Low molecular weight heparin (Fragmin) in pregnant women with a history of uteroplacental insufficiency and thrombophilia, a randomized trial
(FRUIT - study)
Investigator: J.J. Kalk, MD
Supervisor: J.I.P. de Vries, MD, PhD
H.P. van Geijn, MD,PhD
Division of Maternal-Fetal Medicine
Department of Obstetrics & Gynecology
P.C. Huijgens, MD,PhD
Department of Hematology
P.D. Bezemer, PhD.
Department of Epidemiology & Biostatistics
University Hospital Vrije Universiteit Amsterdam
Other participants:
A. Franx, MD, PhD J. van Eyck, MD, PhD
H.W. Bruinse, MD, PhD. H.H. de Haan, MD, PhD
Department of Obstetrics & Gynecology Department of Obstetrics & Gynecology
Academic Hospital Utrecht Isala Hospital Zwolle, locatie Sophia
E. van Beek, MD, PhD. J.M. Middeldorp, MD
Department of Obstetrics & Gynecology Department of Obstetrics &Gynecology
Academic Hospital Nijmegen, St Radboud Leiden University Medical Center
H. Wolf, MD, PhD. W. Visser, MD, PhD.
J.A.M. van der Post, MD, PhD C.J. de Groot, MD, PhD
Department of Obstetrics & Gynecology Department of Obstetrics & Gynecology
Academic Medical Center Academic Hospital Rotterdam, Dijkzigt
S.G. Oei, MD,PhD L.L.H. Peeters, MD, PhD.
Department of Obstetrics & Gynecology Department of Obstetrics &Gynecology
St Joseph Hospital, Veldhoven Academic Hospital Maastricht
G.A. Dekker, MD, PhD, FRACOG E.C.M. van Pampus, MD,PhD
Bill Hague, MD FRACOG, FRACP Department of Hematology
Department of Obstetrics & Gynecology Academic Hospital Maastricht
North Western Adelaide Health Service,
The Lyell McEwin Hospital & P. Hummel, MD, PhD
The Queen Elizabeth Hospital Department of Obstetrics &Gynecology
University of Adelaide, South Australia Medical Center Alkmaar
M.G. van Pampus, MD, PhD
J.T.J. Brons, MD, PhD M.P. Heringa, MD, PhD
Department of Obstetrics &Gynecology Department of Obstetrics &Gynecology
Medical Spectrum Twente, Enschede Academic Hospital Groningen
Protocol 20-01-2000
Summary
The aim of the study is:
Primary: Does preventive treatment with low-molecular-weight heparin reduce the occurrence of preeclampsia in women with thrombophilia and a history of preeclampsia before 34 weeks of pregnancy.
Secondary: A reduction of recurrence of small for gestational age infants in women with a history of small for gestational age infants before 34 weeks and thrombophilia.
Trial:
Multi-center open two-armed randomized study.
Intervention of the trial:
The verum group will receive low-molecular weight heparin (Fragmin, subcutaneously 1 x 5000 IU AXA per day) + low dose acetylsalicylacid (ASA 80mg). Fragmin is started as early as possible between six and twelve weeks gestation, after ultrasound confirmation of a viable intrauterine pregnancy. Fragmin will be continued until six weeks post partum. ASA is given from 12 weeks gestation till 36 weeks gestation. The control group will receive ASA and standard care that is normally given to these high-risk pregnancies.
Population
The recurrence rate of preeclampsia is 35% and small for gestational age infants 21% as recently studied in a Dutch population with a prior pregnancy with severe early onset preeclampsia or small for gestational age infants (before 34 weeks gestation) and coagulation abnormalities, being treated with or without low-molecular-weight heparin and aspirin.
To detect a 50% reduction from 35% recurrence rate of preeclampsia 262 patients will be randomized, aiming for 131 + 131 patients in the 2 arms of the study (2-tailed, an alpha of 0.05 and a power of 80%). Recurrence rate of uteroplacental insufficiency in women with antiphospholipid antibodies is 60%. To detect a 50% reduction from 60% recurrence rate of uteroplacental insufficiency 84 patients will be randomized, aiming for 42 + 42 patients in the 2 arms of the study (2-tailed, an alpha of 0.05 and a power of 80%).
