IP Library › Granted Patent US 12,298,315
Granted Patent B2
US 12,298,315 · App. 18/315,230 · Granted May 13, 2025

Systems and methods to identify and treat subjects at risk for obstetrical complications

Inventors: Tinnakorn Chaiworapongsa (Grosse Pointe Park, MI); Roberto Romero (Grosse Pointe, MI); Sonia S. Hassan (Novi, MI)
Assignees: Wayne State University; The United States of America as Represented by the Secretary, Dept. of Health and Human Services
G01N33/689A61K31/22A61K31/616A61K31/727C12Q1/6883G01N33/6872G16H10/40G16H20/10G16H50/30C12Q2600/158G01N2333/475G01N2333/912G01N2800/368G01N2800/50
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,298,315
App. No.
18/315,230
Granted
May 13, 2025
Kind
B2
Abstract

Provided are systems and methods for assessing the presence or risk of obstetrical complications, particularly those related to an angiogenic and anti-angiogenic imbalance. Also provided are methods of treating an angiogenic and anti-angiogenic imbalance with water-soluble statins, such as pravastatin.

Claims (28)

1. A method of treating an imbalance of angiogenic factor(s) and anti-angiogenic factor(s) in a pregnant female human subject, comprising;

identifying the subject as having or at risk of the imbalance of angiogenic factors and anti-angiogenic factors, wherein the angiogenic factors comprise placental growth factor (PIGF), and/or the anti-angiogenic factors comprise soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and/or soluble endoglin (sEng); and

administering to the subject an effective amount of a water-soluble statin, thereby treating the imbalance of angiogenic factors and anti-angiogenic factors.

2. The method of claim 1 , wherein treating of the imbalance of angiogenic factors and anti-angiogenic factors treats an obstetrical complication.

3. The method of claim 2 , wherein the obstetrical complication comprises one or more of preeclampsia (PE), a small for gestational age (SGA) neonate, fetal death (FD), preterm labor, early-onset fetal growth restriction, anhydramnios, placental perivillous fibrin deposition, maternal floor infarction, maternal vascular underperfusion, placental lesions, placental abruption, mirror syndrome, molar pregnancy, or twin-to-twin transfusion syndrome.

4. The method of claim 3 wherein the obstetrical complication is FD.

5. The method of claim 4 wherein the FD is associated with maternal floor infarction or placental lesions consistent with maternal vascular underperfusion.

6. The method of claim 1 , wherein the water-soluble statin is pravastatin.

7. The method of claim 6 , wherein the effective amount of pravastatin is 20 mg/day.

8. The method of claim 6 , further comprising administering heparin and aspirin to the subject.

9. The method of claim 1 , wherein identifying the subject as having or at risk of the imbalance of angiogenic factors and anti-angiogenic factors comprises:

obtaining a blood or serum sample derived from a subject;

assaying the sample for the concentration of one or more markers selected from the group consisting of placental growth factor (PIGF), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), and soluble endoglin (sEng);

analyzing the concentrations by assessing a ratio of PIGF/sVEGFR-1 and/or PIGF/sEng in the sample;

determining a MoM maternal plasma concentration ratio of PIGF/sVEGFR-1 and/or a MoM maternal plasma concentration ratio of PIGF/sEng;

comparing the determined MoM maternal plasma concentration ratio to a threshold;

identifying a presence or risk of an imbalance of angiogenic factors and anti-angiogenic factors based on the comparison of the MoM maternal plasma concentration ratio to the threshold, wherein a MoM concentration of <0.12 for PIGF/sVEGFR-1 is indicative of an angiogenic and anti-angiogenic imbalance and a MoM concentration of <0.3 for PIGF/sEng is indicative of an angiogenic and anti-angiogenic imbalance.

10. The method of claim 9 , comprising determining a ratio of PIGF/sVEGFR-1 and a ratio of PIGF/sEng.

11. The method of claim 9 , wherein the sample is obtained:

during the third trimester of pregnancy; or

between a 30th week and a 34th week of pregnancy.

