Thromboembolic disease associated with ovarian stimulation and ...

Human Reproduction vol.12 no.10 pp.2167–2173, 1997

OPINION

Thromboembolic disease associated with ovarian stimulation and assisted conception techniques

J.A.Stewart1,3, P.J.Hamilton2 and A.P.Murdoch1 1Centre

2Department

for Reproductive Medicine and of Haematology, Royal Victoria Infirmary, Newcastle-upon-Tyne NE1 4LP, UK

3To

whom correspondence should be addressed

Thromboembolic disease, as a complication of ovarian stimulation and assisted conception techniques, is generally considered to be a rare complication of ovarian hyperstimulation syndrome and, by implication, lower limb in origin. Sporadic cases of unusually sited thromboses, both venous and arterial, have been reported. This paper aims to draw attention to the relatively large number of such thromboses reported in the world literature compared with those cited in previous commentaries, and to emphasize how little is known about their pathogenesis. It is believed that this is an issue which requires to be addressed in order to understand the background pathology to such incidents and if possible to identify women at greatest risk from such potentially debilitating or fatal complications, such that appropriate prophylactic measures can be taken. Key words: assisted reproduction/human/ovarian hyperstimulation syndrome/ovulation induction/thrombosis

Introduction The incidence of thromboembolic disease associated with assisted reproductive techniques is considered to be extremely rare. From reviews of these techniques it is often inferred that lower limb deep venous thrombosis (DVT) is the most likely thromboembolic phenomenon to be encountered and the reasons outlined are reduced venous return secondary to enlarged ovaries and, particularly in the case of ovarian hyperstimulation syndrome (OHSS), the added factors of immobility and ascites (Kaaja et al., 1989; Royal College of Obstetricians and Gynaecologists, 1995). These anatomical features, compounded by high oestrogen concentration and, in OHSS, haemoconcentration and reduced circulating blood volume, are thought to explain the aetiology and pathogenesis. The aim of this paper is to show that this view is probably too simplistic to explain the problem fully and that it may be more significant than previous authors have suggested. The emphasis is on the need for further research into the aetiology and pathogenesis of this complication such that appropriate measures can be taken to avoid it. © European Society for Human Reproduction and Embryology

Case reports As has been suggested from the case reports presented elsewhere, this type of review may oversimplify the problems and neglect important alternative sites. In addition OHSS, although an important aetiological factor, need not be present and indeed stimulation for ovulation induction as opposed to assisted conception may also be a risk factor. These suggestions have been revealed from an extensive search of the world literature, starting from Medline searches. A total of 54 cases of thromboembolic disease have been reported since 1964 (Table I) in association with ovulation induction and assisted conception treatment [33% in association with ovulation induction (Crooke et al., 1964; Mozes et al., 1965; Humbert et al., 1973; Nwosu et al., 1974; Schenker and Weinstein, 1978; Dumont et al., 1980; Dalrymple et al., 1982; Boulieu et al., 1989; Neau et al., 1989; Rajah et al., 1991; Waterstone et al., 1992; Ayhan et al., 1993; Inbar et al., 1994)] including one case where two episodes were associated with clomiphene use alone (Benshushan et al., 1995). There was also one case where clomiphene was used in a man to improve spermatogenesis (Chamberlain and Cumming, 1986). Of the 54 cases 66% were associated with OHSS and 84% of those where it was recorded, with pregnancy. One fatality has been reported (Mozes et al., 1965) although in many cases the outcome has not been specifically recorded. However, although the majority of thromboses reported were venous sites (75%), 60% of these were in upper limb, neck and head veins; with an associated 4–12% risk of pulmonary embolism (PE) (Burihan et al., 1993; Horattas et al., 1988), compared with lower limb DVT or PE. The remaining 25% were arterial thromboses and were mostly intracerebral (Mozes et al., 1965; Humbert et al., 1973; Dumont et al., 1980; Neau et al., 1989; Rizk et al., 1990; Kermode et al., 1993; Inbar et al., 1994; Thill et al., 1994; Kodama et al., 1995). Although the factors described above may promote lower limb thromboses, the pathogenesis of the remainder remains obscure. Spontaneous arterial thrombosis, although common in the elderly in the form of strokes, is rare in young women. Similarly, upper limb venous thromboses are unusual without local trauma, including central venous catheterisation, or compression (Burihan et al., 1993) and represent only 4% of the incidence of DVT in the general population (Horattas et al., 1988). If Virchow’s triad of causative factors is considered, lower limb venous thrombosis could be explained by reduced venous drainage alone. However, with a lack of local causes, upper limb and arterial thromboses must be the result of haematological changes. This introduces the potential phenomenon of the ‘hypercoagulable state’. 2167

J.A.Stewart, P.J.Hamilton and A.P.Murdoch

Table I. Summary of reported cases of thromboembolic disorders associated with ovarian stimulation Author(s)

Treatment

OHSS

Pregnancy

Upper extremity DVT Ayhan et al. (1993) Rajah et al. (1991) Ong et al. (1991)

Ovulation induction Ovulation induction Ovulation induction

Yes Yes Yes

No

Waterstone et al. (1992)

