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

1. A method comprising:

(a) obtaining a maternal plasma sample derived from a female human subject;

(b) assaying the sample from (a) for the concentration of placental growth factor (PIGF) and at least one of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) or soluble endoglin (sEng);

(c) analyzing the concentrations from (b) by assessing a ratio of PIGF/sVEGFR-1 and/or a ratio of PIGF/sEng in the sample;

(d) determining using the analyzing from (c) a Multiple of the Median (MoM) maternal plasma concentration ratio of PIGF/sVEGFR-1 and/or a MoM maternal plasma concentration ratio of PIGF/sEng;

(e) comparing the determined MoM maternal plasma concentration ratio of (d) to a threshold;

(f) identifying a presence or risk of an angiogenic and anti-angiogenic imbalance based on the comparison of the MoM maternal plasma concentration ratio to the threshold from (e), 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; and

(g) administering a water-soluble statin to the subject based on an indication of an angiogenic and anti-angiogenic imbalance from (f).

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

3. The method of claim 1 wherein the presence of an angiogenic and anti-angiogenic imbalance is predictive of obstetrical complications including 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 1 wherein the sample is obtained between a 30th week and a 34th week of pregnancy.

5. The method of claim 4 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.

6. The method of claim 4 wherein the MoM maternal plasma concentration ratio of PIGF/sEng of <0.3 is indicative of a risk for severe late PE or late PE.

7. The method of claim 4 wherein the MoM maternal plasma concentration ratio of PIGF/sVEGFR-1 of <0.12 is indicative of a risk for delivery of an SGA neonate.

8. The method of claim 4 wherein the MoM maternal plasma concentration ratio of PIGF/sEng of <0.3 is indicative of a risk for delivery of an SGA neonate.

9. The method of claim 3 wherein the sample is obtained between a 24th week of pregnancy and a 28th week of pregnancy.

10. The method of claim 9 wherein an anti-angiogenic PIGF/sVEGFR-1 ratio of <10 percentile of uncomplicated pregnancies is indicative of a risk for stillbirth, PE, delivery of an SGA neonate, or pre-term labor.

11. The method of claim 1 wherein the sample is blood or serum and wherein the sample is obtained during a third trimester of a pregnancy.

12. The method of claim 1 , which is a method of treating an angiogenic and anti-angiogenic imbalance in the subject.

13. The method of claim 12 , wherein the treating of the angiogenic and anti-angiogenic imbalance treats an obstetrical complication.

14. The method of claim 13 , wherein the obstetrical complication is fetal death (FD) associated with maternal floor infarction or placental lesions consistent with maternal vascular underperfusion.

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

16. The method of claim 15 , further comprising administering heparin and aspirin to the subject.

17. The method of claim 15 , wherein the pravastatin is administered to the subject at 20 mg/day.

18. A method comprising:

assaying a maternal plasma sample derived from a female human subject sample for the concentration of placental growth factor (PIGF) and at least one of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) or soluble endoglin (sEng);

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

determining, using the analyzing, a Multiple of the Median (MoM) maternal plasma concentration ratio of PIGF/sVEGFR-1 and/or a MoM maternal plasma concentration ratio of PIGF/sEng;

identifying a presence or risk of an angiogenic and anti-angiogenic imbalance based on the comparison of the MoM maternal plasma concentration ratio to a 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; and

administering a water-soluble statin to the subject based on that indication of an angiogenic and anti-angiogenic imbalance.

19. A method comprising:

immunoassaying a maternal plasma sample derived from a female human subject sample for the concentration of placental growth factor (PIGF) and at least one of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) or soluble endoglin (sEng), wherein the maternal plasma sample is obtained from the female human subject either:

between a 30th week and a 34th week of pregnancy; or

between a 24th week and a 28th week of pregnancy;

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

determining, using the analyzing, a Multiple of the Median (MoM) maternal plasma concentration ratio of PIGF/sVEGFR-1 and/or a MoM maternal plasma concentration ratio of PIGF/sEng;

identifying a presence or risk of an angiogenic and anti-angiogenic imbalance based on the comparison of the MoM maternal plasma concentration ratio to a 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; and

identifying the female human subject as being at risk for pregnancy complications based on that indication of an angiogenic and anti-angiogenic imbalance.

20. The method of claim 19 , wherein:

the sample is obtained between the 30th week and the 34th week of pregnancy, and 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 delivery of an SGA neonate; or

the sample is obtained between the 30th week and the 34th week of pregnancy, and 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 delivery of an SGA neonate; or

the sample is obtained between the 24th week of pregnancy and the 28th week of pregnancy, and an anti-angiogenic PIGF/sVEGFR-1 ratio of <10 percentile of uncomplicated pregnancies is indicative of a risk for stillbirth, PE, delivery of an SGA neonate, or pre-term labor.