and hypovolemia, as a result of the increased capillary permeability induced by excessive vasoactive substances produced by the ovaries. In addition, vomiting during OHSS induced by the pressure of intraperitoneal fluid on the bowel and arterial hypotension with a slower blood velocity may contribute to the same changes. Of all the different
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vasoactive cytokines, vascular endothelial growth factor (VEGF), which is triggered by human chorionic gonadotrophin (hCG), is the principal mediator and the most responsible for the vascular hyperpermeability. A generalized capillary leak and acute shift of protein-rich fluid from the intravascular compartment into the third space (ascites, hydrothorax, hydropericardium) may lead to hypoproteinemia, oliguria, acute renal failure and increased blood viscosity with changes in coagulation parameters resulting in thromboembolic events [7]. In an earlier study from 1991 it was found that ovulation induction with hCG for IVF might create a state of hypercoagulability, because a significant rise in plasma fibrinogen with an increase in the clot lysis time and reduction in antithrombin III were observed [8]. It is generally accepted that the multifollicular growth with a high estradiol concentration after ovarian stimulation with gonadotrophins even without OHSS may be responsible for an increased rate of blood clotting [9]. In a later controlled study on haemostatic markers in patients with severe OHSS it was found that tissue factor (TF), D-dimer, thrombinantithrombin complexes (TAT), prothrombin fragment 1 + 2 (F1 + 2), plasmin-antiplasmin complexes (PAP) and von Willebrand factor antigen plasma levels were significantly higher than those observed in controls. However, tissue factor pathway inhibitor (TFPI) levels were significantly lower compared to both case-controls. In addition, D-Dimer and TAT levels were significantly higher in OHSS patients with unsuccessful pregnancy outcome compared to those with successful outcome. The data suggested that a marked hypercoagulability with alterations of TF and TFPI levels is detectable in patients with severe OHSS and that it is related to the clinical outcome [10]. In addition, C-reactive protein (CRP) may be useful as the indicator of severity of the syndrome because significant correlations were observed between CRP concentration and abdominal circumference measured at admission, ovarian size measured by ultrasound and body weight in women with OHSS. It may be of importance since CRP is a well-known promoter of thrombosis after vascular damage and hyperpermeability which is present in OHSS [11]. Moreover, CRP could have an additional role in OHSS hypercoagulability via potentiation of thromboxane activity by using a genetic approach investigating the role of thromboxane receptor pathway in CRP-induced thrombosis [12]. Evaluating status of plasma kinin system showed that the average value of plasma kalikrein in OHSS cycles were significantly lower than that of control cycles. Therefore, activation of the plasma kinin system occurring specifically and occasionally in OHSS patients may be associated with increased blood coagulability [13]. The influence of thrombophilia on OHSS and thrombotic complications of ovarian stimulation is very controversial. The prevalence of thrombophilia in women with severe OHSS undergoing ovulation induction was analysed by determing inherited markers (resistance to activated protein C due to the factor V Leiden mutation; prothrombin G20210A mutation; deficiencies in antithrombin, protein C, and protein S) and acquired markers (presence of circulating lupus anticoagulants and/or anticardiolipin antibodies; deficiencies of antithrombin and protein S; acquired protein C resistance). The results reported that the prevalence of thrombophilia was not increased in women with severe OHSS compared with the controls without OHSS [14]. Additionally, the prevalence of thrombophilic mutations was found to be equal (6.9%) among women requiring IVF and women with spontaneous pregnancy. It was suggested that the presence of factor V Leiden and prothrombin gene G20210A mutation did not represent risk factors for OHSS or thrombosis in women undergoing IVF [15]. However, these results were not confirmed by other studies with anecdotal cases of women with thrombophilia who presented with OHSS and thromboembolic phenomena
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[16–19]. One patient with severe OHSS internal jugular and subclavian venous thrombosis was diagnosed in a twin pregnancy after IVF at 9 weeks amenorrhoea. Search for a cause was negative except a frank drop in protein S activity to 35%. Postpartum assay and assay in family members confirmed that the deficiency was acquired during pregnancy [16]. Another patient developed a right internal jugular vein thrombosis due to a resistance to activated protein C or Dahlba¨ck disease as a complication of severe OHSS 28 days after embryo transfer in spite of anticoagulation with low-dose heparin [17]. Massive deep vein thrombosis was reported in a patient with antithrombin III deficiency in early pregnancy after ovarian hyperstimulation for IVF who was treated successfully and subsequently delivered a healthy infant [18]. Decreased antithrombin levels and homozygosity for MTHFR 677T were found in a patient with severe OHSS following ovulation induction for IVF [19]. In a prospective study of women (n ¼ 61) undergoing ovulation induction it was found that one or more markers of thrombophilia determined during the luteal phase of the cycle (antithrombin, protein S and protein C, antiphospholipid antibodies, the factor V Leiden mutation, and 677T polymorphism) were positive in 21 women with severe OHSS (85%) compared to 41 controls (26.8%). It was suggested that the decrease in antithrombin could provoke a prothrombotic state, which would partly explain why severe OHSS can lead to thromboembolic events. All the clinically thrombotic phenomena were found in women with more than one marker of thrombophilia. Homozygosity for MTHFR 6777TR was found to be asscociated with almost a fivefold increased risk for severe OHSS and its combination with other factors may augment the prothrombotic state. The prevalence of the antiphospholipid syndrome was higher in women with OHSS (25%) compared with controls (7.5%), although without a statistical significance [20].
