The use of angiogenic biomarkers in maternal blood to identify which SGA fetuses will require a preterm delivery and mothers who will develop pre-eclampsia

Objective: To determine (1) whether maternal plasma concentrations of angiogenic and anti-angiogenic factors can predict which mothers diagnosed with suspected small for gestational age fetuses (sSGA) will develop pre-eclampsia (PE) or require an indicated early preterm delivery (34 weeks of gestation); and (2) whether risk assessment performance is improved using these proteins in addition to clinical factors and Doppler parameters.Methods: This prospective cohort study included women with singleton pregnancies diagnosed with sSGA (estimated fetal weight <10th percentile) between 24 and 34 weeks of gestation (n=314). Plasma concentrations of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1), soluble endoglin (sEng) and placental growth factor (PlGF) were determined in maternal blood obtained at the time of diagnosis. Doppler velocimetry of the umbilical (Umb) and uterine (UT) arteries was performed. The outcomes were (1) subsequent development of PE; and (2) indicated preterm delivery at 34 weeks of gestation (excluding deliveries as a result of spontaneous preterm labor, preterm pre-labor rupture of membranes or chorioamnionitis).Results: (1) The prevalence of PE and indicated preterm delivery was 9.2% (n=29/314) and 7.3% (n=23/314), respectively; (2) the area under the receiver operating characteristic curve (AUC) for the identification of patients who developed PE and/or required indicated preterm delivery was greater than 80% for the UT artery pulsatility index (PI) z-score and each biochemical marker (including their ratios) except sVEGFR-1 MoM; (3) using cutoffs at a false positive rate of 15%, women with abnormal plasma concentrations of angiogenic/anti-angiogenic factors were 7-13 times more likely to develop PE, and 12-22 times more likely to require preterm delivery than those with normal plasma MoM concentrations of these factors; (4) sEng, PlGF, PIGF/sEng and PIGF/sVEGFR-1 ratios MoM, each contributed significant information about the risk of PE beyond that provided by clinical factors and/or Doppler parameters: women who had low MoM values for these biomarkers were at 5-9 times greater risk of developing PE than women who had normal values, adjusting for clinical factors and Doppler parameters (adjusted odds ratio for PlGF: 9.1, PlGF/sEng: 5.6); (5) the concentrations of sVEGFR-1 and PlGF/sVEGFR-1 ratio MoM, each contributed significant information about the risk of indicated preterm delivery beyond that provided by clinical factors and/or Doppler parameters: women who had abnormal values were at 8-9 times greater risk for indicated preterm delivery, adjusting for clinical factors and Doppler parameters; and (6) for a two-stage risk assessment (Umb artery Doppler followed by Ut artery Doppler plus biochemical markers), among women who had normal Umb artery Doppler velocimetry (n=279), 21 (7.5%) developed PE and 11 (52%) of these women were identified by an abnormal UT artery Doppler mean PI z-score (>2SD): a combination of PlGF/sEng ratio MoM concentration and abnormal UT artery Doppler velocimetry increased the sensitivity of abnormal UT artery Doppler velocimetry to 76% (16/21) at a fixed false-positive rate of 10% (p=0.06).Conclusion: Angiogenic and anti-angiogenic factors measured in maternal blood between 24 and 34 weeks of gestation can identify the majority of mothers diagnosed with suspected SGA who subsequently developed PE or those who later required preterm delivery 34 weeks of gestation. Moreover, incorporation of these biochemical markers significantly improves risk assessment performance for these outcomes beyond that of clinical factors and uterine and umbilical artery Doppler velocimetry.