Department of Obstetrics and Gynaecology, Helsinki University Central Hospital, PO Box 140, FIN-00290 HUS Helsinki, Finland
1 To whom correspondence should be addressed. e-mail: terhi.saisto{at}hus.fi
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Abstract |
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Key words: hyperreactio luteinalis/low molecular weight heparin/preeclampsia/thrombophilia
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Introduction |
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Inherited thrombophilic disorders are associated with an increased risk of venous thromboembolism during pregnancy. Preliminary research suggested that these disorders might also increase the risk for preeclampsia (PE) (Kahn, 1998; Kupferminc et al., 2001
). PE is known to be associated with an imbalance in coagulation and fibrinolysis that results in a hypercoagulable state in both maternal and placental circulation (de Boer et al., 1988
; Estelles et al., 1991
). It has been suggested that the hypercoagulable state in severe PE is strongly related to the onset of intrauterine growth retardation (IUGR) through the deterioration of placental circulation. Furthermore, it has been suggested that patients with severe PE or IUGR and an inherited thrombophilia may benefit from prophylactic treatment with low molecular weight heparin (LMWH), probably combined with aspirin, in subsequent pregnancies (Kupferminc et al., 2001
). Previously, heparin or antithrombin (AT) therapy has been given to treat severe, early onset PE for 7 days, but neither treatment was able to postpone the delivery after the 32nd gestational week (Nakabayashi et al., 1999
).
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Case report |
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At gestational age 22 weeks and 5 days the patient was referred to our tertiary clinic because of severe PE [hypertension, proteinuria and extreme oedema in lower extremities (weight gained 8000 g in last 2 weeks)]. The reduced diuresis was normalized after 2 days forced oral administration of fluids. On ultrasound examination, the fetus was moving actively, and the measurements of biparietal diameter, abdominal circumference and femur length were all normal according to the gestational age. The amount of amniotic fluid was normal, and the placenta was thick and homogenous. The ultrasound examination revealed large ovaries, both up to 10 x 6 x 7 cm, with multicystic appearance without any solid components.
Because of a manifest severe PE of early onset, extreme oedema, immobilization and high levels of D-dimer (21 mg/l), therapy with LMWH was started at the dose of dalteparin 5000 IU/day at the gestational age of 23 weeks and 1 day. The values of the main parameters followed are shown in Table I.
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During the next 2 weeks, the patient lost 10 kg in weight, blood pressure was normalized to the level of 130/80 mmHg without any antihypertensives, and proteinuria diminished to the level of 1.3 g/day. The fetus grew as expected, and the mother was free of symptoms. After 4 weeks the patient was discharged from hospital, and the situation was monitored in the out-patient clinic every 1014 days. In serial ultrasound measurements the fetus grew normally, and cardiotocography tracings and Doppler measurements were normal. The size of the ovaries diminished slowly, being 4 x 5 cm at 37th gestational week. LMWH therapy was continued. Other values are shown in Table I.
At the gestational age of 38 weeks and 6 days the patient had spontaneous deliverery of a healthy girl weighing 3175 g. The delivery was otherwise uneventful, but the placenta had to be removed manually under general anaesthesia and the blood loss was 1500 ml. Unfortunately, we were unable to retain the placenta for further investigation. LMWH therapy was discontinued 6 weeks after delivery. At that time, the left ovary was normal sized, and the right ovary was enlarged (46 x 31 mm). All anti-DNA antibodies were again negative. Other main values are shown in Table I. Three months later the nephrologist reported normal renal function, with no signs of renal disease.
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Discussion |
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Many patients with hyperreactio luteinalis have undergone exploratory operations because of ovarian masses, or even oophorectomies during Caesarean sections (Wajda et al., 1989; Schnorr et al., 1996
; Bidus et al., 2002
). Usually the pregnancies have otherwise been uncomplicated, although predisposition to venous thrombosis has been reported in association with both iatrogenic and spontaneous OHSS (Kaaja et al., 1989
; Todros et al., 1999
; Dulitzky et al., 2002
). Hormonal changes in OHSS and hyperreactio luteinalis may contribute to alterations in coagulation factors and predispose to thromboembolic complications (Belaen et al., 2001
; Delvigne et al., 2002
). Todros et al. (1999)
reported one case with factor V Leiden mutation and deep venous thromboses with hyperreactio luteinalis, even while administering LMWH. Early severe PE has been diagnosed in a 25-year-old primigravida during gestational week 22, and both her ovaries had been enlarged for 6 weeks. In that case, the pregnancy was terminated due to worsening maternal conditions (Regi et al., 1996
). Our case is unique, with a combination of hereditary (factor V Leiden) and acquired (hyperreactio lutealis) thrombophilia, which lead to transient PE. We believe that the thrombotic process in the placenta was the key mechanism by which PE developed. The fibrin formation in the placenta was stopped by LMWH, as witnessed by normalization of D-dimer, and the pregnancy continued until term.
PE is most common in primigravidas, and its epidemiology suggests that genetic factors can be important in its pathogenesis (Dekker and Sibai, 1999). It is possible that increased thrombosis in the placenta impairs the normal transformation of spiral arteries, and thus heritable thrombophilias are to blame for at least some of the predisposition to PE. However, the evidence currently available shows no clear association between PE and thrombophilias, other than factor V Leiden in severe PE (Morrison et al., 2002
; Walker, 2002
).
The incidence of factor V Leiden mutation in Europe is 25% in unselected populations and 1020% in patients with venous thrombosis (Lockwood, 2002). Our patient did not have any previous or actual thrombosis, or any other risk factor for PE other than primigravidity. High D-dimer levels indicated at least subclinical activation of coagulation, and after administering the treatment, D-dimer levels continually decreased with resolving clinical symptoms. One of the major diseases excluded was renal vein thrombosis. Furthermore, no deep venous thrombosis of the legs was shown. One of the suspected sites for thrombosis could have been placenta, and after treatment with LMWH, no IUGR was observed. To our knowledge this is the first case where PE was cured by treatment with LMWH during pregnancy in a patient with inherited thrombophilia.
It has been suggested that screening for thrombophilia might be worthwhile in women with a family history of thrombosis who undergo infertility treatments and in women who develop severe OHSS (Dulitzky et al., 2002). Although in most of the cases this is done to avoid venous thromboembolic complications, in our case the site of thrombosis was placenta, which lead to severe, early onset PE. We would further suggest that women with severe, early onset PE are advised to be tested for both inherited and acquired thrombophilias (phospholipid antibodies), and that randomized controlled trials for LMWH treatment in severe, early onset PE should be conducted.
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References |
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Submitted on June 27, 2003; accepted on October 22, 2003.