Thrombotic complications Unpredictable thromboembolic accidents are the ultimate and the most feared complications of OHSS that may lead to the fatal outcome for the patient despite adequate treatment. Previously the legs were regarded as the primary site of thrombosis due to reduced venous return caused by compression of ascites and enlarged ovaries. However, this explanation may in part explain the development of thrombosis in these young women because venous thromboses are mostly localised at uncommon sites involving upper limbs, cerebral and cardiac vessels. Owing to a systematic review of the published literature which included 68 cases of thrombosis, 34.3% of them were in arterial and 65.7% in venous sites. The incidence of thrombosis was 83% in the upper part of the body (60% venous and 40% arterial) and 17% in the lower part (81% venous, 19% arterial) [21]. Similar findings were confirmed in other studies in patients with severe OHSS following ovulation induction, reporting the prevalence of venous thromboembolism from 67 to 75% (60–71% in the upper limbs, neck and head) and 25–40% of arterial thromboses occurring as cerebrovascular accidents or strokes [5,6]. In a recent report it was observed that the incidence of first-trimester venous thromboembolism in women undergoing IVF was 0.2% (with up to 1.7% after OHSS), which may represent a 10-fold increase compared with the background population. However, in 6–7% of pregnancies that were complicated with OHSS, a 100-fold increased risk of venous thromboembolism was found, contrary to the fivefold increased risk seen in the patients without OHSS [22]. The timing of these thrombotic phenomena is different regarding the onset of OHSS. Arterial thromboembolism usually occur concurrently with OHSS development and within 2 weeks (a mean 10 days) after embryo transfer. However, venous thrombotic events appear invariably between 1 week after embryo transfer and up to 3
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months of pregnancy or for weeks following the resolution of clinical OHSS (a mean of 40–42 days after embryo transfer). In addition, patients with arterial thromboembolism have a lower rate of inherited thrombophilia and less often get pregnant, contrary to those who develop venous thrombotic events. Therefore, in patients with ovulation induction pregnancy and trombophilia may be two factors which contribute to the development of venous thrombosis [23]. Among more than one hundred cases of vascular thrombosis following ovulation induction and OHSS reported in the literature, the predominant sites of venous thromboembolism were in the upper extremity, neck and head mostly involving the jugular, subclavian and cerebral veins. The majority of thrombotic events occurred in the internal jugular and the subclavian veins, with a slight preponderance of the right side [24–29]. In contrast, venous thromboembolism in pregnancy is most commonly located in the lower extremity with 70% occurring in the ileo-femoral region, with an incidence of 1 in 2500 to 1 in 5000, 20–40-fold lower than what has been reported wih OHSS [30]. However, in women who presented with upper abdominal pain during ART, portal vein and superior mesenteric venous thrombosis were confirmed in the differential diagnosis [31,32]. Finally, an unusual case of a systemic and generalized venous thrombosis in a pregnant patient as a complication of OHSS has been reported [33]. Thromboembolic stroke and systemic arterial thrombosis have been reported rarely during ovarian stimulation in partients resulting from severe OHSS. Although these thromboembolic events are the less common complications of OHSS, they are the most serious. Cerebrovascular thrombosis is perhaps the most dangerous of all. Ischaemic stroke represents a rare but life threatening complication of the syndrome in otherwise healthy women, therefore a sudden onset of neurological deficit in such patients with OHSS symptoms need to bi regarded as a severe OHSS complication. Permanent neurological deficit and death with cerebral infarction have been reported [4,34–37]. Haemoconcentration, different haemostatic markers, the underlying haematological changes during pregnancy in addition to markers of thrombophilia were presented as potential factors in the pathophysiology of thrombosis during OHSS. However, the predilection of venous thrombosis in unusual sites such as the jugular and subclavian veins could not be explained only by the mechanisms of hypercoagulability. Since recently two novel observations have been offered as a new pathophysiologic explanation for the development of venous thrombosis following IVF which will help in solving the mistery of the tendency of vascular sites [23]. A possible explanation in women with OHSS is that peritoneal fluid containing high concentration of estrogens is collected into the lymphatic system, transported and even more concentrated via the cysterna chyli, the thoracic and lymphatic duct and drained into the systemic blood circulation through the junction of the subclavian and jugular veins. It is likely that these higher concentrations of estrogens may cause excessive local state of hypercoagulability predisposing thrombus enlargement at these venos sites. The combination of specific anatomic vascular parts and up to thousand-fold increased estrogen levels represent new insights in explanation of pathogenesis and occurrence of the venous hormone-dependent thrombosis of the upper limbs [38]. Additionally, increased estradiol may down-regulate levels of thrombodulin and up-regulate tissue-factor locally, impairing the antithrombic activity of the endothelium resulting in the increased risk of venous thromboembolism in the upper extremities [39]. Another hypothesis proposes that the increased risk of venous thrombosis in the upper part of the body might be due to rudimentary branchyal cysts in proximity to the jugular and subclavian veins. During OHSS these cysts are usually filled with fluid that may impair blood circulation by mechanical
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compression or increased vascular hyperpermeability of the veins, leading to combined jugular and subclavian vein thrombosis. It is important that these cysts usually regress in diameter when the syndrome completely resolves [40].
