Methods for predicting time-to-delivery in pregnant women

Abstract

The present disclosure relates to methods for predicting time-to-delivery in pregnant women. The methods include predicting that a pregnant woman will deliver within a predetermined time frame if PAMG-1 is determined to be present at a level above a predetermined detection threshold in a vaginal fluid sample obtained from the pregnant woman. Also provided are methods for determining a patient's risk of preterm labor and/or spontaneous rupture of the chorioamniotic membrane.

1 . A method of predicting time to delivery (TTD), the method comprising:
 (a) contacting a vaginal fluid sample obtained from a pregnant woman with at least two PAMG-1-specific monoclonal antibodies, wherein at least one of the antibodies binds to PAMG-1 when present in the sample to form a PAMG-1/monoclonal antibody complex;   (b) detecting the presence of the PAMG-1/monoclonal antibody complex in the sample only when the concentration of PAMG-1 in the sample exceeds a predefined detection threshold; and   (c) predicting that the pregnant woman will deliver within a predetermined time frame if PAMG-1 is detected; or predicting that the pregnant woman will not deliver within the predetermined time frame if PAMG-1 is not detected.   
     
     
         2 . A method for determining the risk of preterm delivery, the method comprising:
 (a) contacting a vaginal fluid sample obtained from a pregnant woman with at least two PAMG-1-specific monoclonal antibodies, wherein at least one of the antibodies binds to PAMG-1 when present in the sample to form a PAMG-1/monoclonal antibody complex;   (b) detecting the presence of the PAMG-1/monoclonal antibody complex in the sample only when the concentration of PAMG-1 in the sample exceeds a predefined detection threshold; and   (c) predicting that the pregnant woman is at risk of preterm delivery if PAMG-1 is detected; or predicting that the pregnant woman is not at risk of preterm delivery if PAMG-1 is not detected.   
     
     
         3 . A method for determining a pregnant woman's risk of spontaneous rupture of the chorioamniotic membranes, the method comprising:
 (a) contacting a vaginal fluid sample obtained from a pregnant woman with at least two PAMG-1-specific monoclonal antibodies, wherein at least one of the antibodies binds to PAMG-1 when present in the sample to form a PAMG-1/monoclonal antibody complex;   (b) detecting the presence of the PAMG-1/monoclonal antibody complex in the sample only when the concentration of PAMG-1 in the sample exceeds a predefined detection threshold; and   (c) determining that the pregnant woman is at risk of spontaneous rupture of the chorioamniotic membranes if PAMG-1 is detected; or determining that the pregnant woman is not at risk of spontaneous rupture of the chorioamniotic membranes if PAMG-1 is not detected.   
     
     
         4 . The method of  claim 1 , further comprising determining that the fetal membranes of the pregnant woman are intact. 
     
     
         5 . The method of  claim 1 , comprising selecting the pregnant woman for analysis by the method only if the pregnant woman presents with one or more of the following:
 (i) signs, symptoms or complaints suggestive of preterm labor;   (ii) a gestational age between 20 weeks and 36 weeks, 6 days;   (iii) a cervical length of 25 mm or more; and   (iv) a cervical dilatation of 3 cm or less.   
     
     
         6 . The method of  claim 5 , comprising selecting the pregnant woman for analysis by the method only if the pregnant woman presents with two or more of (i), (ii), (iii), and (iv). 
     
     
         7 . The method of  claim 6 , comprising selecting the pregnant woman for analysis by the method only if the pregnant woman presents with three or all four of signs (i), (ii), (iii), and (iv). 
     
     
         8 . The method of  claim 1 , comprising collecting the vaginal fluid sample from the pregnant woman with a collection device. 
     
     
         9 . The method of  claim 8 , wherein the collection device is a flocked swab. 
     
     
         10 . The method of  claim 9 , wherein the flocked swab provides a 1:4 dilution of any PAMG-1 present in the vaginal fluid sample. 
     
     
         11 . The method of  claim 8 , comprising contacting the collection device with a solvent to release the collected vaginal fluid sample. 
     
     
         12 . The method of  claim 1 , comprising collecting the vaginal fluid sample over a time period of about 30 seconds. 
     
     
         13 . The method of  claim 8 , comprising contacting the collection device with the solvent for about 30 seconds after collecting the vaginal fluid sample. 
     
     
         14 . The method of  claim 1 , wherein the vaginal fluid sample is contacted with the at least two PAMG-1-specific monoclonal antibodies for 5 minutes. 
     
     
         15 . The method of  claim 1 , wherein the predefined detection threshold level of PAMG-1 is 4 ng/ml. 
     
     
         16 . The method of  claim 1 , wherein the predetermined time frame for predicting TTD is:
 (i) within 48 hours;   (ii) within 7 days; or   (iii) within 14 days.   
     
     
         17 . The method of  claim 1 , wherein the method has one or more of the following positive predictive values (PPVs):
 (i) at least 39% for predicting TTD within 48 hours;   (ii) at least 64% for predicting TTD within 7 days; and   (iii) at least 77% for predicting TTD within 14 days.   
     
