Spontaneous ovarian hyperstimulation syndrome and deep vein thrombosis in pregnancy: Case report

T. Todros1,3, C.M. Carmazzi1, S. Bontempo1, P. Gaglioti1, V. Donvito2 and M. Massobrio1

1 Department of Gynecology and Obstetrics, University of Turin, Via Ventimiglia 3, 10100 Turin and 2 Department of Internal Medicine, Sant'Anna Hospital, Turin, Italy


    Abstract
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 Abstract
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 Case report
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This report describes a case of spontaneous ovarian hyperstimulation syndrome (OHSS) occurring in a pregnant woman carrying the factor V Leiden mutation. Even though prophylactic treatment for thrombo-embolism was adopted by administering low molecular weight heparin, the pregnancy was complicated by thromboses of the left subclavian, axillary, humeral and internal jugular veins during the second trimester of gestation. The pregnancy was managed conservatively and a healthy newborn was delivered at term. In order to avoid unnecessary laparotomy, we emphasize the importance of careful diagnosis in order to differentiate spontaneous OHSS from ovarian carcinoma, as well as the necessity to look for the presence of coagulation disorders in women affected by OHSS.

Key words: factor V Leiden mutation/pregnancy/spontaneous ovarian hyperstimulation syndrome/thrombo-embolism


    Introduction
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 Abstract
 Introduction
 Case report
 Discussion
 References
 
Ovarian hyperstimulation syndrome (OHSS) is a well known disease that complicates assisted reproduction procedures in approximately 10% of cases (Schenker and Ezra, 1994Go). In 1–2% it is severe (Smitz et al., 1990Go), with ovarian enlargement >10 cm, ascites, pleural effusion, reduction of intravascular volume and haemoconcentration. Venous or arterial thrombosis and renal and/or hepatic insufficiency may occur (Pride et al., 1990Go; Rizk and Aboulghar, 1991Go; Schenker, 1993Go). The main pathophysiological change responsible for OHSS development is thought to be an acute change in vascular permeability (Schenker, 1993Go; Elchalal and Schenker, 1997Go), although other authors suggest a key role for arteriolar vasodilation (Balasch et al., 1998Go) and for several ovarian factors, such as the ovarian renin-angiotensin system, cytokines or the vascular endothelial growth factor (VEGF)(Elchalal and Schenker, 1997Go; Rizk et al., 1997Go).

Severe OHSS associated with spontaneous pregnancy is extremely rare. We describe one case that was complicated by subclavian, axillary, humeral and internal jugular vein thromboses in a woman carrying the factor V Leiden mutation.


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 Case report
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A 30 year old nulligravid woman was referred to our department at 10 weeks gestation because bilateral ovarian cysts had been observed during a routine ultrasound scanning.

The woman had always been healthy, with regular menstrual cycles; she had not been on oral contraceptives nor had taken any other medication in the 6 months prior to conception. She had never taken drugs for ovulation induction. The family history was negative for metabolic, cardiovascular and thrombotic diseases.

Our ultrasound examination showed a normally developing fetus, enlarged multicystic ovaries (120x80 mm right, 150x110 mm left) and mild ascites. Colour and pulsed Doppler examination revealed normal uterine and ovarian vessels. A few days later she started complaining of abdominal pain. The ascites had moderately increased and X-ray examination of the chest showed mild, right pleural effusion. Laboratory testing revealed normal concentrations of haemoglobin, haematocrit, platelets, creatinine and blood urea nitrogen; the ß subunit of human chorionic gonadotrophin (ß-HCG) was below normal range for gestational age (40 600 IU/l). There were increased concentrations of oestradiol (9033 pg/ml), progesterone (750 ng/ml) and CA 125 (519 IU/ml). Clinical and laboratory findings are reported in Table IGo. We made the diagnosis of grade 3 moderate OHSS, according to Golan's classification (Golan et al., 1989Go).