12. The method of claim 11 wherein:

the MoM maternal plasma concentration ratio of PIGF/sVEGFR-1 of <0.12 is indicative of a risk for severe late PE and/or FD; or

the MoM maternal plasma concentration ratio of PIGF/sEng of <0.3 is indicative of a risk for severe late PE or late PE; or

the MoM maternal plasma concentration ratio of PIGF/sVEGFR-1 of <0.12 is indicative of a risk for delivery of an SGA neonate; or

the MoM maternal plasma concentration ratio of PIGF/sEng of <0.3 is indicative of a risk for delivery of an SGA neonate.

13. The method of claim 9 wherein the sample is obtained between a 24th week of pregnancy and a 28th week of pregnancy.

14. The method of claim 13 wherein an anti-angiogenic PIGF/sVEGFR-1 ratio is indicative of a risk for stillbirth, PE, delivery of an SGA neonate, or pre-term labor.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 25, 2023
From: CHAIWORAPONGSA, TINNAKORN; HASSAN, SONIA S.
To: WAYNE STATE UNIVERSITY
Reel/Frame 063763/0682 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 25, 2023
From: ROMERO, ROBERTO
To: THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES
Reel/Frame 063763/0885 →
Continuity (4)
Continuation 16387486 · Apr 17, 2019
Division 15129771
Provisional Application 61971486 · Mar 27, 2014
Related Publication 20230341414A1 · Oct 26, 2023
References Cited (79)
US 10281475B2 · Chaiworapongsa et al. · 2019 [cited by applicant]
US 11686735B2 · Chaiworapongsa · 2023 [cited by examiner]
US 20090176247A1 · Bashirians et al. · 2009 [cited by applicant]
US 20100304412A1 · Cuckle et al. · 2010 [cited by applicant]
US 20120201746A1 · Liu et al. · 2012 [cited by applicant]
US 20170242021A1 · Chaiworapongsa et al. · 2017 [cited by applicant]
Agarwal, et al., “Preeclampsia and the Anti-Angiogenic State”, Pregnancy Hypertens, Jan. 2011, 1 (1), 2011, pp. 17-21. [cited by applicant]
Ahmed and Cudmore, “Can the biology of VEGF and haem oxygenases help solve pre-eclampsia?” Biochem. Soc. Trans., vol. 37, Part 6, 2009, pp. 1237-1242. [cited by applicant]
Alahakoon, et al., “Discordant Clinical Presentations of Preeclampsia and Intrauterine Fetal Growth Restriction With Similar Pro and Anti-Angiogenic Profiles,” J. Matern. Fetal Neonatal Med., vol. 27, No. 18, 2014, pp. … [cited by applicant]
Asvold, et al., “Angiogenic Factors in Maternal Circulation and the Risk of Severe Fetal Growth Restriction,” Am. J. Epidemiol., vol. 173, No. 6, 2011, pp. 630-639. [cited by applicant]
Bauer, et al., “Pravastatin Attenuates Hypertension, Oxidative Stress, and Angiogenic Imbalance in Rat Model of Placental Ischemia-Induced Hypertension,” Hypertension, vol. 61, No. 5, 2013, pp. 1103-1110. [cited by applicant]
Bujold, et al., “Evidence Supporting That the Excess of the sVEGFR-1 Concentration in Maternal Plasma in Preeclampsia Has a Uterine Origin,” J. Matern. Fetal Neonatal Med., vol. 18, No. 1, 2005, pp. 9-16. [cited by applicant]
Carver, et al., “Maternal Pravastatin Prevents Altered Fetal Brain Development in a Preeclamptic CD-1 Mouse Model,” PLoS One, vol. 9, e100873, 2014, 9 pages. [cited by applicant]
Carver, et al., “The Effect of Maternal Pravastatin Therapy on Adverse Sensorimotor Outcomes of the Offspring in a Murine Model of Preeclampsia,” Int. J. Dev. Neurosci., vol. 33, 2014, pp. 33-40. [cited by applicant]