Analysis
Differences between the groups treated with low-molecular weight heparin and aspirin versus aspirin only will be assessed, accounting for prognostic factors, with the Mantel-Haenszel method or with logistic regression. Quantitative analysis will be assessed with linear regression.
Introduction
The aim of this trial is to evaluate the effects of low-molecular-weight heparin in pregnant women with thrombophilia and a history of uteroplacental insufficiency before 34 weeks.
Occurrence
Nowadays, uteroplacental insufficiency resulting in preeclampsia, hemolysis, elevated liver enzymes and low platelets (HELLP syndrome), eclampsia, intra-uterine growth restriction and preterm birth is one of the major problems in perinatal medicine. Hypertensive disorders of pregnancy occur in 15-20% of pregnancies and preeclampsia in approximately 3-5%. The latter is a major cause of maternal mortality in the United States and other developed countries.1 In the Netherlands, it is estimated that about 2000 (1%) of all pregnant women per year (200.000 births) develop severe complications due to uteroplacental insufficiency.
Clinical features
Maternal and fetal morbidity and mortality are a major problem especially in early preeclampsia before 34 weeks. Uteroplacental insufficiency is associated with endothelial cell dysfunction resulting in widespread vasoconstriction, plasmavolume reduction, hypertension and localized intravascular coagulation. Eventually the end result is hypoperfusion of maternal organs and further impairment of placental bloodflow. 2
Maternal risks vary from headache, impaired vision, edema, nausea, upper abdominal pain to eclampsia, intracranial hemorrhage, liver rupture, disseminated intravascular coagulation, adult respiratory distress syndrome and multiple organ failure.3 These complications still account for the major proportion of the maternal mortality rate in Western countries.4
Perinatal morbidity and mortality are related to both the intra-uterine growth restriction as well as to (often iathrogenic) prematurity. Intra-uterine growth restriction is a major health issue since impaired fetal growth is not only associated with short term morbidity, but also with an increased incidence of hypertension, coronary artery disease and diabetes in adult life, the so-called insulin resistance syndrome (syndrome-X) initially described by Barker.5;6 Uteroplacental insufficiency with or without abruptio placentae may also cause intrauterine fetal death.
Etiology
The exact cause of uteroplacental insufficiency is unknown, a multifactorial origin is suggested. Immune maladaption (fetal-maternal) as well as genetic factors are probably involved in its etiology7, and there is more or less consensus that endothelial cell dysfunction/activation represents the final common pathway in the maternal syndrome preeclampsia. It is known that in women with diseases inducing vessel wall damage (diabetes mellitus, chronic hypertension, systemic lupus erythematosis) the incidence of uteroplacental insufficiency is increased. More recently several investigators confirmed the presence of thrombophilic disorders in a substantial percentage of women with a history of severe early onset preeclampsia, severe intra-uterine growth restriction and/or abruptio placentae in the absence of a history of arterial or venous thrombosis. 8-10
The thrombophilic factors examined are coagulation abnormalities, hyperhomocysteinemia and antiphospholipid antibodies. For this study we focus on coagulation abnormalities. To elucidate inclusion and exclusion criteria the current knowledge on hyperhomocysteinemia and antiphospholipid antibodies in relation to pregnancy is described as well.
Coagulation abnormalities
Deficiencies and/or some mutations in the pro- and anticoagulant route are known to be associated with a marked increase in thrombotic disorders. From the procoagulant route the Factor (f) XII deficiency, f II mutation and from the anticoagulant pathway protein S deficiency, protein C deficiency, activated protein C (aPC) resistance (with or without the factor V Leiden mutation) are most frequently involved. Antithrombin III deficiency is rare, which probably reflects the fact that antithrombin is the main physiological coagulation inhibitor. Percentages of coagulation abnormalities in general population are described in tabel 1. Percentages of coagulation abnormalities in women with normal progeniture are described in tabel 2. Table 3 and 4 summarize the coagulation abnormalities in women with a history of preeclampsia and small for gestational age, respectively. The data are derived from the following studies.
