Prevention of Maternal and Perinatal Complications by Enoxaparin in Women With Previous Severe Preeclampsia

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.

1. 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).
2. 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.
3. 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.
4. 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.