Chaiworapongsa, et al. “Unexplained Fetal Death is Associated With Increased Concentrations of Anti-Angiogenic Factors in Amniotic Fluid”, J. Matern. Fetal Neonatal Med., vol. 23, No. 8, 2010, pp. 794-805. [cited by applicant]
Chaiworapongsa, et al., “A Subset of Patients Destined to Develop Spontaneous Preterm Labor Has an Abnormal Angiogenic/Anti-Angiogenic Profile in Maternal Plasma: Evidence in Support of Pathophysiologic Heterogeneity of… [cited by applicant]
Chaiworapongsa, et al., “Fetal Death : A Condition With a Dissociation in the Concentrations of Soluble Vascular Endothelial Growth Factor Receptor-2 Between the Maternal and Fetal Compartments”, J. Matern. Fetal Neonat… [cited by applicant]
Chaiworapongsa, et al., “Maternal Plasma Concentrations of Angiogenic/Anti-Angiogenic Factors Are of Prognostic Value in Patients Presenting to the Obstetrical Triage Area With the Suspicion of Preeclampsia,” J. Materna… [cited by applicant]
Chaiworapongsa, et al., “Maternal Plasma Concentrations of Angiogenic/Antiangiogenic Factors in the Third Trimester of Pregnancy to Identify the Patient at Risk for Stillbirth at or Near Term and Severe Late Preeclampsi… [cited by applicant]
Chaiworapongsa, et al., “Plasma Soluble Vascular Endothelial Growth Factor Receptor-1 Concentration Is Elevated Prior to the Clinical Diagnosis of Pre-Eclampsia,” J. Matern. Fetal Neonatal Med., vol. 17, No. 1, 2005, pp… [cited by applicant]
Chaiworapongsa, et al., “The Maternal Plasma Soluble Vascular Endothelial Growth Factor Receptor-1 Concentration Is Elevated in SGA and the Magnitude of the Increase Relates to Doppler Abnormalities in the Maternal and … [cited by applicant]
Clinical Trials, “View of NCT01717586 on Jan. 21, 2014”, retrieved on Jun. 11, 2015 at <<https://clinicaltrials.gov/archive/NCT01717586/2014_01_21>>, ClinicalTrials.gov, pp. 1-8 2015. [cited by applicant]
Costantine, et al., “Pravastatin for the Prevention of Preeclampsia in High-Risk Pregnant Women”, Obstet. Gynecol., vol. 121, No. 2 0 1, 2013, pp. 1-7. [cited by applicant]
Costantine, et al., “Using Pravastatin to Improve the Vascular Reactivity in a Mouse Model of Soluble Fms-Like Tyrosine Kinase-1-Induced Preeclampsia,” Obstet. Gynecol., vol. 116, No. 1, 2010, pp. 114-120. [cited by applicant]
Crispi, et al., “Predictive Value of Angiogenic Factors and Uterine Artery Doppler for Early- Versus Late-Onset Pre-Eclampsia and Intrauterine Growth Restriction,” Ultrasound Obstet. Gynecol., vol. 31, 2008, pp. 303-309. [cited by applicant]
Edison and Muenke, “Mechanistic and Epidemiologic Considerations in the Evaluation of Adverse Birth Outcomes Following Gestational Exposure to Statins,” Am. J. Med. Genet. A., vol. 131, No. 3, 2004, pp. 287-298. [cited by applicant]
Elahi, et al., “Long-Term Statin Administration to Dams on High-Fat Diet Protects Not Only Them but Also Their Offspring From Cardiovascular Risk,” Ann. Nutr. Metab., vol. 62, 2013, pp. 250-256. [cited by applicant]
Elahi, et al., “Statin Treatment in Hypercholesterolemic Pregnant Mice Reduced Cardiovascular Risk Factors in Their Offspring,” Hypertension, vol. 51, 2008, pp. 939-944. [cited by applicant]