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Table I. Clinical and laboratory parameters of the patient presented at different gestation times
 
The clinical conditions and the laboratory testing were stable during the following weeks. We started prophylactic treatment with low molecular weight heparin (0.3 ml s.c. every 24 h) at 11 weeks.

At 16 weeks we performed the triple test to screen for Down's syndrome. HCG, oestradiol and {alpha}-fetoprotein values were normal, giving a risk factor of 1:1200.

At 17 weeks the patient was admitted to hospital again because of pain and swelling of the left arm and neck. Doppler ultrasound revealed thrombosis in the left internal jugular vein in its proximal part and in the ipsilateral subclavian, axillary and humeral veins. The veins of the forearm were pervious. After deep vein thrombosis was diagnosed, coagulation parameters were assessed: PT, aPTT, and platelets were within normal ranges; antithrombin III activity was slightly reduced (Table IGo). Further examinations were carried out: antiphospholipid antibodies (IgG and IgM) were negative and the concentrations of protein C and protein S were within normal limits. We took this approach because deep vein thrombosis took place despite antithrombotic prophylactic treatment with low molecular weight heparin which had already been underway for several weeks. The concentration of activated protein C was below 2 SD of the mean. Molecular studies were then carried out by means of polymerase chain reaction (PCR) technique, which showed that the patient was a heterozygous carrier of a mutation (G1691) for factor V (factor V Leiden mutation). We started treatment with 30 000 IU/day of heparin i.v., and continued with 25 000 IU/day s.c. The symptoms regressed and at 19 weeks we substituted heparin with warfarin. We continued this therapy until 32 weeks gestation when we switched back to heparin (25 000 IU/day s.c.) until term. By 20 weeks the maximum ovarian diameter was 66 mm and the cysts were regressing. Doppler ultrasound examination of the epiaortic vessels at 23 weeks showed an almost complete disappearance of the thromboses. At 37 weeks the patient went into spontaneous labour and vaginally delivered a healthy male baby weighing 2640 g.

The dimension and structure of the ovaries were normal at the ultrasound scanning 3 months after delivery. Ovarian and thyroid function were normal as well, as indicated by the plasma concentrations of follicle stimulating hormone, luteinizing hormone, prolactin, oestradiol, testosterone, dehydroepiandrosterone sulphate, androstenedione, free triiodothyronine, free thyroxine and thyroid stimulating hormone (Table IIGo).


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Table II. Hormonal parameters of the patient presented, 3 months after delivery in early follicular phase
 

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This report describes one of five cases of normal singleton successful pregnancies following spontaneous OHSS (Ayhan et al., 1996Go; Lipitz et al., 1996Go; Olatumbosun et al., 1996Go; Abu-Louz et al., 1997Go; Di Carlo et al., 1997Go).

The physiopathological mechanism causing spontaneous OHSS has not yet been sufficiently explained. Some authors have postulated the existence of an underlying polycystic ovary syndrome in these cases, with the typical hormonal and ovulatory alterations associated with this dysfunction (Zalel et al., 1992Go, 1995Go). Relatively increased concentrations of oestradiol in the early follicular phase, high concentrations of androgens and lack of synchrony between follicular gathering and ripening have already been suggested as predisposing factors in patients undergoing ovulation induction treatments, but could also be implicated in the onset of the syndrome in non-stimulated cycles (Kemmann et al., 1981Go; Navot et al., 1988Go). However, our patient did not show any signs of hyperandrogenism or of polycystic ovary syndrome, as confirmed by the blood and ultrasound examinations we performed a few months after delivery (Table IIGo).

Endogenous HCG secreted by the trophoblast 7–8 days after fertilization might represent an additional factor in sustaining and exacerbating ovarian hyperstimulation (Zalel et al., 1992Go). Elevated concentrations of HCG and spontaneous OHSS have been described in twins (Leis et al., 1978Go) as well as in molar pregnancies (Hooper et al., 1966Go; Moneta et al., 1974Go; Cappa et al., 1976Go; Ludwig et al., 1998Go), but also in one case of normal singleton pregnancy (Rosen and Lew, 1991Go). On the other hand, normal concentrations of HCG are reported in spontaneous OHSS (Zalel et al., 1992Go; Abu-Louz et al., 1997Go) In our case HCG values were below the normal ranges at 10 and 16 weeks (Table IGo). Therefore, HCG may not be the trigger in every instance of OHSS.