Kupferminc et al10 studied 110 women who had one of the obstetrical complications such as severe preeclampsia, abruptio placentae, fetal growth retardation, and stillbirth associated with intervillous or spiral artery thrombosis and inadequate placental perfusion. These women were compared with 110 women with normal pregnancies. Women with serious obstetrical complications have an increased incidence of mutations predisposing them to thrombosis and other inherited and acquired forms of thrombophilia (tabel 2-4).
Dekker et al 8 showed that in a group of 101 patients with severe early-onset preeclampsia 38.6% had chronic hypertension. Of the 85 patients tested for protein S deficiency 24.7% were positive, of the 50 patients tested for activated protein C resistance, 16% were positive. 95 patients were tested for anticardiolipin antibodies; 29.4% had detectable immunoglobulin G and/or M anticardiolipin antibodies. Riyazi11 enlarged this group and found the same percentages (tabel 3 and 4). Van Pampus et al12 also found a high incidence in coagulation abnormalities and hyperhomocysteinemia in women with severe preeclampsia and HELLP-syndrome.
De Vries et al 9 demonstrated in a group of 62 women with a history of placental abruption, intrauterine fetal death or small for gestational age infants without hypertensive disorders that there was a high incidence of coagulation abnormalities, anti-phospholipid antibodies and hyperhomocysteinemia (tabel 4).
>From the above mentioned coagulation abnormalities all will be included in this study except for antithrombin deficiency. In contrast to the other anomalies the latter is known to induce recurrent thrombosis under low-risk thrombotic circumstances. All women with antithrombin deficiency and pregnancy will be treated with anticoagulants.
Hyperhomocysteinemia has also been identified as an additional risk factor to develop preeclampsia, small for gestational age infants/or abruptio placentae. In most patients the metabolic defect can be treated with vitamin suplementation (folic acid with or without pyridoxine) 13. The reason to describe this metabolic disease lays in the fact that women with hyperhomocysteinemia in combination with one of the earlier described coagulation abnormalities are included in the study, whereas women with only hyperhomocysteinemia are excluded.
A randomized study of Rai et al 14 demonstrated the positive effects of unfractionated heparin (Calciparin) and low-dose aspirin on pregnancy outcome in women with recurrent miscarriages associated with antiphospholipid antibodies, however with unknown coagulation abnormalities or hyperhomocysteinemia.
Tabel 1. Thrombophilia in men and women in a general population
Antithrombin deficiency / 0.1% 15
Protein C deficiency / 0.1-0.3% 16
Activated protein C resistance / 3.0-7.0% 17
Protein S deficiency / 0.2-2.0% 18
Factor II mutation / 0.0-4.0% 19
Hyperhomocysteinemia / 2.0-5.0% 20-22
Anticardiolipin antibodies / 1.0-3.0% 23;24
Tabel 2. Two studies of thrombophilia in women with uncomplicated pregnancies.