Ovulation induction

Yes

Yes

Boulieu et al. (1989)

Ovulation induction

No

Yes


IVF

No

Yes

Boulieu et al. (1989) Fournet et al. (1991) Mills et al. (1992) Mills et al. (1992) Vauthier–Brouzes et al. (1993) Bachmeyer et al. (1994) Beńifla et al. (1994) el Kouri et al. (1995) el Kouri et al. (1995)

IVF IVF IVF IVF IVF

Yes Yes Yes Yes Yes

Yes Yes Yes Yes Yes

IVF IVF IVF IVF

Yes Yes Yes Yes

Yes Yes Yes Yes

Hignett et al. (1995) Hocke et al. (1995)

IVF IVF

Yes Yes

Yes Yes

Hocke et al. (1995)

IVF

Yes

Yes

Stewart et al. (1997) Hocke et al. (1995) Horstkamp et al. (1996)

IVF IVF IVF

Yes Yes Yes

Yes Yes Yes

Hulinsky and Smith (1995) GIFT Stewart et al. (1997) GIFT

Yes No

Yes Yes

Stewart et al. (1997)

No

Yes

N/A

N/A

GIFT

Lower limb DVT or PE Chamberlain and Cumming Clomiphene (1986) Benshushan et al. (1995) Clomiphene

Predisposing factors

Yes

Costoclavicular nipping

Activated protein C resistance

Timing

L internal jugular vein Internal jugular vein PE.L internal jugular vein

14 days 21 days 27 days HCG 20 days

R transverse sinus, internal cerebral vein and vein of Galen Phlebitis, R subclavicular and axillary veins L (internal jugular and) subclavicular veins R venous innominate trunk R jugular and subclavian veins Subclavian vein Subclavian vein L jugular, subclavian and axillary veins Internal jugular vein L jugular and subclavian veins L internal jugular vein R internal jugular and subclavicular veins R internal jugular vein R humeral and internal jugular veins R subclavian and internal jugular veins L axillary vein Superior sagittal sinus R internal jugular vein

R external jugular vein Laparotomy for R subclavian vein ectopic pregnancy Mother died from L jugular, subclavian and massive PE later brachiocephalic veins PE, male on clomiphene Previous DVT and PE, postoperatively Previous DVT and PE, postoperatively. Previous DVT on clomiphene

Two complicated cycles

Site of thrombus

post HCG

37 days after ovulation 28 days after ovulation 28 days from OR 32 days post HCG 50 days post HCG 50 days post HCG 22/40 gestation 7 weeks gestation 9/40 gestation 42 days post HCG 49 days post HCG 42 days post HCG 47 days post embryo transfer 40 days post HCG 37 days post HCG 15 days post embryo transfer 30 days post HCG 38 days post HCG 51 days post HCG 44 days post HCG

N/A

R DVT R popliteal vein and superficial femoral vein

Crooke et al. (1964) Schenker and Weinstein (1978) Schenker and Weinstein (1978) Nwosu et al. (1974)

Ovulation induction Ovulation induction

No Yes

Yes No

Saphenous vein DVT, thrombophlebitis

Ovulation induction

Yes

No

DVT, thrombophlebitis

Ovulation induction

Yes

Yes

L superficial phlebitis and PE

Dalrymple et al. (1982–3)

Ovulation induction

No

No

Thill et al. (1994) and Aurousseau et al. (1995) Huong et al. (1996)

IVF

No

No

IVF

No

No

Kligman et al. (1995) Boulieu et al. (1989)

IVF IVF

No No

Yes Yes

Previous R DVT and PE postoperatively. Previous spontaneous PE Laparotomy. Sepsis Mixed connective tissue disease. AT III deficiency Low protein S

post HCG post HCG and 40 days post

11 days post HCG, and 46 days post HCG

L femoral and external iliac veins. Common iliac and distal veins PE

6 days post HCG

Inferior vena cava. L renal vein DVT L popliteal and iliofemoral phlebitis

2 weeks after treatment 70 days after ovulation continued.

2168

Thromboembolism risk and assisted reproduction

Table I. Continued Author(s)

Treatment

OHSS

Pregnancy

Predisposing factors


IVF

No

Yes

Kaaja et al. (1989) Salat-Baroux et al. (1987)

IVF IVF

Yes Yes

Yes Yes

Yes

Yes

Previous R phlebitis (iliofemoral vein) superficial and inferior vena cava phlebitis of lower limb. Family history of thromboembolic disease L posterior fibular veins Laparotomy 5 Small R PE, not formally days post HCG proven PE

Stewart et al. (unpublished) GIFT Arterial thrombosis Mozes et al. (1965)

Ovulation induction

Inbar et al. (1994) Mozes et al. (1965) Humbert et al. (1973)

Ovulation induction Ovulation induction Ovulation induction

No Yes Yes

No

Dumont et al. (1980) Neau et al. (1989) Thill et al. (1994) and Aurousseau et al. (1995)