Diagnosis of thrombosis In pregnant patients who develop unusual symptoms like neck swelling and pain weeks after OHSS symptoms have resolved, the possibility of venous thromboembolism should be considered. However, a sudden onset of neurological signs concurrently with OHSS and within 2 weeks after embryo transfer must be considered as an acute ischaemic stroke. Therefore, a rapid diagnosis is important to avoid imminent life-threatening complications for both maternal and fetal well-being [23]. There is no significant difference in the diagnostic approach in suspected thrombosis in a pregnant women from that in a non-pregnant state. Echography and Doppler ultrasound were shown to be very useful in demonstrating an occlusive thrombus inside the affected blood vessel [6,9]. Computed tomography (CT) can be used during the entire period of pregnancy in detecting the site of of thrombosis, if the uterus is protected during the examination. As the radiation dose during a routine head examination with CT is only 1 mrad, it appears to be safe for the embryo [32,36,41]. Although previously magnetic resonance imaging (MRI) was not recommended within the first 12 weeks of pregnancy, the safe use of MRI was recently reported in detection of the occlusion in the middle cerebral artery. No foetal injury appeared in the presented case despite the fact that the MRI was performed 9 days after the embryo transfer [34]. In addition, looking for evidence of a rudimentary branchial cyst by using ultrasound or MRI would also be advisable in cases with combined jugular and subclavian vein thrombosis [40].
Prevention and treatment Preventive measures of OHSS are the best means in reducing the risk of thrombosis after ovarian stimulation. The first step in prevention of OHSS is identification of patients at risk because the appropriate stimulation protocol and dose of gonadotrophins need to chosen for high risk groups. The risk of developing OHSS increases with known risk factors such as younger age, a history of a good response to gonadotrophins, thin women, polycystic ovary syndrome, antral follicle count, baseline anti-Mu¨llerian hormone level, a rapid rise in estradiol level and multifollicular growth during ovarian stimulation, blood group and history of allergies [42]. Various preventive strategies may be used once ovulation induction has begun. Cancelling the cycle, coasting, individualizing the hCG trigger dose or using a gonadotrophinreleasing hormone (GnRH) agonist, the use of intravenous fluids at the time of oocyte retrieval, dopamine agonists, in vitro maturation, and elective cryopreservation of all embryos for subsequent transfer in an unstimulated cycle have been showed to be associated with a reduced risk of OHSS [43]. In addition, the level of inhibins A and B in sera collected at the time of oocyte collection may contribute to the prognosis and prevention of OHSS [44]. Despite many years of clinical experience, there are no precise methods to completely prevent severe OHSS, except by withholding the ovulation-inducing trigger of hCG. Preventive measures that appear highly effective combining GnRH antagonist co-treatment and GnRH agonist to trigger final oocyte maturation have become a common tool aiming to eliminate severe early OHSS [45,46]. In addition, the implementation of four new modalities may represent a new algorhitm by the combined use of a GnRH antagonist protocol with GnRH agonist triggering and subsequent single blastocyst transfer or embryo/ oocyte vitrification which would in the near future completely
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avoid the risk of OHSS in stimulated cycles for IVF [47]. These novel risk reduction strategies of OHSS represent a novel approach which may ensure a venous thromboembolism risk equivalent to natural conception that can be combined with conventional thromboprophylaxis [48]. If thrombosis is diagnosed with severe OHSS, the use of haemodilution and Intravenous infusion of crystaloids is justified as a method of choice and remains the mainstay of treatment with the goal to ahieve and maintain normovolemia and normal urinary output [49]. Once thromboembolism develops, acute management with close follow-up is crucial. For arterial and venous thromboses in patients with severe OHSS, appropriate anticoagulation modalities should be applied similarly like in the general population. The use of dose-adjusted heparin, unfractionated or low-molecular-weight (LMWH), is recommended as the first-line treatment of choice, even when pregnancy occurs [22,50,51]. Pregnant women may also be treated safely with thrombolytics, although the use of intravascular thrombolysis is aggresive treatment, but risks and benefits to mother and fetus must be carefully weighed [52]. Although progression of thrombosis may occur despite therapeutic and prophylactic anticoagulation in 7.5% of cases with OHSS [6], thromboprophylaxis using pregnancy-related LMWH (e.g. 40 mg enoxaparin) has been administered for patients who develop moderate-to-severe OHSS with many treatment protocols [9,13,22,23,25,31,32,34,37,50]. Moreover, anticoagulant therapy with LMWH has been suggested prophylactically in all OHHS patients [53]. Although the appropriate duration of thromboprophylaxis is unknown, it should be considered for patients with moderate-to-severe OHSS for 4–8 weeks beyond the resolution of the symptoms. Most of the patients who conceive usually receive LMWH throughout pregnancy, otherwise in case without pregnancy it is advisable to treate these patients for at least 3–6 months [23,50]. In addition, introduction of low-dose aspirin treatment during ovulation induction demonstrated high efficacy in the prevention of OHSS in high-risk patients [54]. Since the influence of thrombophilia on OHSS and thrombotic complications is controversial, it is not clear if patients should be screened for thrombophilias prior to IVF. By determining that the prevalence of markers of thrombophilia in patients with severe OHSS were not increased, it was suggested that screening for the factor V Leiden and prothrombin G20210A mutation in an IVF general population was not cost-effective [14]. Because similar findings were confirmed in another study, it was suggested that screening of the same markers appeared to be unjustified in identification of the patients at the risk for OHSS or for thrombotic complications [15]. It seems that screening for thrombophilia may be important in women with a family and personal history of hypercoagulability planned for ovulation induction, or for those with previous or present OHSS of severe stage following ovarian stimulation [20]. However, the use of thromboprophylaxis should be seriously considered for patients with moderate-to-severe OHSS for a period of beyond of resolution of symptoms and for women undergoing IVF with inherited or acquired thrombophilia [23].
