Predictors of Pregnancy Outcome in Systemic Lupus Erythematosus (SLE) and Antiphospholipid Syndrome (APS)

Study Overview
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Brief Summary
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The PROMISSE Study is an observational study of 700 pregnant patients, enrolled at nine major clinical centers. The purpose of the study is 1) to determine whether certain proteins (called complement split products) that can injure healthy organs can be used to predict poor pregnancy outcome in patients with systemic lupus erythematosus (SLE) and anti-phospholipid syndrome (APS), and/or 2) to determine whether elevated levels of circulating antiangiogenic factors predict pregnancy complications in patients with aPL antibodies and/or SLE.

Detailed Description
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Thrombosis and pregnancy loss are common features of systemic lupus erythematosus (SLE), particularly in the presence of antiphospholipid (aPL) antibodies. The in vivo mechanisms by which aPL antibodies lead to vascular events and, specifically, to recurrent fetal loss are largely unknown. Studies in a mouse model of antiphospholipid antibody syndrome (APS) indicate that in vivo complement activation is necessary for fetal loss caused by aPL antibodies. This study represents an effort to translate these research observations on the potential role of complement activation in the pathogenesis of aPL antibody-mediated pregnancy loss to a clinically relevant human study. In addition, studies in humans and mice have shown 1) that the balance of circulating angiogenic and antiangiogenic factors predicts preeclampsia and fetal growth restriction in healthy women, 2) circulating antiangiogenic factors cause endothelial dysfunction and abnormal placental development in animal models, and 3) complement activation leads to elevated levels of circulating antiangiogenic factors and complement inhibition prevents increased levels of antiangiogenic factors, placental dysfunction and fetal growth restriction in a mouse model of APS. This study will permit testing the hypothesis that, like in healthy women, the balance of circulating angiogenic and antiangiogenic factors predict complications in women with SLE and APS and to translate the findings in animal models into humans. The PROMISSE Study is a prospective observational study that will follow 700 pregnant patients who will be grouped and analyzed according to the presence or absence of aPL antibodies and preexisting SLE. The patients are followed regularly during the course of the pregnancy, collecting medical and obstetrical information as well as serial blood specimens for complement and cytokine assays. The data obtained will be analyzed and used to identify mechanisms and predictors of poor fetal outcome. We expect that the insights provided through this study will suggest means to prevent, arrest or modify these conditions.

Official Title
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Predictors of Pregnancy Outcome in Systemic Lupus Erythematosus (SLE) and Antiphospholipid Syndrome (APS)

Conditions
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Systemic Lupus Erythematosus, Antiphospholipid Syndrome

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient pregnant with live intrauterine pregnancy, as defined by positive test for elevated β-HCG, but ≤ 12 weeks by gestation (for subjects without aPL antibodies) and ≤18 weeks (for subjects with aPL antibodies) Patient between the ages of 18-45 and able to give informed consent, or age < 18 years with parental consent Hematocrit > 26% For APL positive: aCL: IgG >= 40 GPL units; IgM >= 40 MPL units Positive LAC (RVVT, Kaolin, dilute TTI or PTT LA) Anti-β2GPI: IgG >= 40 GPL units; IgM >= 40 MPL units For control subjects: At least one successful pregnancy No history of fetal death (death of conceptus ≥ 10 weeks' gestation) No more than 1 miscarriage < 10 weeks' gestation No history of positive aPL in local lab or positive aPL in core labs at screening Not currently a smoker No medical problems requiring chronic treatment Exclusion Criteria: Diabetes mellitus (Type I and Type II) antedating pregnancy Known or suspected hereditary complement deficiency (defined by CH50 = 0)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1: aPL+/SLE-<br>Positive antiphospholipid antibodies (aPL) defined as positive LAC and/or anti cardiolipin IgG/IgM >= 40 units and/or anti-beta 2 glycoprotein I IgG or IgM >= 40 units; no SLE | |
| Group 2: aPL+/SLE+<br>Positive antiphospholipid antibodies (aPL) defined as positive LAC and/or anti cardiolipin IgG/IgM >= 40 units and/or anti-beta 2 glycoprotein I IgG or IgM >= 40 units AND SLE defined as four or more American College of Rheumatology criteria for SLE. | |
| Group 3: aPL-/SLE+<br>No antiphospholipid antibodies; SLE defined as four or more American College of Rheumatology criteria for SLE. | |
| Group 4: aPL-/SLE-<br>Healthy controls: no antiphospholipid antibodies; no SLE | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Otherwise unexplained fetal death occurring after 12 weeks gestation | Fetal death occurring after 12 weeks' gestation and not explained by chromosomal abnormalities, anatomic malformations, or congenital infections. | End of pregnancy | 
| Neonatal death | Neonatal death prior to hospital discharge and due to complications of prematurity | Time of neonatal death | 
| Preterm delivery prior to 36 weeks' gestation | Indicated preterm delivery prior to 36 weeks' gestation because of gestational hypertension, preeclampsia-eclampsia or placental insufficiency | End of pregnancy | 
| Small for gestational age (SGA) <5th %ile | Small for gestational age (SGA) <5th %ile in the absence of anatomical or chromosomal abnormalities and/or delivery before 36 weeks because of intrauterine growth restriction (IUGR). | End of pregnancy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gestational age | Gestational age (weeks and days) at the end of pregnancy | End of pregnancy | 
| Birth weight | Birth weight | End of pregnancy | 
| Number of days neonate requires positive pressure ventilation | Number of days neonate requires positive pressure ventilation | Neonate discharge from hospital | 
| Total number of days neonate is hospitalized | Total number of days neonate is hospitalized | Neonate discharge from hospital | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antiphospholipid syndrome, Pregnancy outcomes, Systemic lupus erythematosus