     
         18 . The method of  claim 1 , wherein the method has one or more of the following PPVs:
 (i) about 45.5% for predicting TTD within 48 hours;   (ii) about 78% for predicting TTD within 7 days; and   (iii) about 87% for predicting TTD within 14 days.   
     
     
         19 . The method of  claim 1 , wherein the method has a negative predictive value (NPV) of 87% or greater. 
     
     
         20 . The method of  claim 1 , wherein the method has one or more of the following NPVs:
 (i) 100% for predicting TTD within 48 hours;   (ii) 97.4% for predicting TTD within 7 days; and   (iii) 93.6% for predicting TTD within 14 days.   
     
     
         21 . The method of  claim 1 , wherein the at least two PAMG-1 specific monoclonal antibodies are used in a lateral flow device. 
     
     
         22 . The method of  claim 21 , wherein the lateral flow device comprises a pad region and a test region. 
     
     
         23 . The method of  claim 22 , wherein the pad region of the test device comprises one of the at least two PAMG-1 specific monoclonal antibodies and the test region comprises the other of the two, and wherein the PAMG-1 specific monoclonal antibody in the pad region is mobilizable and the PAMG-1 specific monoclonal antibody in the test region is immobilized. 
     
     
         24 . The method of  claim 23 , wherein the test region of the test device further comprises a control region. 
     
     
         25 . The method of  claim 1 , wherein one or more of the at least two PAMG-1-specific monoclonal antibodies is an antibody selected from the group consisting of M271, produced by hybridoma N271, deposited with the Russian National Collection of Industrial Microorganisms (VKPM) Depository and assigned accession number VKPM-93; and M52, produced by hybridoma N52, deposited with the VKPM and assigned accession number VKPM-92; and M42, produced by hybridoma N42, deposited with the VKPM and assigned accession number VKPM-94. 
     
     
         26 . The method of  claim 23 , wherein the mobilizable antibody in the pad region is M271, produced by hybridoma N271, deposited with the Russian National Collection of Industrial Microorganisms (VKPM) Depository and assigned accession number VKPM-93, and the immobilized antibody in the test region is M52, produced by hybridoma N52, deposited with the VKPM and assigned accession number VKPM-92. 
     
     
         27 . The method of  claim 1 , wherein the device is the device illustrated in  FIGS. 1 and 2 . 
     
     
         28 . A kit comprising: (a) a device for detecting the presence of PAMG-1 in a vaginal fluid sample when present at a level above a predetermined threshold; and a vaginal swab. 
     
     
         29 . The kit of  claim 28 , wherein the vaginal swab is flocked. 
     
     
         30 . The kit of  claim 28 , further comprising a vial. 
     
     
         31 . The kit of  claim 28 , further comprising instructions for use. 
     
     
         32 . The kit of  claim 28 , wherein the predetermined threshold is 4 ng/ml. 
     
     
         33 . The kit of  claim 28 , wherein the device comprises a first and a second monoclonal antibody specific for PAMG-1. 
     
     
         34 . The kit of  claim 33 , wherein the first and second PAMG-1-specific monoclonal antibodies have different binding specificities and affinities for PAMG-1. 
     
     
         35 . The kit of  claim 33 , wherein each of the first and second PAMG-1-specific monoclonal antibodies is an antibody selected from the group consisting of M271, produced by hybridoma N271, deposited with the Russian National Collection of Industrial Microorganisms (VKPM) Depository and assigned accession number VKPM-93; M52, produced by hybridoma N52, deposited with the VKPM and assigned accession number VKPM-92; and M42, produced by hybridoma N42, deposited with the VKPM and assigned accession number VKPM-94. 
     
     
         36 . The kit of  claim 28 , wherein the device is a lateral flow device. 
     
     
         37 . The kit of  claim 33 , wherein the device comprises a pad region and a test region. 
     
     
         38 . The kit of  claim 37 , wherein the pad region of the test device comprises one of the first and second PAMG-1-specific monoclonal antibodies and the test region comprises the other of the first and second PAMG-1-specific monoclonal antibodies, and wherein the PAMG-1-specific monoclonal antibody in the pad region is mobilizable and the PAMG-1-specific monoclonal antibody in the test region is immobilized 
     
     
         39 . The kit of  claim 38 , where the mobilizable antibody in the pad region is M271, produced by hybridoma N271, deposited with the Russian National Collection of Industrial Microorganisms (VKPM) Depository and assigned accession number VKPM-93, and the immobilized antibody in the test region is M52, produced by hybridoma N52, deposited with the VKPM and assigned accession number VKPM-92. 
     
     
         40 . The kit of  claim 37 , wherein the test region of the test device further comprises a control region. 
     
     
         41 . The kit of  claim 28 , for use in a method of predicting TTD. 
     
     
         42 . The kit of  claim 28 , for use in a method of predicting risk of preterm delivery. 
     
     
         43 . The kit of  claim 28 , wherein the device is the device illustrated in  FIGS. 1 and 2 . 
     
     
         44 . The kit of  claim 28 , for use in a method of determining a pregnant woman's risk of spontaneous rupture of the chorioamniotic membranes. 
     
     
         45 . The method of  claim 9 , wherein the flocked swab provides a dilution of any PAMG-1 present in the vaginal fluid sample in a range of 1:1 to 1:10.