The association of spontaneous OHSS with hypothyroidism was described in two case reports (Rotmensch and Scommegna, 1989Go; Nappi et al., 1998Go). In women with hypothyroidism, the elevated concentrations of thyroid-stimulating hormone may mediate an ovarian hyperstimulation because of the presence of nuclear thyroid receptors TR{alpha} and TRß in the granulosa cells. In this case the hormonal tests for thyroid function were normal 3 months after delivery (Table IIGo).

We considered terminating the pregnancy. However, since the aetiology and pathogenesis of the disease is unknown, we could not provide any statistics about its recurrence risk. Of course, we first excluded diagnoses of molar pregnancy and ovarian cancer; the former because the ß-subunit HCG concentrations were low, the latter because the ultrasonographic examination revealed the classic `spokewheel' appearance that is characteristic of theco-luteal cysts, while colour-Doppler analysis of the ovarian vessels excluded the presence of pathological flow. Serum CA 125 measurements were not useful for the differential diagnosis since they were elevated, as expected in patients with gross ovarian enlargement We therefore chose conservative management, which was accompanied by strict observation of the patient within the hospital environment.

The deep venous thrombosis that occurred during the second trimester is the first vascular accident resulting from spontaneous OHSS to be reported in literature. Venous and arterial thromboses of the inferior limbs or of the jugular vein, subclavian vein and upper limbs are indeed serious and not infrequent complications in cases of OHSS that are induced by pharmacological stimulation of ovulation (Beniflà et al., 1994Go; Aurousseau et al., 1995Go). When involving the upper parts of the body they are believed to be mainly due to haemoconcentration (Fournet et al., 1991Go; Mills et al., 1992Go; Beniflà et al., 1994Go).

Since our patient's haemoglobin and haematocrit values were within the normal range, we looked for other possible causes and found the factor V Leiden mutation.

It has been demonstrated that the mutation of factor V Leiden is the most frequent genetic predisposition to thrombosis (Bertina et al., 1994Go; Dahlbak, 1994). The mutation consists of a change to a single nucleotide in the gene that codes factor V, which in turn causes an amino acid substitution (glutamine for arginine) in position 506 of the molecule. This mutation makes factor V resistant to proteolytic inactivation by activated protein C, causing the predisposition to thrombosis. Svensson and Dahlback (1994) believe that carriers of such a mutation are at a frequency of 2–4% in the general population. However, the percentage reaches 40–60% among individuals having a personal or family history of thrombosis (Svensson and Dahlback, 1994Go). These percentages are similar to those verified in a group of healthy, pregnant women (Dizon-Townson et al., 1997Go). The occurrence of thrombosis of the internal jugular veins in patients affected by OHSS associated with Leiden factor V mutation was described in two cases who underwent in-vitro fertilization procedures (Horstkamp et al., 1996Go; Ellis et al., 1998Go). It is therefore difficult to say whether the thrombotic event in these cases is mainly due to the factor V Leiden mutation or to the simultaneous presence of the mutation and OHSS.

Our case emphasizes the fact that thrombotic prophylaxis does not always prevent thrombosis: Hignett (Hignett et al., 1995Go) described a case of iatrogenic OHSS with internal jugular vein thrombosis despite the administration of heparin.

In conclusion, when OHSS concomitant with spontaneous pregnancy is diagnosed, continuation of the pregnancy should be encouraged. Prophylactic treatment for thrombosis should be started and other possible risk factors investigated. If any are found, anticoagulant therapy must be considered.


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    References
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 Abstract
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 Case report
 Discussion
 References
 
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Submitted on March 1, 1999; accepted on May 13, 1999.