Kupferminc (n=110)10 / V Pampus (n=65) 12AT def / 1/110 = 0.9% / -
aPCR / - / 0/65 = 0.0%
fVL mut / 7/110 = 6.4% / 1/65= 1.5%
PS-def / 1/110 = 0.9% / 6/65 = 9.2%
fII-mut / 3/110 = 2.7% / -
HHC / 9/110 = 8.2% / 3/65 = 4.6%
ACA ³ 10 GPL/MPL
ACA ³ 20 GPL/MPL / 5/67 = 7.5%
1/67 = 1.5%
ACA / 0/110 = 0% / -
AT def = antithrombin deficiency; aPCR = activated protein C resistance; fVL = factor V Leiden mutation; PS-def = protein S deficiency; fII-mut = factor II mutation; HHC = hyperhomocysteinemia; ACA= anticardiolipin antibodies
Tabel 3. Four studies in women with a history of preeclampsia
Kupferminc(n=34)10 / Van Pampus
(n=251)12 / Riyazi
(n=242)11 / Leeda
(n=204)13
ATIII-def / - / - / 4/216 = 1.9% / -
PC-def. / - / - / 1/215 = 0.5% / -
APCR / - / <28 weeks 16%
>28 weeks 10% / 18/179 = 10.1% / -
FVL-mut. / 9/34 = 26.5% / <28 weeks 8%
>28 weeks 6% / - / -
PS-def. / - / <28 weeks 19%
>28 weeks 10% / 52/217 =23.5% / -
FII-mut / 2/34 = 5.9% / - / - / -
HHC / 7/34 = 20.6% / <28 weeks 19%
>28 weeks 11% / - / 32/181 = 17.7%
ACA ³10 GPL/MPL
ACA ³20 GPL/MPL / <28weeks 27.4%
>28weeks 19.3%
<28weeks 1.6%
>28weeks 3.5%
ACA / - / - / 52/216 = 24.1%
AT def = antithrombin deficiency; PC-def = protein C deficiency; aPCR = activated protein C resistance; fVL = factor V Leiden mutation; PS-def = protein S deficiency; fII-mut = factor II mutation; HHC = hyperhomocysteinemia; ACA= anticardiolipin antibodies
Tabel 4. Four studies in women with a history of small for gestational age infants
Kupferminc10(n=44) / De Vries 9
(n=13) / Leeda 13
(n=26) / Riyazi 11
(n=34)
ATIII-def / - / 0/13 = 0% / - / 0/29 = 0.0%
PC-def / - / 1/13 = 7.7% / - / 2/29 = 6.9%
APCR / - / 2/8 = 25.0% / - / 2/24 = 8.3%
fVL-mut / 5/44 = 11.4% / 1/8 = 12.5% / - / -
PS-def / - / 3/13 = 23.1% / - / 7/29 = 24.1%
fII-mut / 5/44 = 11.4% / - / - / -
HHC / 12/44 = 27.3% / 5/13 = 38.5% / 5/26 = 19.2% / -
ACA / - / 1/13 = 7.7% / - / 7/31 = 22.6%
AT def = antithrombin deficiency; PC-def = protein C deficiency; aPCR = activated protein C resistance; fVL = factor V Leiden mutation; PS-def = protein S deficiency; fII-mut = factor II mutation; HHC = hyperhomocysteinemia; ACA= anticardiolipin antibodies
Recurrence rate
The recurrence rate is derived from a Dutch retrospective study. Obstetricians from 9 hospitals in The Netherlands who decided to participate in the prospective trial evaluated the outcome of the pregnancy after the index pregnancy with preeclampsia or small for gestational age infants before 34 weeks (Kalk et al). 25 In total 1146 women with such an obstetric history were tested and 410 (35%) were found to have coagulation abnormalities and/or anticardiolipin antibodies and/or hyperhomocysteinemia. Only 51 women with coagulation abnormalities, but no anticardiolipin antibodies had a consecutive pregnancy and in 35% preeclampsia and in 21% small for gestational age infants recurred. The treatment in the following pregnancy was with either low-molecular-weight heparin (Fraxiparin 2x 2850 units per day) plus aspirin (80 mg) (n=22) or aspirin only (n=19) or nothing (n=10). It is not known if the medical treatment in the different clinics was started at the same gestational age. Within the limits of this small retrospective studied population no significant difference was found in the recurrence rate of preeclampsia or small for gestational age infants between the group who received low-molecular weight heparin and the group that did not.
This multi-center study is supported by the smaller study of Riyazi et al.11 They tested a total of 276 patients with a history of preeclampsia and/or fetal growth restriction for the presence of coagulation abnormalities and anticardiolipin antibodies. Ninety patients with preeclampsia and 15 patients with isolated fetal growth restriction had haemostatic abnormalities. In 26 patients a subsequent pregnancy occurred and they were treated with low-molecular-weight heparin and low-dose aspirin. Preeclampsia recurred in 38%, and intra-uterine-growth restriction in 15 % of pregnancies.