Ovulation induction Ovulation induction IVF

Yes Yes No

Yes Yes Yes

Germond et al. (1996) Kodama et al. (1995) Aurousseau et al. (1995) Thill et al. (1994)

IVF IVF IVF

Yes Yes No

Yes Yes

Kermode et al. (1993)

GIFT

Yes

No

Rizk et al. (1990)

GIFT

Yes

Yes

Choktanasiri and Rojanasakul (1995)

GIFT

Yes

Yes

‘Kinking’ of internal carotid arteries

Site of thrombus

R femoral artery, L popliteal artery, PE and L femoral vein R middle cerebral artery L internal carotid artery Basilar artery and probably L vertebral artery L anterior cerebral artery R middle cerebral artery R internal carotid artery

Aorta, subclavian artery R middle cerebral artery Smoker. Previous Mesenteric artery L popliteal arterial thrombosis after IVF L internal carotid artery and R internal iliac vein Middle cerebral artery 13 days post HCG Bilateral external iliac and femoropopliteal arteries

Timing 42 days after ovulation

24 days post HCG

15 days from last injection 7 days post HCG 5 days post HCG 1 day post HCG 36 days post HCG 10 days post HCG 7 days post HCG 14 days post HCG 30 days post HCG

11 days post HCG

17 days post HCG

OHSS 5 ovarian hyperstimulation syndrome; DVT 5 deep venous thrombosis; L5 left; R 5 right; PE 5 pulmonary embolism; IVF 5 in-vitro fertilization; OR 5 oocyte retrieval; HCG 5 human chorionic gonadotrophin; GIFT 5 gamete intra-Fallopian transfer; AT 5 anti-thrombin.

‘Hypercoagulable state’ This term has been used to refer to any haematological changes resulting in increased risk of thrombogenesis. The natural assumption in the case of assisted conception and ovulation induction is that raised oestrogen concentration is to blame. Hyper-oestrogenism Evidence that administration of exogenous oestrogens promotes thrombogenesis is undisputed although it is dose (Inman et al., 1970) and preparation (Bonnar 1987) dependent, hence the recent controversy surrounding combined oral contraceptive pill (COCP) use (McPherson, 1996). The role of endogenous oestrogens is less clear. Pregnancy is a hyperoestrogenic state associated with an increased risk of thromboembolism [3– 12 per 1000 pregnancies (de Swiet 1989)], with maximum concentrations of endogenous oestradiol reaching 22.53– 127 nmol/l (O’Leary et al., 1991). There are recognized haematological changes associated with pregnancy, predominantly increased concentrations of factors VII, VIII, IX, X and XII and fibrinogen (Strauss and Diamond, 1963), presumed in part to be an oestrogen effect, also a reduction of the concentra-

tion of protein S (Comp et al., 1986; Boerger et al., 1987) and a reduction in fibrinolytic activity including antithrombin (AT) III (Schafer, 1985; Wright et al., 1988). The result appears to be a relative thrombophilia. Of the reported cases of thromboembolic disease associated with ovulation induction and assisted conception, 72% were in pregnancy cycles; although this may be considered an explanation in part, it is important to note that thrombosis in pregnancy is much more likely to occur at term and post-partum when anatomical factors also play a role. The pregnancy-associated thromboses reviewed here occurred almost exclusively in first trimester. Also antenatal arterial thrombosis is rare in pregnancy, as is upper limb venous thrombosis; three cases are reported associated with pregnancy; one associated with AT III deficiency (Mackie et al., 1978), one in third trimester (Ben-Shlomo et al., 1992) and one at 12 weeks gestation in a molar pregnancy (Årstad et al., 1980). Lower limb DVT greatly predominates. The most useful study of the effects of endogenous oestrogen on coagulation has been performed by Kim et al. (1981), when the coagulation parameters of seven women undergoing ovulation induction treatment were measured. They reported 2169