Conclusions OHSS is the main risk factor for thrombosis, and therefore prevention of the syndrome by using a GnRH agonist and freezing of oocytes and embryos with subsequent frozen embryo transfer will lower the risk of thromboembolism similar to the risk found in natural conception and conventional thromboprophylaxis. Once early diagnosis is established, it crucial to use an anticoagulant treatment with LMWH with close monitoring. However, duration of thromboprophylaxis and its routine use in patients with moderate-to-severe OHSS as well as in patients with
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thrombophilia undergoing remains to be determined. Therefore, future larger randomised studies are required on the optimal strategy for acute management and prevention of vascular thrombosis in patients with OHSS following ovulation induction.
Declaration of interest The author report no declaration of interest
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37. Garcı´a-Benı´tez CQ, Avile´s-Cabrera RN. Arterial thrombosis in ovarian hyperstimulation syndrome. Ginecol Obstet Mex 2011;79: 152–5. 38. Bauersachs RM, Manalopoulos K, Hoppe I, et al. More on: ART behind clot: solving the mistery. J Thromb Haemost 2007;5:438–9. 39. Richardson MA, Berg DT, Calnek DS, et al. 17beta-estradiol, but not raloxifene, decreases thrombodulin in the antithrombotic protein C patway. Endocrinology 2000;141:3908–11. 40. Salamon O, Schiby G, Heiman Z, et al. Combined jugular and subclavian vein thrombosis following assisted reproductive technology – new observation. Fertil Steril 2009;92:620–5. 41. Schwartz RB. Neuroradiographic imaging: techniques and safety consideration. Adv Neurol 2002;90:1–8. 42. Humaidan P, Quartarolo J, Papanikolaou EG. Preventing ovarian hyperstimulation syndrome: guidance for the clinician. Fertil Steril 2010;94:389–400. 43. Fiedler K, Ezcurra D. Predicting and preventing ovarian hyperstimulation syndrome (OHSS): the need for individualized not standardized treatment. Reprod Biol Endocrinol 2012;10: 32–6. 44. Ulcova-Gallova Z, Babcova K, Micanova Z, et al. Hyperstimulation syndrome: the levels of inhibin A and B in the sera of follicular fluids. Gynecol Endocrinol 2014;30:298–301. 45. Alama P, Bellver J, Vidal C, Giles J. GnRH analogues in the prevention of ovarian hyperstimulation syndrome. Int J Endocrinol Metab 2013; 1:107–16. 46. Orvieto R. Ovarian hyperstimulation syndrome – an optimal solution for an unresolved enigma. J Ovarian Res 2013;6:77–81. 47. Papanikolaou EG, Humaidan P, Polyzos N, et al. New algorithm for OHSS prevention. Reprod Biol Endocrinol 2011;9:147–51. 48. Nelson SM. Venous thrombosis during assisted reproduction: novel risk reduction strategies. Thromb Res 2013;131:S1–3. 49. Budev MM, Aroliga AC, Falcone T. Ovarian hyperstimulation syndrome. Crit Care Med 2003;33:S301–6. 50. Nelson SM. Prophilaxis of VTE in women – during assisted reproductive technique. Thromb Res 2009;123:S8–15. 51. Ou YC, Kao YL, Lai SL, et al. Thromboembolism after ovarian stimulation: successful management of a woman with superior sagittal sinus thrombosis after IVF and embryo transfer: case report. Hum Reprod 2003;18:2375–81. 52. Mugappan A, Coplin WM, Al-Sadat AN, et al. Thrombolytic of acute ischaemic stroke during pregnancy. Neurology 2006;66: 768–70. 53. Jo´z´wik M. The mechanism of thromboembolism in the course of ovarian hyperstimulation syndrome. Med Wieku Rozwoj 2012;16: 269–71. 54. Va´rnagy A, Bo´dis J, Ma´nfai Z, et al. Low-dose aspirin therapy to prevent ovarian hyperstimulation syndrome. Fertil Steril 2010;93: 2281–4.