Erez, et al., “The Change in Concentrations of Angiogenic and Anti-Angiogenic Factors in Maternal Plasma Between the First and Second Trimesters in Risk Assessment for the Subsequent Development of Preeclampsia and Smal… [cited by applicant]
Espinoza, et al., “A Role of the Anti-Angiogenic Factor sVEGFR-1 in the “Mirror Syndrome” (Ballantyne's Syndrome),” J. Matern. Fetal. Neonatal. Med., vol. 19, No. 10, 2006, pp. 607-613. [cited by applicant]
Espinoza, et al., “Unexplained Fetal Death: Another Anti-Angiogenic State”, J. Matern. Fetal Neonatal. Med., vol. 20, No. 7, 2007, pp. 495-507. [cited by applicant]
Fox, et al., “Effects of Pravastatin on Mediators of Vascular Function in a Mouse Model of Soluble Fms-Like Tyrosine Kinase-1-Induced Preeclampsia,” Am. J. Obstet. Gynecol., vol. 205, 2011, pp. 366-367. [cited by applicant]
Frick, et al., “Statins Differentially Regulate Vascular Endothelial Growth Factor Synthesis in Endothelial and Vascular Smooth Muscle Cells,” Atherosclerosis, vol. 170, 2003, pp. 229-236. [cited by applicant]
Garovic, “The Role of Angiogenic Factors in the Prediction and Diagnosis of Preeclampsia Superimposed on Chronic Hypertension,” Hypertension, vol. 59, 2012, pp. 555-557. [cited by applicant]
Girardi G., “Pravastatin Prevents Miscarriages in Antiphospholipid Antibody-Treated Mice,” J. Reprod. Immunol., vol. 82, 2009, pp. 126-131. [cited by applicant]
Gu, et al., “Placental Productions and Expressions of Soluble Endoglin, Soluble Fms-Like Tyrosine Kinase Receptor-1, and Placental Growth Factor in Normal and Preeclamptic Pregnancies,” J. Clin. Endocrinol. Metab., vol.… [cited by applicant]
Hagmann, et al., “The Promise of Angiogenic Markers for the Early Diagnosis and Prediction of Preeclampsia,” Clinical Chem., vol. 58, No. 5, 2012, pp. 837-845. [cited by applicant]
International Preliminary Report on Patentability for International Application No. PCT/US2015/023117, mailed on Oct. 6, 2016, 9 pgs. [cited by applicant]
Kumasawa, et al., “Pravastatin Induces Placental Growth Factor (PGF) and Ameliorates Preeclampsia in a Mouse Model,” Proc. Natl. Acad. Sci. U.S.A., vol. 108, No. 4, 2011, pp. 1451-1455. [cited by applicant]
Kusanovic, et al., “A Prospective Cohort Study of the Value of Maternal Plasma Concentrations of Angiogenic and Anti-Angiogenic Factors in Early Pregnancy and Midtrimester in the Identification of Patients Destined to D… [cited by applicant]
Kusters, et al., “Statin Use During Pregnancy: A Systematic Review and Meta-Analysis,” Expert Rev. Cardiovasc. Ther., vol. 10, No. 3, 2012, pp. 363-378. [cited by applicant]
Lam, et al., “Circulating Angiogenic Factors in the Pathogenesis and Prediction of Preeclampsia,” Hypertension, vol. 46, 2005, pp. 1077-1085. [cited by applicant]
Levine, et al., “Circulating Angiogenic Factors and the Risk of Preeclampsia,” N. Engl. J. Med., vol. 350, No. 7, 2004, pp. 672-683. [cited by applicant]
Levine, et al., “Soluble Endoglin and Other Circulating Antiangiogenic Factors in Preeclampsia,” N. Engl. J. Med., vol. 355, No. 10, 2006, pp. 992-1005. [cited by applicant]
Li, et al., “Recombinant Vascular Endothelial Growth Factor 121 Attenuates Hypertension and Improves Kidney Damage in a Rat Model of Preeclampsia,” Hypertension, vol. 50, 2007, pp. 686-692. [cited by applicant]
Llurba, et al., “Angiogenic and Antiangiogenic Factors Before and After Resolution of Maternal Mirror Syndrome,” Ultrasound Obstet. Gynecol., vol. 40, 2012, pp. 367-369. [cited by applicant]