a rise in fibrinogen concentration that correlated well with the rise in oestrogen concentration as the cycle progressed. There were no significant changes in prothrombin time (PT) or activated partial thromboplastin time (APTT) but there was a significant rise in factor VIIIR.VWF (von Willebrand factor) and reduction of AT III, signifying a relative hypercoagulable state. The drawback of this study with regard to many of the cases discussed here is that measurements were concluded after human chorionic gonadotrophin (HCG) administration and therefore were not representative of the times at which many women appear to experience thromboembolic complications of treatment. Aune et al. (1991) reported that ovarian stimulation for IVF induced a hypercoagulable state. They considered 12 IVF cycles, measuring whole blood clotting time (WBCT), whole blood clot lysis time (CLT), antithrombin III (AT III), plasma fibrinogen and factor VII, both before stimulation and after HCG administration, at the ‘peak’ of oestradiol concentration. Their findings showed a significant increase in fibrinogen and reduction in AT III concentration and a significant increase in CLT over this time, implying a disruption of the balance of coagulation and thrombolysis leading to a relative increase in coagulability. In contrast Lox et al. (1995) claim to have excluded the hypercoagulable state in IVF cycles. They assessed coagulation parameters up to 14 days post HCG. They noted significant correlations of certain factors with changes in oestradiol and in PT and APTT; however, none of these changes were out with their laboratory’s normal ranges and they concluded therefore that these changes could not constitute a promotion of coagulability and challenged others’ findings on that basis. Colburn and Buonassisi (1978) suggested that endothelial cells expressing oestrogen hormone receptors may specifically contribute to thrombotic events locally, e.g. by changes in platelet–endothelial interactions. If hyperoestrogenism alone is responsible for the risk of thromboembolic disease in the reported cases, then it is interesting that in many cases the thromboembolic event is diagnosed some time after the expected peak oestradiol concentration (around the time of HCG administration). Perhaps in some cases, for example, OHSS prolongs the risk period in some way. Mills et al. (1992) suggested this could result from the prolonged hepatic dysfunction secondary to OHSS, described by Ryley et al. (1990). Bremme et al. (1994), although only assessing the period of stimulation and immediately afterwards, suggest that a decrease in factor VII and increase in free protein S may be thrombo-protective at high concentrations of endogenous oestradiol. Perhaps this phenomenon contributes to the delay in thrombogenesis if the fall in oestradiol is prolonged. Ovarian hyperstimulation syndrome Delvigne et al. (1993) estimated a prevalence of thromboembolic disease of one in 128 women exhibiting severe OHSS, and severe, complicated OHSS is reported to account for 0.56– 6.5% of cases (Pride et al., 1990). Invoking OHSS as the major cause of thrombogenesis in this group of cases, however, is difficult, firstly because it does not occur in all cases, but 2170

also because over three decades and international boundaries, it is likely that the definition of OHSS and its diagnosis has varied widely, particularly preceding any form of clinical and biochemical grading of the condition. In addition in our case of OHSS and others reported, the development of thrombosis appears to have occurred after clinical resolution of the syndrome. As has been discussed previously OHSS certainly predisposes to lower limb DVT. How it contributes to thromboses in other sites is less clear but presumably by the promotion of a hypercoagulable state. Few studies have been carried out to examine the haematological changes occurring during ovarian stimulation complicated by OHSS. Importantly, as with the studies discussed above, they have not been extended much beyond the administration of HCG and certainly not into early pregnancy where women appear to be at greatest risk. In addition none seem to give conclusive evidence of thrombophilia. Kodama et al. (1995) performed prospective tests on 23 women admitted with severe OHSS in IVF cycles. Of these women, 14 became pregnant in these cycles and one developed thrombosis of the right middle cerebral artery ~2 weeks following HCG. Samples were taken once only, ~9 days (9.2 6 4.6) after HCG administration, and they were able to show that at the time of sampling the woman developing the thromboembolism had a decreased concentration of α2 plasmin inhibitor, an increased concentration of plasmin–α2 antiplasmin complexes and higher concentration of D-dimers than the other patients with uncomplicated OHSS. These results cannot be considered representative because of the limited sampling. In addition the differences shown, by virtue of the timing of sampling and occurrence of thromboembolism, may represent active coagulopathy as opposed to any predisposition to thrombosis. Phillips et al. (1975) reported that two women, receiving human menopausal gonadotrophins (HMG) for ovulation induction and suffering from severe OHSS, exhibited increased concentrations of factor V, platelets, fibrinogen, profibrinolysin and fibrinolytic inhibitors suggestive of increased risk of thrombosis. Todorow et al. (1993) performed a retrospective study assessing the changes in vWF in OHSS. They measured vWF-associated antigen (vWF.ag) and ristocetin cofactor activity (an indicator of vWF function). They found that women subsequently developing OHSS showed an increase in vWF.ag which persisted into the luteal phase following embryo transfer, where a decline was seen in unaffected women. Kaaja et al. (1989) had suggested that raised vWF could result from increased platelet adhesion potentiated by haemoconcentration and therefore could be an indicator of impending OHSS development. Todorow implied that, by measuring vWF.ag, OHSS could be predicted with its concomitant risk of thrombosis. Although studies have shown neutrophil-induced thrombogenic effects on endothelial cells (Pintucci et al., 1993; Kolpakov et al., 1994), and although Germond et al. (1996) have introduced the possibility of endothelial damage by activated polymorphonuclear leukocytes as a result of stressinduced leukocytosis in OHSS, neither have been further substantiated. Balasch et al. (1996) found that tissue factor expression by monocytes was induced by the plasma of nine