REVIEW ARTICLE
Thrombosis following ovarian hyperstimulation syndrome Miro Kasum1, Damir Danolic´2, Slavko Oresˇkovic´1, Davor Jezˇek3, Lidija Beketic´-Oresˇkovic´4, and Marijeta Pekez5 1
Department of Obstetrics and Gynaecology, University Hospital Centre Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia, Department of Gynecologic Oncology, University Hospital Centre Sestre Milosrdnice, University Hospital for Tumors, Zagreb, Croatia, 3Department of Histology, School of Medicine, University of Zagreb, Zagreb, Croatia, 4Department of Oncology, Clinical Hospital Centre Sestre Milosrdnice, School of Medicine, University of Zagreb, Zagreb, Croatia, and 5Clinical Hospital Centre Zagreb, School of Medicine, University of Zagreb, Zagreb, Croatia
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Abstract
Keywords
The aim of this review is to analyse the pathophysiology and complications of thrombosis in conjuction with ovarian hyperstimulation syndrome (OHSS) following ovulation induction and to suggest practical guidelines usefull for the prevention and treatment. Although the incidence of thrombosis varies from 0.2% among in vitro fertilization (IVF) cycles and up to 10% for severe cases of the syndrome, it represents the most dangerous complication of OHSS. Different changes in haemostatic markers have been found to create a state of hypercoagulability, but no single standard test is available to estimate the state of thrombosis. The role of markers for thrombophilia is controversial. Thromboses are mostly venous (67–75%) involving upper limbs and neck, then arterial (25–33%) which are mainly intracerebral. The predominant sites of venous thromboembolism in the upper part of the body may be explained by higher concentrations of estrogens drained through lymphatic ducts from ascites and by compression of rudimentary branchyal cysts. Once early diagnosis is established, it is crucial to use an anticoagulant treatment with heparin proceeded with thromboprophylaxis. However, identification of patients at risk and preventive measures of OHSS are the best means in reducing the risk of thrombosis after ovarian stimulation.
Ovarian hyperstimulation syndrome, pathophysiology, prevention and treatment, thrombosis
Introduction Ovarian hyperstimulation syndrome (OHSS) is the most serious complication of ovulation induction with gonadotrophins of infertile women in in-vitro fertilization (IVF) program. It is characterized by bilateral, multiple follicular and theca-lutein cysts and an acute vascular hyperpermeability resulting in ascites and pleural effusion, electrolyte imbalance, hypovolemia, liver dysfunction, oliguria, haemoconcentration and thrombosis. The overall incidence of OHSS is estimated at 0.6–14% of all ovarian stimulation cycles and severe OHSS accounts for 0.5–5% of all cases of the syndrome [1]. Thromboembolic disease has been reported in many sites of the body, including internal jugular, subclavian, axillary, ulnar, popliteal, cortical, mesenteric, coronary, and cerebral vessels. Vascular thrombosis is an uncommon, yet potentially fatal complication of assisted reproductive technology (ART) and represents the most serious complication of OHSS with an incidence ranging from 0.2% among IVF cycles up to 10% for severe cases of the syndrome [2]. Although OHSS may be an important factor in the pathogenesis of thrombosis, it does not precede all cases because one in 128 women with severe OHSS develops thromboembolic disease [3]. Cerebrovascular thromboembolism is perhaps the most dangerous thrombosis with fatal cases of OHSS with cerebral infarction having been reported [4]. In an earlier review between 1964 and 1997 of 54 cases with Address for correspondence: Prof. Miro Kasum, Department of Obstetrics and Gynaecology, School of Medicine, University Hospital Centre, Petrova 13, 10 000 Zagreb, Croatia. Tel: (+385) 1 4604646. Fax: (+385) 1 2376267. E-mail: [email protected]
History Received 28 February 2014 Revised 29 April 2014 Accepted 21 May 2014 Published online 11 July 2014
thromboembolic phenomena associated with ovulation induction, it was found that 66% of these cases were in conjuction with OHSS and 84% were during pregnancy. In addition, 75% of the cases were venous in origin (60% in the upper limbs, neck area and head) while 25% were arterial thromboses (mostly intracerebral) [5]. Similar findings were confirmed in a later review by including an additional 43 cases of thromboembolism associated with ovulation induction between 1997 and 2003. Among the 97 cases, 74% of cases were associated with OHSS and 77% were during pregnancy. Sixty-seven of the reported cases were venous in origin (71% involved the upper limb, neck and head) while 33% were arterial thromboses [6]. Although thromboembolic phenomena are not frequently encountered in the course of OHSS associated with ART, they may be potentially serious with dangerous sequellae in a proportion of affected patients. The aim of this review would be to report an update of our knowledge regarding the pathogenesis and complications of thrombotic events and to suggest practical guidelines which would be usefull for the prevention and treatment of ART-associated thromboses.