Luttun and Carmeliet,“Soluble VEGF Receptor Flt1: the Elusive Preeclampsia Factor Discovered?” J. Clin. Invest., vol. 111, No. 5, 2003, pp. 600-602. [cited by applicant]
Maxwell, “The Dose Response Relationship and Clinical Trials”, Dose-response relationships in clinical pharmacology, 1989, pp. 131-143. [cited by applicant]
Maynard and Karumanchi, “Angiogenic Factors and Preeclampsia,” Semin. Nephrol., vol. 31, No. 1, 2011, pp. 33-46. [cited by applicant]
McDonnold, et al., “The Effect of Prenatal Pravastatin Treatment on Altered Fetal Programming of Postnatal Growth and Metabolic Function in a Preeclampsia-Like Murine Model,” Am. J. Obstet. Gynecol., vol. 210, 2014, pp.… [cited by applicant]
McElrath, et al., “Longitudinal Evaluation of Predictive Value for Preeclampsia of Circulating Angiogenic Factors Through Pregnancy,” Am. J. Obstet. Gynecol., vol. 207, 2012, pp. 407.e1-407.e7. [cited by applicant]
Myatt, et al., “Can Changes in Angiogenic Biomarkers Between the First and Second Trimesters of Pregnancy Predict Development of Pre-Eclampsia in a Low-Risk Nulliparous Patient Population?” BJOG, vol. 120, No. 10, 2013,… [cited by applicant]
Myers, et al., “Angiogenic Factors Combined With Clinical Risk Factors to Predict Preterm Pre-Eclampsia in Nulliparous Women: A Predictive Test Accuracy Study,” BJOG, vol. 120, 2013, pp. 1215-1223. [cited by applicant]
Office Action for U.S. Appl. No. 16/387,486, mailed on Dec. 23, 2022, Chaiworapongsa, “Systems and Methods to Identify and Treat Subjects at Risk for Obstetrical Complications”, 9 Pages 2022. [cited by applicant]
Office action for U.S. Appl. No. 15/129,771, mailed on Jul. 20, 2018, Chaiworapongsa, “Systems and Methods to Identify and Treat Subjects at Risk for Obstetrical Complications”, 15 pages, 2018. [cited by applicant]
Office Action for U.S. Appl. No. 16/387,486, mailed on Jul. 6, 2022, Chaiworapongsa, “Systems and Methods to Identify and Treat Subjects at Risk for Obstetrical Complications”, 17 Pages 2022. [cited by applicant]
Powers, et al., “Soluble fms-Like Tyrosine Kinase 1 (sFlt1), Endoglin and Placental Growth Factor (PIGF) in Preeclampsia among High risk Pregnancies”, PloS ONE, Oct. 2010, vol. 5, Issue 10, 2010, pp. 1-12. [cited by applicant]
Ramma and Ahmed, “Therapeutic Potential of Statins and the Induction of Heme Oxygenase-1 in Preeclampsia,” J. Reprod. Immunol., vol. 101-102, No. 100, 2014, pp. 153-160. [cited by applicant]
Rana, et al., “Angiogenic Factors and the Risk of Adverse Outcomes in Women With Suspected Preeclampsia,” Circulation, vol. 125, 2012, pp. 911-919. [cited by applicant]
Rana, et al., “Sequential Changes in Antiangiogenic Factors in Early Pregnancy and Risk of Developing Preeclampsia,” Hypertension, vol. 50, 2007, pp. 137-142. [cited by applicant]
Redecha, et al., “Pravastatin Prevents Miscarriages in Mice: Role of Tissue Factor in Placental and Fetal Injury,” Blood, vol. 113, No. 17, 2009, pp. 4101-4109. [cited by applicant]
Romero, et al., “A Longitudinal Study of Angiogenic (Placental Growth Factor) and Anti-Angiogenic (Soluble Endoglin and Soluble Vascular Endothelial Growth Factor Receptor-1) Factors in Normal Pregnancy and Patients Des… [cited by applicant]