Thromboembolism risk and assisted reproduction

women with severe OHSS and suggest that this may play a role in thrombogenesis in this condition. Recently, important conditions which could potentiate the risk of thrombosis under conditions of relative hypercoagulability have been described — the thrombophilias. Thrombophilia The major thrombophilias comprise protein C, protein S and AT III deficiencies and the antiphospholipid syndrome, but by far the most important, described by Koster et al. (1993) and Bertina et al. (1994), is expression of factor V Leiden, resulting in activated protein C resistance. This condition, described in 5% of the Dutch population, has a similar incidence in the UK, and has a significant bearing on thromboembolic disease in all areas, e.g. the additional risk of DVT in a COCP user with factor V Leiden is 25 per 10 000 woman-years (Vandenbroucke et al., 1996). Only the most recently reported cases in the above series have specifically been investigated for thrombophilia. Horstkamp et al. (1996) reported a case where activated protein C resistance was subsequently exposed as a predisposing factor. Kligman’s case (Kligman et al., 1995) was specifically related to AT III deficiency. Huong et al. (1996) have reported a case of inferior vena caval and left renal vein thrombosis in a cycle of IVF complicated by known mixed connective tissue disease associated with features of systemic lupus erythematosus (SLE) including raised anticardiolipin antibodies. Beńifla et al. (1994) reported reduction in protein S in their case; however, this did not persist after delivery and was believed to be pregnancy-related, whilst one of the cases reported by Boulieu et al. (1989) was found to have reduced protein S concentration even after delivery. Otherwise findings have been negative or unreported. Other predisposing factors Thill et al. (1994) (and Aurousseau et al., 1995), in reporting three cases of thromboembolic disease in the absence of OHSS, argued that this is unlikely to occur without another predisposing factor. They stated that the coagulation changes related to hyperoestrogenism may not be enough to precipitate thrombosis alone and that by virtue of the biochemical and circulatory changes of severe OHSS, thromboembolism is precipitated. In their cases, other predisposing factors, previous DVT, ‘kinking’ of the internal carotid arteries and peritonitis were used to explain the occurrence of thromboembolism in these women. Boulieu et al. (1989) described a case of phlebitis of the right axillary and subclavicular veins in association with costoclavicular ‘nipping’ of the subclavicular vein. Five cases (Dalrymple et al., 1982–3; Boulieu et al., 1989; Thill et al., 1994; Benshushan et al., 1995; Stewart et al., 1997) had either a personal or family history of thromboembolic disease without evidence of familial thrombophilia. Site of thrombosis There is no clear explanation for the propensity to produce thromboses in unusual sites in these women where there appear

to be no specific local effects. In particular, central venous catheterization is not a prominent feature in the reported cases. It is possible that lower limb DVT is under-reported as it is ‘expected’, and thus alternative sites are disproportionately represented. It seems likely that multiple sites could be affected in the same woman although most cases report only one site or an extended site as opposed to two distinct thromboembolic events (PE excluded as a secondary event). Exceptions are reports by Kermode et al. (1993) and Mozes et al. (1965). Arterial and venous thromboses may be found to have different pathogeneses as the timing of these events appear to differ. Although the appearance of thrombosis is delayed in relation to clinical events when the reported cases are reviewed overall, it is of interest that arterial thrombosis appears to occur much earlier than venous thrombosis in the timescale of events. The mean timing, from HCG administration, of the occurrence of venous thrombosis in the case reports reviewed is 38 days, and of arterial thrombosis 14 days. It is clear that arterial thrombosis may result in serious sequelae particularly as most were intracerebral in origin. Stroke may have severe longterm disability as an outcome if survived. The one reported death occurred in this group (Mozes et al., 1965), whilst dysphasia and hemiparesis (Kermode et al., 1993), motor deficit of the upper limb (Neau et al., 1989) and coma, tetraplegia and aphasia (Humbert et al., 1973) have been the long-term outcomes recorded for some cases. Venous thrombosis is not usually fatal unless accompanied by significant pulmonary embolism or other thromboembolic events causing end organ damage. It is important to note, however, that although recanalization of vessels after DVT occurs as does the development of collateral vessels, there can be significant long-term morbidity following venous thrombosis which again may be disabling particularly in the upper limb. Tilney et al. (1970) reported that in a series of 48 cases of upper extremity DVT, 74% had residual disability up to 6 years later in the form of persistent discomfort, exerciseinduced cramp, cold hand and weakness. Conclusion Reported here have been cases of thromboembolic disease of an unusual nature and without specific aetiologies. It is hoped that by reviewing these cases, it has been brought to notice that this is a significant problem in relation to all methods of assisted conception treatment involving superovulation and ovulation induction. Significant research is required in order to elucidate the expected ‘normal’ coagulation changes occurring through treatment cycles and into early pregnancy including those cycles complicated by OHSS. In this way it is to be hoped that specific risk factors can be identified along with definition of the pathogenesis, such that these complications can be anticipated and thus avoided. At present best advice includes selecting out women who may be at greatest risk: those with a family history of thromboembolic disease, those developing OHSS and those in whom pregnancy is achieved. Serious thought must be given to the use of screening for thrombophilias. A recent article suggests that this is not cost-effective in COCP users 2171