Pathophysiology of thrombosis Although the exact mechanism of thrombosis has not yet been elucidated entirely, it has been surmised that the hypercoagulable state is created due to haemoconcentration and hypovolemia, as a result of the increased capillary permeability induced by excessive vasoactive substances produced by the ovaries. In addition, vomiting during OHSS induced by the pressure of intraperitoneal fluid on the bowel and arterial hypotension with a slower blood velocity may contribute to the same changes. Of all the different
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vasoactive cytokines, vascular endothelial growth factor (VEGF), which is triggered by human chorionic gonadotrophin (hCG), is the principal mediator and the most responsible for the vascular hyperpermeability. A generalized capillary leak and acute shift of protein-rich fluid from the intravascular compartment into the third space (ascites, hydrothorax, hydropericardium) may lead to hypoproteinemia, oliguria, acute renal failure and increased blood viscosity with changes in coagulation parameters resulting in thromboembolic events [7]. In an earlier study from 1991 it was found that ovulation induction with hCG for IVF might create a state of hypercoagulability, because a significant rise in plasma fibrinogen with an increase in the clot lysis time and reduction in antithrombin III were observed [8]. It is generally accepted that the multifollicular growth with a high estradiol concentration after ovarian stimulation with gonadotrophins even without OHSS may be responsible for an increased rate of blood clotting [9]. In a later controlled study on haemostatic markers in patients with severe OHSS it was found that tissue factor (TF), D-dimer, thrombinantithrombin complexes (TAT), prothrombin fragment 1 + 2 (F1 + 2), plasmin-antiplasmin complexes (PAP) and von Willebrand factor antigen plasma levels were significantly higher than those observed in controls. However, tissue factor pathway inhibitor (TFPI) levels were significantly lower compared to both case-controls. In addition, D-Dimer and TAT levels were significantly higher in OHSS patients with unsuccessful pregnancy outcome compared to those with successful outcome. The data suggested that a marked hypercoagulability with alterations of TF and TFPI levels is detectable in patients with severe OHSS and that it is related to the clinical outcome [10]. In addition, C-reactive protein (CRP) may be useful as the indicator of severity of the syndrome because significant correlations were observed between CRP concentration and abdominal circumference measured at admission, ovarian size measured by ultrasound and body weight in women with OHSS. It may be of importance since CRP is a well-known promoter of thrombosis after vascular damage and hyperpermeability which is present in OHSS [11]. Moreover, CRP could have an additional role in OHSS hypercoagulability via potentiation of thromboxane activity by using a genetic approach investigating the role of thromboxane receptor pathway in CRP-induced thrombosis [12]. Evaluating status of plasma kinin system showed that the average value of plasma kalikrein in OHSS cycles were significantly lower than that of control cycles. Therefore, activation of the plasma kinin system occurring specifically and occasionally in OHSS patients may be associated with increased blood coagulability [13]. The influence of thrombophilia on OHSS and thrombotic complications of ovarian stimulation is very controversial. The prevalence of thrombophilia in women with severe OHSS undergoing ovulation induction was analysed by determing inherited markers (resistance to activated protein C due to the factor V Leiden mutation; prothrombin G20210A mutation; deficiencies in antithrombin, protein C, and protein S) and acquired markers (presence of circulating lupus anticoagulants and/or anticardiolipin antibodies; deficiencies of antithrombin and protein S; acquired protein C resistance). The results reported that the prevalence of thrombophilia was not increased in women with severe OHSS compared with the controls without OHSS [14]. Additionally, the prevalence of thrombophilic mutations was found to be equal (6.9%) among women requiring IVF and women with spontaneous pregnancy. It was suggested that the presence of factor V Leiden and prothrombin gene G20210A mutation did not represent risk factors for OHSS or thrombosis in women undergoing IVF [15]. However, these results were not confirmed by other studies with anecdotal cases of women with thrombophilia who presented with OHSS and thromboembolic phenomena
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[16–19]. One patient with severe OHSS internal jugular and subclavian venous thrombosis was diagnosed in a twin pregnancy after IVF at 9 weeks amenorrhoea. Search for a cause was negative except a frank drop in protein S activity to 35%. Postpartum assay and assay in family members confirmed that the deficiency was acquired during pregnancy [16]. Another patient developed a right internal jugular vein thrombosis due to a resistance to activated protein C or Dahlba¨ck disease as a complication of severe OHSS 28 days after embryo transfer in spite of anticoagulation with low-dose heparin [17]. Massive deep vein thrombosis was reported in a patient with antithrombin III deficiency in early pregnancy after ovarian hyperstimulation for IVF who was treated successfully and subsequently delivered a healthy infant [18]. Decreased antithrombin levels and homozygosity for MTHFR 677T were found in a patient with severe OHSS following ovulation induction for IVF [19]. In a prospective study of women (n ¼ 61) undergoing ovulation induction it was found that one or more markers of thrombophilia determined during the luteal phase of the cycle (antithrombin, protein S and protein C, antiphospholipid antibodies, the factor V Leiden mutation, and 677T polymorphism) were positive in 21 women with severe OHSS (85%) compared to 41 controls (26.8%). It was suggested that the decrease in antithrombin could provoke a prothrombotic state, which would partly explain why severe OHSS can lead to thromboembolic events. All the clinically thrombotic phenomena were found in women with more than one marker of thrombophilia. Homozygosity for MTHFR 6777TR was found to be asscociated with almost a fivefold increased risk for severe OHSS and its combination with other factors may augment the prothrombotic state. The prevalence of the antiphospholipid syndrome was higher in women with OHSS (25%) compared with controls (7.5%), although without a statistical significance [20].