Romero, et al., “An Imbalance Between Angiogenic and Anti-Angiogenic Factors Precedes Fetal Death in a Subset of Patients: Results of a Longitudinal Study”, J. Matern. Fetal Neonatal Med., vol. 23, No. 12, 2010, pp. 138… [cited by applicant]
Romero, et al., “Maternal Floor Infarction/Massive Perivillous Fibrin Deposition: A Manifestation of Maternal Antifetal Rejection,” Am. J. Reprod. Immunol., vol. 70, No. 4, 2013, pp. 285-298. [cited by applicant]
Saad, et al., “Effects of Pravastatin on Angiogenic and Placental Hypoxic Imbalance in a Mouse Model of Preeclampsia,” Reprod. Sci., vol. 21, No. 1, 2014, pp. 138-145. [cited by applicant]
Sergio, et al., “Prophylaxis of Recurrent Preeclampsia: Low-Molecular-Weight Heparin Plus Low-Dose Aspirin Versus Low-Dose Aspirin Alone”, Hypertens Pregnancy, 2006, vol. 25, No. 2, pp. 115-127. [cited by applicant]
Simas, et al., “Angiogenic Biomarkers for Prediction of Early Preeclampsia Onset in High-Risk Women,” J. Matern. Fetal Neonatal Med., vol. 27, No. 10, 2013, pp. 1038-1048. [cited by applicant]
Soto, et al., “Late-Onset Preeclampsia is Associated With an Imbalance of Angiogenic and Anti-Angiogenic Factors in Patients With and Without Placental Lesions Consistent With Maternal Underperfusion,” J. Matern. Fetal … [cited by applicant]
PCT Search Report and Written Opinion for International Application No. PCT/US2015/023117, mailed Jul. 10, 2015, 11pgs. [cited by applicant]
Stepan, et al., “Predictive Value of Maternal Angiogenic Factors in Second Trimester Pregnancies With Abnormal Uterine Perfusion,” Hypertension, vol. 49, 2007, pp. 818-824. [cited by applicant]
Tannetta, et al., “Characterisation of Syncytiotrophoblast Vesicles in Normal Pregnancy and Pre-Eclampsia: Expression of Flt-1 and Endoglin,” PLoS One, vol. 8, No. 2, 2013, 13 pages. [cited by applicant]
Thadhani, et al., “Pilot Study of Extracorporeal Removal of Soluble Fms-Like Tyrosine Kinase 1 in Preeclampsia,” Circulation, vol. 124, 2011, pp. 940-950. [cited by applicant]
Therapeutics Initiative Evidence Based Drug Therapy, Statins benefit for secondary prevention confirmed, Therapeutics letter, Jul.-Sep. 2003, 2 pgs. [cited by applicant]
Torzewski, et al, “Animal Models of C-Reactive Protein”, Hindawl Publishing Corporation, Mediators of Inflammation, vol. 2014, Article ID 683598, 2014, pp. 1-7. [cited by applicant]
Van Der Vekens, et.al, “Human and Equine Cardiovascular Endocrinology: Beware to Compare”, Cardiovascular Endocrinology, vol. 2, No. 4, 2013, pp. 67-76. [cited by applicant]
Verlohren, et al., “Angiogenic Growth Factors in the Diagnosis and Prediction of Pre-Eclampsia,” Clinical Science, vol. 122, 2012, pp. 43-52. [cited by applicant]
Whitten, et al., “Evidence of an Imbalance of Angiogenic/Antiangiogenic Factors in Massive Perivillous Fibrin Deposition (Maternal Floor Infarction): A Placental Lesion Associated With Recurrent Miscarriage and Fetal De… [cited by applicant]
Wong, et al., “A Deficiency in Haem Oxygenase-1 Induces Foetal Growth Restriction by Placental Vasculature Defects,” Acta Paediatr., vol. 101, 2012, pp. 827-834. [cited by applicant]
Zhao, et al., “Maternal Heme Oxygenase 1 Regulates Placental Vasculature Development Via Angiogenic Factors in Mice,” Biol. Reprod., vol. 85, No. 5, 2011, pp. 1005-1012. [cited by applicant]