(Vandenbroucke, 1996) and may deny some women the choice of effective contraception. However, as a short-term treatment, assisted conception is more amenable to prophylactic cover and therefore screening may be more important as discussed by Horstkamp and Spence (1996). The decision over whom to screen falls between everyone, a significant burden on laboratory resources, or only those with a personal or significant family history for whom the outcome may be critical. At periods of high risk, appropriate prophylaxis should be used including thrombosis deterrant stockings and s.c. heparin, and consideration should be given to continuation of this treatment throughout any resultant pregnancy (Beńifla et al., 1994) as short-term prophylactic measures may not be sufficient (Mills et al., 1992; Hignett et al., 1995; Stewart et al., 1997), particularly where thrombophilia has been detected (Horstkamp and Spence, 1996). At all times a high index of suspicion should be maintained to avoid delayed diagnosis and treatment of what is a potentially fatal yet completely iatrogenic condition. References Årstad, B.H., Bergsjø, P. and Eie, H. (1980) Hydatidiform mole with large ovarian cysts and venous thrombosis: a case report. Int. J. Gynaecol. Obstet., 17, 323–327. Aune, B., Høie, K.E., Øian, P. et al. (1991) Does ovarian stimulation for invitro fertilization induce a hypercoagulable state? Hum. Reprod., 6, 925–927. Aurousseau, M.H., Samama, M.M., Belhassen, A. et al. (1995) Risk of thromboembolism in relation to an in-vitro fertilization programme: three case reports. Hum. Reprod., 10, 94–97. Ayhan, A., Urman, B., Gu¨rgen, T. et al. (1993) Thrombosis of the internal jugular vein associated with severe ovarian hyperstimulation syndrome. Aust. NZ J. Obstet. Gynecol., 33, 436. Bachmeyer, C., Grateau, G., Bruel, D. et al. (1994) Thrombose de la veine jugulaire interne au cours d’un syndrome d’hyperstimulation ovarienne. Rev. Me´d. Interne, 15, 52–54. Balasch, J., Ta`ssies, D., Reverter, J.C. et al. (1996) Increased induced monocyte tissue factor expression by plasma from patients with severe ovarian hyperstimulation syndrome. Fertil. Steril., 66, 608–613. Beńifla, J.-L., Conard, J., Naouri, M. et al. (1994) Syndrome d’hyperstimulation ovarienne et thrombose. J. Gynecol. Obstet. Biol. Reprod., 23, 778–783. Ben-Shlomo, I., Azogui, G., Prober, A. et al. (1992) Axillary vein thrombosis during pregnancy: A case report. Obstet. Gynecol., 80, 495–497. Benshushan, A., Shushan, A., Paltiel, O. et al. (1995) Ovulation induction with clomiphene citrate complicated by deep vein thrombosis. Eur. J. Obstet. Gynecol. Reprod. Biol., 62, 261–262. Bertina, R.M., Koeleman, B.P.C., Koster, T. et al. (1994) Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature, 369, 64– 67. Boerger, L.M., Morris, P.C., Thurnan, G.R. et al. (1987) Oral contraceptives and gender affect protein s status. Blood, 69, 692–694. Bonnar, J. (1987) Coagulation effects of oral contraception. Am. J. Obstet. Gynecol., 157, 1042–1048. Boulieu, D., Ninet, J., Pinede, L. et al. (1989) Thrombose veineuse prećoce de sie`ge inhabituel, en de´but de grossesse apre`s hyperstimulation ovarienne. Contracept. Fertil. Sex., 17, 725–727. Bremme, K., Wramsby, H., Andersson, O. et al. (1994) Do lowered factor VII levels at extremely high endogenous oestradiol levels protect against thrombin production? Blood Coagul. Fibrinolysis, 5, 205–210. Burihan, E., de Figueiredo, L.F., Francisco Junior, J. et al. (1993) Upper extremity deep venous thrombosis: analysis of 52 cases. Cardiovasc. Surg., 1, 19–22. Chamberlain, R.A. and Cumming, D.C. (1986) Pulmonary embolism during clomiphene therapy for infertility in a male: A case report. Int. J. Fertil., 31, 198–199. Choktanasiri, W. and Rojanasakul, A. (1995) Acute arterial thrombosis after gamete intrafallopian transfer: A case report. J. Assist. Reprod. Genet., 12, 335–337.