Thrombotic complications Unpredictable thromboembolic accidents are the ultimate and the most feared complications of OHSS that may lead to the fatal outcome for the patient despite adequate treatment. Previously the legs were regarded as the primary site of thrombosis due to reduced venous return caused by compression of ascites and enlarged ovaries. However, this explanation may in part explain the development of thrombosis in these young women because venous thromboses are mostly localised at uncommon sites involving upper limbs, cerebral and cardiac vessels. Owing to a systematic review of the published literature which included 68 cases of thrombosis, 34.3% of them were in arterial and 65.7% in venous sites. The incidence of thrombosis was 83% in the upper part of the body (60% venous and 40% arterial) and 17% in the lower part (81% venous, 19% arterial) [21]. Similar findings were confirmed in other studies in patients with severe OHSS following ovulation induction, reporting the prevalence of venous thromboembolism from 67 to 75% (60–71% in the upper limbs, neck and head) and 25–40% of arterial thromboses occurring as cerebrovascular accidents or strokes [5,6]. In a recent report it was observed that the incidence of first-trimester venous thromboembolism in women undergoing IVF was 0.2% (with up to 1.7% after OHSS), which may represent a 10-fold increase compared with the background population. However, in 6–7% of pregnancies that were complicated with OHSS, a 100-fold increased risk of venous thromboembolism was found, contrary to the fivefold increased risk seen in the patients without OHSS [22]. The timing of these thrombotic phenomena is different regarding the onset of OHSS. Arterial thromboembolism usually occur concurrently with OHSS development and within 2 weeks (a mean 10 days) after embryo transfer. However, venous thrombotic events appear invariably between 1 week after embryo transfer and up to 3
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months of pregnancy or for weeks following the resolution of clinical OHSS (a mean of 40–42 days after embryo transfer). In addition, patients with arterial thromboembolism have a lower rate of inherited thrombophilia and less often get pregnant, contrary to those who develop venous thrombotic events. Therefore, in patients with ovulation induction pregnancy and trombophilia may be two factors which contribute to the development of venous thrombosis [23]. Among more than one hundred cases of vascular thrombosis following ovulation induction and OHSS reported in the literature, the predominant sites of venous thromboembolism were in the upper extremity, neck and head mostly involving the jugular, subclavian and cerebral veins. The majority of thrombotic events occurred in the internal jugular and the subclavian veins, with a slight preponderance of the right side [24–29]. In contrast, venous thromboembolism in pregnancy is most commonly located in the lower extremity with 70% occurring in the ileo-femoral region, with an incidence of 1 in 2500 to 1 in 5000, 20–40-fold lower than what has been reported wih OHSS [30]. However, in women who presented with upper abdominal pain during ART, portal vein and superior mesenteric venous thrombosis were confirmed in the differential diagnosis [31,32]. Finally, an unusual case of a systemic and generalized venous thrombosis in a pregnant patient as a complication of OHSS has been reported [33]. Thromboembolic stroke and systemic arterial thrombosis have been reported rarely during ovarian stimulation in partients resulting from severe OHSS. Although these thromboembolic events are the less common complications of OHSS, they are the most serious. Cerebrovascular thrombosis is perhaps the most dangerous of all. Ischaemic stroke represents a rare but life threatening complication of the syndrome in otherwise healthy women, therefore a sudden onset of neurological deficit in such patients with OHSS symptoms need to bi regarded as a severe OHSS complication. Permanent neurological deficit and death with cerebral infarction have been reported [4,34–37]. Haemoconcentration, different haemostatic markers, the underlying haematological changes during pregnancy in addition to markers of thrombophilia were presented as potential factors in the pathophysiology of thrombosis during OHSS. However, the predilection of venous thrombosis in unusual sites such as the jugular and subclavian veins could not be explained only by the mechanisms of hypercoagulability. Since recently two novel observations have been offered as a new pathophysiologic explanation for the development of venous thrombosis following IVF which will help in solving the mistery of the tendency of vascular sites [23]. A possible explanation in women with OHSS is that peritoneal fluid containing high concentration of estrogens is collected into the lymphatic system, transported and even more concentrated via the cysterna chyli, the thoracic and lymphatic duct and drained into the systemic blood circulation through the junction of the subclavian and jugular veins. It is likely that these higher concentrations of estrogens may cause excessive local state of hypercoagulability predisposing thrombus enlargement at these venos sites. The combination of specific anatomic vascular parts and up to thousand-fold increased estrogen levels represent new insights in explanation of pathogenesis and occurrence of the venous hormone-dependent thrombosis of the upper limbs [38]. Additionally, increased estradiol may down-regulate levels of thrombodulin and up-regulate tissue-factor locally, impairing the antithrombic activity of the endothelium resulting in the increased risk of venous thromboembolism in the upper extremities [39]. Another hypothesis proposes that the increased risk of venous thrombosis in the upper part of the body might be due to rudimentary branchyal cysts in proximity to the jugular and subclavian veins. During OHSS these cysts are usually filled with fluid that may impair blood circulation by mechanical
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compression or increased vascular hyperpermeability of the veins, leading to combined jugular and subclavian vein thrombosis. It is important that these cysts usually regress in diameter when the syndrome completely resolves [40].
Diagnosis of thrombosis In pregnant patients who develop unusual symptoms like neck swelling and pain weeks after OHSS symptoms have resolved, the possibility of venous thromboembolism should be considered. However, a sudden onset of neurological signs concurrently with OHSS and within 2 weeks after embryo transfer must be considered as an acute ischaemic stroke. Therefore, a rapid diagnosis is important to avoid imminent life-threatening complications for both maternal and fetal well-being [23]. There is no significant difference in the diagnostic approach in suspected thrombosis in a pregnant women from that in a non-pregnant state. Echography and Doppler ultrasound were shown to be very useful in demonstrating an occlusive thrombus inside the affected blood vessel [6,9]. Computed tomography (CT) can be used during the entire period of pregnancy in detecting the site of of thrombosis, if the uterus is protected during the examination. As the radiation dose during a routine head examination with CT is only 1 mrad, it appears to be safe for the embryo [32,36,41]. Although previously magnetic resonance imaging (MRI) was not recommended within the first 12 weeks of pregnancy, the safe use of MRI was recently reported in detection of the occlusion in the middle cerebral artery. No foetal injury appeared in the presented case despite the fact that the MRI was performed 9 days after the embryo transfer [34]. In addition, looking for evidence of a rudimentary branchial cyst by using ultrasound or MRI would also be advisable in cases with combined jugular and subclavian vein thrombosis [40].
