1 Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tsukuba, 11-1 Tennodai, Tsukuba, Ibaraki 305 and 2 Departments of Obstetrics and Gynecology, Metropolitan Aoyama Hospital, 5533 Jingumae, Shibuya-ku, Tokyo 1500001, Japan
3 To whom correspondence should be addressed. e-mail: sato{at}sohda.com
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Abstract |
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Key words: acquired haemophilia/assisted conception/factor VIII inhibitor/OHSS
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Introduction |
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Case report |
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Three days after embryo transfer, the patient complained of acute abdominal distension, nausea and vomiting. Her systolic blood pressure had dropped to 50 mmHg, and her diastolic blood pressure and pulse rate were undetectable. Transvaginal ultrasound revealed bilateral ovarian enlargement and massive ascites. Laboratory studies disclosed the following values: white blood cell count, 32.5 x 103/mm3; haematocrit, 48.5%; and haemoglobin, 16.7 g/dl. These signs and symptoms suggested severe OHSS. The patient was admitted to our hospital for observation and treatment.
On admission to our intensive care unit, the patient received a large volume of plasma expander and dopamine hydrochloride to correct her hypovolaemic shock. She received 3000 ml of plasma protein fraction for 6 days and 25 g of human serum albumin for 2 days together with furosemide to prevent acute renal failure. She recovered from the hypovolaemic shock on hospital day 14.
Her pregnancy test was positive 17 days after embryo transfer. Her abdominal distension and dyspnoea became more severe. Abdominal paracentesis and thoracocentesis were performed, and 3600 ml of ascitic fluid and 600 ml of pleural effluent were drained respectively.
On hospital day 29, the symptoms of OHSS lessened and the patient gradually improved, but she developed gross haematuria and ecchymosis on her right leg. Laboratory values at this time were haemoglobin, 8.0 g/dl; platelet count, 612 x 109/l; prothrombin time (PT), 12.3 s (control, 13.7 s); activated partial thromboplastin time (aPTT), 95.5 s (control, 34.4 s); and bleeding time, 5.0 min (normal reference, 27.5 min). Haematological evaluation revealed the presence of a clotting inhibitor. The patient had a factor VIII level of 2.5% (normal reference, 60145%). The test result for factor VIII inhibitors was positive, the inhibitor level was 10.0 Bethesda units (BU). Test results of rheumatoid factor, antinuclear antibody and anticardiolipin IgG were all normal or negative. We made a diagnosis of acquired haemophilia.
The patient was given an i.v. dose of 50 IU/kg of factor VIII inhibitor bypassing agent (FEIBA) to achieve haemostasis. After she received the FEIBA therapy, both the amount of gross haematuria and the size of the ecchymosis decreased. Her factor VIII inhibitor titre gradually decreased and then disappeared. Her subsequent hospital stay was uneventful, and the patient was discharged 10 weeks after her initial admission.
The patients pregnancy was complicated by pre-term labour at 32 weeks gestation culminating in the spontaneous vaginal delivery of a healthy boy. On the day of delivery, coagulation studies showed an aPTT of 44.0 s (control, 36.7 s), a factor VIII level of 80% and no detectable factor VIII inhibitor.
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Discussion |
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OHSS, which occurs in 110% of the IVF cycles and in <4% of cycles for ovulation induction, is the most serious complication of assisted conception (Myrianthefs et al., 2000
). Severe OHSS is a life-threatening condition and continues to be the most serious complication of controlled ovarian stimulation. Severe OHSS is further defined by renal failure, thromboembolic phenomena and adult respiratory distress syndrome. The mechanisms for the development of OHSS are still not clear. The characteristic features of OHSS are cystic enlargement of the ovaries and fluid loss from capillaries into the extravascular compartment leading to dehydration, hypovolaemia, haemoconcentration, oedema, ascites, hydrothorax, dyspnoea, electrolyte imbalance, abdominal distension and pain. These findings may be due to increased capillary permeability and new capillary vessel formation (Tollan et al., 1990
). Haemorrhage is a rare symptom in OHSS.
Most patients with acquired haemophilia present with spontaneous bleeding into muscle or soft tissue or with ecchymoses. Bleeding is usually severe and occurs concurrently at several different anatomical sites (Morrison and Ludlam, 1995). Lottenberg et al. reported that they had observed two deaths directly due to severe bleeding associated with acquired haemophilia (Lottenberg et al., 1987
). The aPTT is greatly prolonged, but the bleeding time and platelet count are normal in patients with acquired haemophilia. Clotting factor VIII activity decreases and the factor VIII inhibitor level increases. Because of a delay in diagnosis, patients with acquired factor VIII inhibitor have a greater risk of death due to uncontrolled haemorrhage than do haemophilia patients with inhibitors. Mortality due to haemorrhage in these cases varies between 12 and 22% in some reports (Green, 1999
).
The primary aim of medical management of patients with acquired haemophilia is to control the acute bleeding. Factor VIII concentrate may reverse the effects of acquired haemophilia in mild cases where inhibitor titres are low. If a patient has a higher titre of factor VIII antibodies and severe bleeding occurs, then the patient must be treated with recombinant factor VIII or, alternatively, FEIBA, an activated prothrombin complex concentrate (PCC) that includes factor IX and activated factor VIIa. FEIBA may be beneficial (Morrison et al., 1993; Shobeiri et al., 2000
), but its haemostatic effect is not well understood, and the safety of FEIBA therapy in pregnant women has not yet been established. Some concerns exist regarding the risk of adverse effects such as disseminated intravascular coagulation, acute myocardial infarction or viral infection, particularly hepatitis B and C.
The secondary aim of medical management is to accelerate the disappearance of the factor VIII inhibitors. This may be achieved with immunosuppressive drugs such as corticosteroids, cyclophosphamide or azathioprine, and immunotherapy (Shobeiri et al., 2000).
In this case, we could have avoided the OHSS by not using hCG during the luteal phase, because this patient had three known risk factors for OHSS; estradiol slope, estradiol level and number of oocyte retrieval. Also the luteal phase administration of human hCG was associated with a higher incidence of severe OHSS than was supplementation with progesterone alone (McClure et al., 1992). Progesterone is the product of choice as it is associated with a lower incidence of OHSS. The most recent studies are very clear regarding the treatment choice of the luteal supplementation with or without risk factor of OHSS by progesterone, because of no differences in outcomes (Penzias, 2002
).
Acquired haemophilia is a life-threatening disorder. Low levels of factor VIII inhibitors have been detected in 17% of healthy individuals who have no clinical symptoms and no other biological abnormalities (Algiman et al., 1992). It is worthwhile to measure factor VIII activity and its inhibitor in patients with bleeding and a prolonged aPTT but with a normal bleeding time and a normal platelet count, even in patients with OHSS. Further study is needed to understand the role of acquired haemophilia in OHSS.
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References |
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Submitted on August 27, 2002; accepted on November 20, 2002.