2172

Colburn, P. and Buonassisi, V. (1978) Estrogen-binding sites in endothelial cell cultures. Science, 201, 817–819. Comp, P.C., Thurnan, G.R., Welsh, J. et al. (1986) Functional and immunologic protein S levels are decreased during pregnancy. Blood, 68, 881–885. Crooke, A.C., Butt, W.R., Carrington, S.P. et al. (1964) Pregnancy in women with secondary amenorrhoea treated with human gonadotrophins. Lancet, i, 184–188. Dalrymple, J.C., Smith, D.H., Sinosich, M.J. et al. (1982–3) Venous thrombosis with high estradiol levels following gonadotrophin therapy. Infertility, 5, 239–245. Delvigne, A., Demoulin, A., Smitz, J. et al. (1993) The ovarian hyperstimulation syndrome in in-vitro fertilization: a Belgian multicentric study. 1. Clinical and biological features. Hum. Reprod., 8, 1353–1360. de Swiet, M. (1989) Thromboembolism. In de Swiet (ed.), Medical Disorders in Obstetric Practice. Blackwell, Oxford, p. 167. Dumont, M., Combet, A. and Domenichini, Y. (1980) Thrombose arte´rielle ce´re´brale a` la suite d’une hyperstimulation ovarienne, grossesse sextuple. Avortement the´rapeutique. Nouv. Presse Med., 9, 3628–3631. el Kouri, D., Bani–Sadr, F., De Faucal, Ph. et al. (1995) Thrombose jugulaire apre`s hyperstimulation ovarienne: Une complication e´vitable? Presse Medicale, 24, 547. Fournet, N., Surrey, E. and Kerin, J. (1991) Internal jugular vein thrombosis after ovulation induction with gonadotrophins. Fertil. Steril., 56, 354–356. Germond, M., Wirthner, D., Thorin, D. et al. (1996) Aorto-subclavian thromboembolism: a rare complication associated with moderate ovarian hyperstimulation syndrome. Hum. Reprod., 11, 1173–1176. Hignett, M., Spence, J.E.H. and Claman, P. (1995) Internal jugular vein thrombosis: a late complication of ovarian hyperstimulation despite minidose heparin prophylaxis. Hum. Reprod., 10, 3121–3123. Hocke, C., Guyon, F., Dulucq, M.C. et al. (1995) Accidents thromboemboliques et hyperstimulation ovarienne. J. Gynecol. Obstet. Biol. Reprod., 24, 691–696. Horattas, M.C., Wright, D.J., Fenton, A.H. et al. (1988) Changing concepts of deep venous thrombosis of the upper extremity — report of a series and review of the literature. Surgery, 104, 561–567. Horstkamp, B. and Spence, J.E.H. (1996) Internal jugular vein thrombosis: a late complication of ovarian hyperstimulation syndrome. Hum. Reprod., 11, 1358–1359. Horstkamp, B., Lu¨bke, M., Kentenich, H. et al. (1996) Internal jugular vein thrombosis caused by resistance to activated protein C as a complication of ovarian hyperstimulation after in-vitro fertilization. Hum. Reprod., 11, 280–282. Hulinsky, I. and Smith, H.C. (1995) External jugular vein thrombosis: a complication of the ovarian hyperstimulation syndrome. Med. J. Aust., 162, 335–336. Humbert, G., Delauney, P., Leroy, J. et al. (1973) Accident vasculaire ce´re´bral au cours d’un traitement par les gonadotrophines. Nouv. Presse Med., 2, 28–30. Huong, D.L.T., Wechsler, B., Piette, J.-C. et al. (1996) Risks of ovulationinduction therapy in systemic lupus erythematosus. Br. J. Rheumatol., 35, 1184–1186. Inbar, O.J., Levran, D., Shlomo, M. et al. (1994) Ischemic stroke due to induction of ovulation with clomiphene citrate and menotropins without evidence of ovarian hyperstimulation syndrome. Fertil. Steril., 62, 1075– 1076. Inman, W.H.W., Vessey, M.P., Westerholm, B. et al. (1970) Thromboembolic disease and the steroidal content of oral contraceptives. A report to the committee on safety of drugs. Br. Med. J., 2, 203–209. Kaaja, R., Siegberg, R., Tiitinen, A. et al. (1989) Severe ovarian hyperstimulation syndrome and deep venous thrombosis. Lancet, ii, 1043. Kermode, A.G., Churchyard, A. and Carroll, W.M. (1993) Stroke complicating severe ovarian hyperstimulation syndrome. Aust. NZ J. Med., 23, 219. Kim, H.C., Kemmann, E., Shelden, R. et al. (1981) Response of blood coagulation parameters to elevated endogenous 17β-estradiol levels induced by human menopausal gonadotrophins. Am. J. Obstet. Gynecol., 140, 807–810. Kligman, I., Noyes, N., Benadiva, C.A. et al. (1995) Massive deep vein thrombosis in a patient with antithrombin III deficiency undergoing ovarian stimulation for in vitro fertilization. Fertil. Steril., 63, 673–676. Kodama, H., Matsui, T., Fukuda, J. et al. (1995) Characteristics of blood hemostatic markers in a patient with ovarian hyperstimulation syndrome who actually developed thromboembolism. Fertil. Steril., 64, 1207–1209. Kolpakov, V., D’Adamo, M.C., Salvatore, L. et al. (1994) Neutrophil derived cathepsin G induces potentially thrombogenic changes in human endothelial