Prevention and treatment Preventive measures of OHSS are the best means in reducing the risk of thrombosis after ovarian stimulation. The first step in prevention of OHSS is identification of patients at risk because the appropriate stimulation protocol and dose of gonadotrophins need to chosen for high risk groups. The risk of developing OHSS increases with known risk factors such as younger age, a history of a good response to gonadotrophins, thin women, polycystic ovary syndrome, antral follicle count, baseline anti-Mu¨llerian hormone level, a rapid rise in estradiol level and multifollicular growth during ovarian stimulation, blood group and history of allergies [42]. Various preventive strategies may be used once ovulation induction has begun. Cancelling the cycle, coasting, individualizing the hCG trigger dose or using a gonadotrophinreleasing hormone (GnRH) agonist, the use of intravenous fluids at the time of oocyte retrieval, dopamine agonists, in vitro maturation, and elective cryopreservation of all embryos for subsequent transfer in an unstimulated cycle have been showed to be associated with a reduced risk of OHSS [43]. In addition, the level of inhibins A and B in sera collected at the time of oocyte collection may contribute to the prognosis and prevention of OHSS [44]. Despite many years of clinical experience, there are no precise methods to completely prevent severe OHSS, except by withholding the ovulation-inducing trigger of hCG. Preventive measures that appear highly effective combining GnRH antagonist co-treatment and GnRH agonist to trigger final oocyte maturation have become a common tool aiming to eliminate severe early OHSS [45,46]. In addition, the implementation of four new modalities may represent a new algorhitm by the combined use of a GnRH antagonist protocol with GnRH agonist triggering and subsequent single blastocyst transfer or embryo/ oocyte vitrification which would in the near future completely
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avoid the risk of OHSS in stimulated cycles for IVF [47]. These novel risk reduction strategies of OHSS represent a novel approach which may ensure a venous thromboembolism risk equivalent to natural conception that can be combined with conventional thromboprophylaxis [48]. If thrombosis is diagnosed with severe OHSS, the use of haemodilution and Intravenous infusion of crystaloids is justified as a method of choice and remains the mainstay of treatment with the goal to ahieve and maintain normovolemia and normal urinary output [49]. Once thromboembolism develops, acute management with close follow-up is crucial. For arterial and venous thromboses in patients with severe OHSS, appropriate anticoagulation modalities should be applied similarly like in the general population. The use of dose-adjusted heparin, unfractionated or low-molecular-weight (LMWH), is recommended as the first-line treatment of choice, even when pregnancy occurs [22,50,51]. Pregnant women may also be treated safely with thrombolytics, although the use of intravascular thrombolysis is aggresive treatment, but risks and benefits to mother and fetus must be carefully weighed [52]. Although progression of thrombosis may occur despite therapeutic and prophylactic anticoagulation in 7.5% of cases with OHSS [6], thromboprophylaxis using pregnancy-related LMWH (e.g. 40 mg enoxaparin) has been administered for patients who develop moderate-to-severe OHSS with many treatment protocols [9,13,22,23,25,31,32,34,37,50]. Moreover, anticoagulant therapy with LMWH has been suggested prophylactically in all OHHS patients [53]. Although the appropriate duration of thromboprophylaxis is unknown, it should be considered for patients with moderate-to-severe OHSS for 4–8 weeks beyond the resolution of the symptoms. Most of the patients who conceive usually receive LMWH throughout pregnancy, otherwise in case without pregnancy it is advisable to treate these patients for at least 3–6 months [23,50]. In addition, introduction of low-dose aspirin treatment during ovulation induction demonstrated high efficacy in the prevention of OHSS in high-risk patients [54]. Since the influence of thrombophilia on OHSS and thrombotic complications is controversial, it is not clear if patients should be screened for thrombophilias prior to IVF. By determining that the prevalence of markers of thrombophilia in patients with severe OHSS were not increased, it was suggested that screening for the factor V Leiden and prothrombin G20210A mutation in an IVF general population was not cost-effective [14]. Because similar findings were confirmed in another study, it was suggested that screening of the same markers appeared to be unjustified in identification of the patients at the risk for OHSS or for thrombotic complications [15]. It seems that screening for thrombophilia may be important in women with a family and personal history of hypercoagulability planned for ovulation induction, or for those with previous or present OHSS of severe stage following ovarian stimulation [20]. However, the use of thromboprophylaxis should be seriously considered for patients with moderate-to-severe OHSS for a period of beyond of resolution of symptoms and for women undergoing IVF with inherited or acquired thrombophilia [23].
Conclusions OHSS is the main risk factor for thrombosis, and therefore prevention of the syndrome by using a GnRH agonist and freezing of oocytes and embryos with subsequent frozen embryo transfer will lower the risk of thromboembolism similar to the risk found in natural conception and conventional thromboprophylaxis. Once early diagnosis is established, it crucial to use an anticoagulant treatment with LMWH with close monitoring. However, duration of thromboprophylaxis and its routine use in patients with moderate-to-severe OHSS as well as in patients with
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thrombophilia undergoing remains to be determined. Therefore, future larger randomised studies are required on the optimal strategy for acute management and prevention of vascular thrombosis in patients with OHSS following ovulation induction.
Declaration of interest The author report no declaration of interest
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