Prevention of Maternal and Perinatal Complications by Enoxaparin in Women With Previous Severe Preeclampsia
Prevention of Maternal and Perinatal Complications by Enoxaparin in Women With Previous Severe Preeclampsia
Preeclampsia (PE) complicates 2-8% of pregnancies. It is associated with an increased risk of
 adverse maternal (death, eclampsia, abruptio placenta, HELLP syndrome) and perinatal
 (perinatal death, growth restriction, prematurity) outcomes. The only definite treatment of
 PE remains pregnancy termination. Therefore, prevention of PE remains an important challenge.
 Low dose aspirin may be used in the prevention of PE, particularly in women who had a severe
 preeclampsia before 34 weeks. Its efficiency, however, is very weak. Recently, it has been
 suggested that low molecular weight heparin might be useful in the prevention of PE.

 The aim of this study is to analyze the usefulness of the enoxaparin 4000 UI/day in the
 prevention of a composite maternal or perinatal morbidity (occurrence of one of the following
 events: maternal death, PE, fetal growth retardation, abruptio placenta, perinatal death) in
 women who previously had a severe preeclampsia at less than 34 weeks' gestation. To answer
 this question, the investigators propose to conduct a multicenter prospective randomized
 trial that will compare two groups in parallel: a group where women will have an association
 of enoxaparin 4000 U/day and aspirin 100 mg/day and another group where women would have only
 aspirin 100 mg/day. The number of patients needed is 255 (amendment n°2-approved 06/12/2011)
 .
1. Purpose of the study: To determine whether low molecular weight heparin (LMWH)
 enoxaparin decreases the rate of maternal and perinatal composite morbidity in women who
 previously had a severe preeclampsia that occurred at less than 34 weeks' gestation.

 2. Patients and methods: Multicenter, prospective, randomized trial comparing 2 groups of
 patients:

 -  First group treated with aspirin 100 mg/day until 35 weeks' gestation and
 enoxaparin subcutaneous 4000 UI/day until delivery.

 -  Second group treated with aspirin 100 mg/day alone until 35 weeks' gestation.

 At first prenatal visit between 7-13 weeks, inclusion and exclusion criteria will be
 searched. Randomization will be performed by internet software. It will be performed by
 center.

 After randomization at first prenatal visit patients will be allocated to
 aspirin-enoxaparin or aspirin alone as mentioned above. Enoxaparin will be stopped the
 day of delivery or after the occurrence of a complication that necessitates delivery.
 Pregnancy management will be performed as recommended by standard care. Each month,
 blood samples will be drawn for platelets count and the analysis of angiogenic factors
 (sFlt1, sEng, free PlGF and VEGF). In addition, blood sample will be drawn at first
 prenatal visit for thrombophilia work-up (Prot C, Factor V Leiden, Prothrombin gene
 polymorphism). Only results of platelet count will be given to local investigators
 during the study. All other analysis will be performed at the end of the study by Pr
 Gris at NIMES, and will be blinded to clinical results.

 3. Statistical analysis: Women with previous severe preeclampsia at less than 34 weeks'
 gestation have a 40% risk of occurrence of a composite morbidity (primary outcome
 defined above) at the next pregnancy. A 33% decrease of the composite morbidity defined
 above in women treated with LMWH enoxaparin is considered to be efficient. With an alpha
 risk of .05 and a beta risk of .20, the number of patients needed is 255 (amendment
 n°2-approved 06/12/2011) . This trial will be analyzed as an "Intention to treat study".
 No interim analysis for the primary outcome will be performed. Results will be
 stratified by center.

 Primary outcome (categorical variable) will be analyzed by chi-square test. Secondary
 outcomes will analyzed by chi-square test for categorical variables or ANOVA for
 continuous variables.

 Statistical significance will be considered with a p value <.05. Statistical analysis
 will be performed by STATA software (StataCorp, 2003, TX).

 4. Registry of non-included patients: Each patient that has been non-eligible for the trial
 will be noted in a registry as well as the reason of exclusion.

 5. Independent committee for analysis of adverse outcome: An independent committee will
 analyze adverse maternal and perinatal outcomes before statistical analysis at the end
 of the study. This analysis will be blinded for the treatment allocated for the
 patients.

 6. Definitions:

 -  Preeclampsia: Preeclampsia is defined by the association of gestational
 hypertension (after 20 weeks' gestation, a systolic blood pressure > 140 mmHg
 and/or a diastolic blood pressure > 90 mmHg, persistent at least at 4 hours apart,
 or a persistent diastolic blood pressure > 110 mmHg) and proteinuria (24 hours
 proteinuria > 300 mg, or at least 1+ persistent at least at 4 hours apart).

 -  Fetal growth restriction: Fetal growth restriction is defined by a birthweight <
 10th percentile.

 -  Abruptio placentae: Abruptio placenta is defined by the association of bleeding and
 one of the following criteria:

 -  Abnormal fetal heart rate,

 -  Abdominal pain,

 -  Perinatal death: Perinatal death is a death that occurs during fetal or neonatal
 Period, from 22 weeks' gestation until the 28th day of life.

 -  Severe preeclampsia is defined, in a woman with preeclampsia, by the presence of
 one of the following criteria:

 Maternal:

 -  Severe hypertension (systolic blood pressure >160 MmHg and/or diastolic blood pressure >
 110 mm Hg),

 -  Persistent headaches or visual disturbances,

 -  Persistent epigastric or RUQ pain,

 -  24 hours proteinuria ≥ 5gr,

 -  Oliguria < 500 ml/24h, or serum creatinine > 120 µmol/L,

 -  Eclampsia,

 -  Pulmonary edema,

 -  Abruption,

 -  Platelet count < 100,000/ µL,

 -  lactate dehydrogenase (LDH) > 600U/L, aspartate transaminase (ASAT) > 2 normal.

 Fetal:

 -  Severe fetal growth restriction (< 5ème percentile)

 -  Severe Oligohydramnios.
Inclusion Criteria:

 -  Patient ≥ 18 years

 -  Patient with a previous severe preeclampsia that occurred at less than 34 weeks'
 gestation

 -  Patient between 7 and 13 weeks +6 days at first prenatal visit

 -  Singleton pregnancy

 -  Affiliation to social security

 -  Informed consent given after receiving information on the study.

 Exclusion Criteria:

 -  Patient under law protection

 -  Inability to sign written consent

 -  Inability to follow the protocol because of a psychiatric disease

 -  History of deep venous thromboembolism during previous pregnancy

 -  Need of low molecular weight heparin during pregnancy

 -  Previous arterial thrombosis

 -  Patient having a cardiac valvular prosthesis that necessitates anticoagulation during
 pregnancy

 -  Renal failure (creatinine clearance < 30 ml/min, or serum creatinine > 180 µmol/L

 -  Previous hemorrhagic disease

 -  A disease that might bleed (gastric ulcer)

 -  Antiphospholipid antibody syndrome

 -  Allergy to Aspirin

 -  Allergy to heparins

 -  Thrombocytopenia related to heparin use

 -  Thrombocytopenia <100,000 /µL at first prenatal visit

 -  Antecedent of osteoporosis

 -  Inability to do subcutaneous injection of heparin

 -  Weight > 100 kg

 -  Patient included in another interventional trial

 -  Patient positive for anti-phospholipids antibodies

 -  Patient positive for HIV or HCV or HBS