Thromboembolism risk and assisted reproduction cells: a scanning electron microscopy study in static and dynamic conditions. Thromb. Haemost., 72, 140–145. Koster, T., Rosendaal, F.R., de Ronde, H. et al. (1993) Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet, 342, 1503–1506. Lox, C., Dorsett, J., Can˜ez, M. et al. (1995) Hyperoestrogenism induced by menotropins alone or in conjunction with luprolide acetate in in vitro fertilization cycles: the impact on hemostasis. Fertil. Steril., 63, 566–570. Mackie, M., Bennet, B., Ogston, D. et al. (1978) Familial thrombosis: inherited deficiency of antithrombin III. Br. Med. J., 1, 136–138. McPherson, K. (1996) Third generation oral contraception and venous thromboembolism. Br. Med. J., 312, 68–69. Mills, M.S., Eddowes, H.A., Fox, R. et al. (1992) Subclavian vein thrombosis: a late complication of ovarian hyperstimulation syndrome. Hum. Reprod., 7, 370–371. Mozes, M., Bogokowsky, H., Anteri, E. et al. (1965) Thromboembolic phenomena after ovarian stimulation with human gonadotrophins. Lancet, ii, 1213–1215. Neau, J.-Ph., Marećhaud, M., Guitton, P. et al. (1989) Occlusion de l’arte`re ce´re´brale moyenne lors d’une induction de l’ovulation par les gonadotrophines. Rev. Neurol. (Paris), 145, 859–861. Nwosu, U.C., Corson, S.L. and Bolognese, R.J. (1974) Hyperstimulation and multiple side-effects of menotropin therapy: a case report. J. Reprod. Med., 12, 117–120. O’Leary, P., Boyne, P., Flett, P. et al. (1991) Longitudinal assessment of changes in reproductive hormones during normal pregnancy. Clin. Chem., 37, 667–672. Ong, A.C.M., Elsen, V., Rennie, D.P. et al. (1991) The pathogenesis of ovarian hyperstimulation syndrome (OHS): a possible role for ovarian renin. Clin. Endocrinol., 34, 43–49. Phillips, L.L., Gladstone, W. and van de Wiele, R. (1975) Studies of the coagulation and fibrinolytic systems in hyperstimulation syndrome after administration of human gonadotrophins. J. Reprod. Med., 14, 138–143. Pintucci, G., Iacoviello, L., Castelli, M.P. et al. (1993) Cathepsin G-induced release of PAI-1 in the culture medium of endothelial cells: A new thrombogenic role for polymorphonuclear leukocytes? J. Lab. Clin. Med., 122, 69–79. Pride, S.M., James, C.St.J. and Yuen, B.H. (1990) The ovarian hyperstimulation syndrome. Semin. Reprod. Endocrinol., 8, 247–260. Rajah, R., Boothroyd, A. and Lees, W.R. (1991) Case of the month. A pain in the neck! Br. J. Radiol., 64, 867–868. Royal College of Obstetricians and Gynaecologists (1995) Management and prevention of ovarian hyperstimulation syndrome (OHSS). RCOG Guidelines, 5, 1–10. Rizk, B., Meagher, S. and Fisher, A.M. (1990) Severe ovarian hyperstimulation syndrome and cerebrovascular accidents. Hum. Reprod., 5, 697–698. Ryley, N.G., Forman, R., Barlow, D. et al. (1990) Liver abnormality in ovarian hyperstimulation syndrome. Hum. Reprod., 5, 938–943. Salat–Baroux, J., Cornet, D., Antoine, J.M. et al. (1987) Un cas de stimulation grave au cours d’une fećondation in vitro suivie de grossesse. Gynećologie, 38, 69–72. Schafer, A.I. (1985) The hypercoagulable states. Ann. Int. Med., 102, 814–828. Schenker, J.G. and Weinstein, D. (1978) Ovarian hyperstimulation syndrome: a current survey. Fertil. Steril., 30, 255–268. Stewart, J.A., Hamilton, P.J. and Murdoch, A.P. (1997) Upper limb thrombosis associated with assisted conception treatment. Human Reprod., 12, 2174– 2175. Strauss, H.S. and Diamond, L.K. (1963) Elevation of factor VIII (antihemophilic factor) during pregnancy in normal persons and in a patient with von Willebrand’s disease. N. Engl. J. Med., 269, 1251–1252. Thill, B., Rathat, C., Akula, A. et al. (1994) Accidents thrombo-emboliques lors des fećondations in vitro. Ann. Fr. Anesth. Reánim., 13, 726–729. Tilney, N.L., Griffiths, H.J.G. and Edwards, E.A. (1970) Natural history of major venous thrombosis of the upper extremity. Arch. Surg., 101, 792–796. Todorow, S., Schricker, S.T., Siebzenruebl, E.R. et al. (1993) Von Willebrand factor: an endothelial marker to monitor in vitro fertilization patients with ovarian hyperstimulation syndrome. Hum. Reprod., 8, 2039–2049. Vandenbroucke, J.P., van der Meer, F.J.M., Helmerhorst, F.M. et al. (1996) Factor V Leiden: should we screen oral contraceptive users and pregnant women? Br. Med. J., 313, 1127–1130. Vauthier-Brouzes, D., Lefebvre, G., Seebacher, J. et al. (1993) Thrombose veineuse jugulaire interne en cours de grossesse apre`s hyperstimulation ovarienne pour FIV. Contracept. Fertil. Sex., 21, 33–35. Waterstone, J.J., Summers, B.A., Hoskins, M.C. et al. (1992) Ovarian

hyperstimulation syndrome and deep cerebral venous thrombosis. Br. J. Obstet. Gynaecol., 99, 439–440. Wright, J.G., Cooper, P., Astedt, B. et al. (1988) Fibrinolysis during normal human pregnancy: complex inter-relationships between plasma levels of tissue plasminogen activator and inhibitors and the euglobulin clot lysis time. Br. J. Haematol., 69, 253– 258. Received on April 28, 1996; accepted on July 29, 1997

2173