Methods of predicting and decreasing the risk of pregnancy loss

Abstract

Described are methods for diagnosing and predicting the risk of pregnancy loss in a subject based on the presence of an aberrant humoral response to three proteins, Apolipoprotein B-100, alpha2macrogloblin (alpha2M), and fibronectin. The presence or a detectable level of maternal IgG antibodies to trophoblast-derived fibronectin and/or ApoB-100, and/or the absence or a non-detectable level of antibodies specifically binding to alpha2M is associated with a history of RPL and an increased risk of pregnancy loss. Also described are methods for identifying subjects at risk of pregnancy loss, selecting subjects for participation in a clinical study, and methods of decreasing the risk of pregnancy loss in a subject which include detecting the presence or absence of antibodies to one or more of trophoblast-derived ApoB-100, alpha2M, and fibronectin. Also provided are kits that contain ApoB-100, alpha2M, and fibronectin.

1 . A method for predicting risk of pregnancy loss in a subject, the method comprising:
 (a) providing a sample comprising serum from a subject; and   (b) performing an assay to determine the presence or absence of antibodies to fibronectin in the sample; and   (c) determining that a subject having a detectable level of antibodies to fibronectin present in the sample has an increased risk of pregnancy loss.   
     
     
         2 . The method of  claim 1 , further comprising in (b) performing an assay to determine the presence or absence of antibodies to Apolipoprotein B-100 (ApoB-100) in the sample, and in (c) determining that a subject having a detectable level of antibodies to fibronectin or ApoB-100 present in the sample has an increased risk of pregnancy loss. 
     
     
         3 . The method of  claim 1 , further comprising in (b) performing an assay to determine the presence or absence of antibodies to alpha2-macroglobulin (α2M) in the sample, and in (c) determining that a subject having a detectable level of antibodies to fibronectin, or having a non-detectable level of antibodies to α2M present in the sample has an increased risk of pregnancy loss. 
     
     
         4 . The method of  claim 1 , wherein performing an assay to determine the presence or absence of antibodies to fibronectin comprises contacting the sample with one or more antigens selected from the group consisting of fibronectin and antigenic fragments of fibronectin, and detecting binding of antibodies in the sample to the one or more antigens. 
     
     
         5 .- 11 . (canceled) 
     
     
         12 . A method of decreasing the risk of pregnancy loss in a subject comprising:
 (a) providing a sample comprising serum from a subject;   (b) performing an assay to determine the presence or absence of antibodies to fibronectin in the sample; and   (c) administering a therapeutic treatment to a subject having a detectable level of antibodies to fibronectin present in the sample.   
     
     
         13 . The method of  claim 12 , further comprising in (b) performing an assay to determine the presence or absence of antibodies to Apolipoprotein B-100 (ApoB-100) in the sample, and in (c) administering a therapeutic treatment to a subject having a detectable level of antibodies to fibronectin or ApoB-100 present in the sample. 
     
     
         14 . The method of  claim 12 , further comprising in (b) performing an assay to determine the presence or absence of antibodies to alpha2-macroglobulin (α2M) in the sample, and in (c) administering a therapeutic treatment to a subject having a detectable level of antibodies to fibronectin, or having a non-detectable level of antibodies to α2M present in the sample. 
     
     
         15 . The method of  claim 1 , wherein the subject has had at least one previous pregnancy loss or is suspected of having had at least one previous pregnancy loss. 
     
     
         16 . The method of  claim 1 , wherein the subject is not pregnant, but is planning or considering a future pregnancy. 
     
     
         17 . The method of  claim 1 , wherein the subject is pregnant. 
     
     
         18 . The method of  claim 1 , wherein the sample in (a) is obtained from the subject within the first 20 weeks, within the first 13 weeks, or within the first 12 weeks of pregnancy. 
     
     
         19 . The method of  claim 12 , wherein performing an assay to determine the presence or absence of antibodies to fibronectin comprises contacting the sample with one or more antigens selected from the group consisting of fibronectin and antigenic fragments of fibronectin, and detecting binding of antibodies in the sample to the one or more antigens. 
     
     
         20 . The method of  claim 1 , wherein the subject is human. 
     
     
         21 . The method of  claim 1 , wherein said therapeutic treatment is selected from the group consisting of: complement inhibitors, hormone treatment, steroid treatment, passive immunotherapy with intravenous immunoglobulins, aspirin, and tumor necrosis factor (TNF)-α antagonists. 
     
     
         22 . A kit consisting essentially of ApoB-100, fibronectin, and α2M, or antigenic fragments thereof. 
     
     
         23 . The method of  claim 2 , further comprising in (b) performing an assay to determine the presence or absence of antibodies to alpha2-macroglobulin (α2M) in the sample, and in (c) determining that a subject having a detectable level of antibodies to fibronectin or ApoB-100, or having a non-detectable level of antibodies to α2M present in the sample has an increased risk of pregnancy loss. 
     
     
         24 . The method of  claim 13 , further comprising in (b) performing an assay to determine the presence or absence of antibodies to alpha2-macroglobulin (α2M) in the sample, and in (c) administering a therapeutic treatment to a subject having a detectable level of antibodies to fibronectin, or having a non-detectable level of antibodies to α2M present in the sample.