Pregnancy complications in women with the antiphospholipid syndrome (APS) and/or SLE include recurrent miscarriage, preeclampsia, placental insufficiency, and intrauterine growth restriction (IUGR). The mechanisms leading to placental and fetal injury in vivo are incompletely understood and treatment remains sub-optimal. We have identified complement as an early effector in pregnancy loss and/or IUGR associated with placental inflammation in a mouse model of APS and shown that complement activation causes the release of anti- angiogenic factors and abnormal placental development. The PROMISSE Study (Predictors of pRegnancy Outcome: bioMarkers In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus) is a first-time effort to translate our novel findings in mice to humans and determine if elevations of complement split products predict pregnancy complications in patients with antiphospholipid (aPL) antibodies and/or SLE. In the first 4 years of this prospective, observational study of pregnant patients grouped and analyzed according to the presence or absence of aPL antibodies and preexisting SLE, we have enrolled 342 pregnant patients in 7 centers, obtained detailed medical and obstetrical information monthly, and serially collected plasma, serum, DNA, RNA, and urine. Preliminary data suggest that elevated levels of complement activation products antecede and predict poor fetal outcome, consistent with our hypothesis that complement is a proximal mediator of fetal loss and IUGR. We propose to increase our target sample size from 400 to 700 pregnant patients to maintain study power given lower than expected outcome rates, and to leverage the infrastructure and rich collection of patient data and samples by expanding the array of biomarkers and scope of adverse pregnancy outcomes. Specifically, in Aim 1 we will determine whether elevations of split products generated by activation of complement pathways predict poor fetal and/or maternal outcome in patients with aPL antibodies and/or SLE and, in Aim 2, whether the balance of circulating angiogenic and antiangiogenic factors predicts preeclampsia or delivery of IUGR infants.
In Aim 3, a new direction, we will use the PROMISSE cohort to affirm in humans our recent findings in mice, that certain anti-DNA antibodies cross-react with N-methyl D- aspartate receptors (NMDAR) and cause neuronal death with ensuing cognitive and behavioral impairment. We propose to quantitate anti-NMDAR antibody levels throughout pregnancy in PROMISSE SLE patients and test the hypothesis that in utero exposure to maternal anti-NMDAR antibodies alters behavior and cognitive development in offspring by evaluating cortical function tasks in 12 month and 3.5 year old children. This competitive renewal and extension of the PROMISSE Study provides an outstanding opportunity to translate knowledge from mouse models to patients, define pathogenic mechanisms, identify predictors of poor pregnancy outcome in APL and/or SLE, and define novel therapeutic targets to prevent such outcomes.Patients with systemic lupus erythematosus (SLE) and/or antiphospholipid (aPL) antibodies are at increased risk for miscarriage, preeclampsia and fetal growth restriction - major causes of maternal, fetal, and neonatal morbidity and mortality in the US and worldwide - whose etiology and mechanism remain unknown and for which therapy is limited. In addition to causing placental dysfunction, maternal autoantibodies may also directly impair fetal brain development. Identification of biomarkers that predict poor pregnancy outcome in these patients will elucidate mechanisms of disease, define targets for treating patients, and generate clinically applicable indicators to permit initiation of interventional trials in patients at greatest risk for pregnancy complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049772-10
Application #
8319250
Study Section
Special Emphasis Panel (ZAR1-KM-H (J1))
Program Officer
Wang, Yan Z
Project Start
2003-04-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2012
Total Cost
$1,213,915
Indirect Cost
$256,505
Name
Hospital for Special Surgery
Department
Type
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021
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Michael D Lockshin; Cohn, Elisabeth; Aslam, Aanam et al. (2013) Sex ratios among children of lupus pregnancies. Arthritis Rheum 65:282
Mulla, Melissa J; Salmon, Jane E; Chamley, Larry W et al. (2013) A role for uric acid and the Nalp3 inflammasome in antiphospholipid antibody-induced IL-1* production by human first trimester trophoblast. PLoS One 8:e65237
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Lynch, Anne M; Gibbs, Ronald S; Murphy, James R et al. (2011) Early elevations of the complement activation fragment C3a and adverse pregnancy outcomes. Obstet Gynecol 117:75-83
Salmon, Jane E; Heuser, Cara; Triebwasser, Michael et al. (2011) Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med 8:e1001013
Kaplan, Mariana J; Salmon, Jane E (2011) How does interferon-ýý insult the vasculature? Let me count the ways. Arthritis Rheum 63:334-6
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Lynch, A M; Murphy, J R; Gibbs, R S et al. (2010) The interrelationship of complement-activation fragments and angiogenesis-related factors in early pregnancy and their association with pre-eclampsia. BJOG 117:456-62
Lynch, A M; Salmon, J E (2010) Dysregulated complement activation as a common pathway of injury in preeclampsia and other pregnancy complications. Placenta 31:561-7

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