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

Abstract

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 preeclampsia (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 prelabor rupture of the membranes, or chorioamnionitis). Results 1) The prevalence of PE and indicated preterm delivery were 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, PlGF/sEng, and PlGF/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 a...

Mild intrauterine hypoperfusion reproduces neurodevelopmental disorders observed in prematurity

“…The inflammatory cytokine levels might have been insufficient to upregulate these cell adhesion molecules. MIUH upregulated vWF, VEGF and adiponectin levels, which are known endothelial injury markers and have been reported to be candidate biomarkers for preeclampsia3637. Adiponectin suppresses insulin signaling and the uptake of insulin-stimulated amino acids in the placenta, and its regulation has important implications for nutrient transport in the placenta383940.…”

Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

“…29,30 Thus, there has been a great deal of interest in whether or not circulating levels of molecules that could have negative effects on the maternal vasculature can be used to predict and/or diagnose PE. 31, 32, 33 …”

Is an episode of suspected preterm labor that subsequently leads to a term delivery benign?

“…The balance of angiogenic and anti-angiogenic factors appears to be key in the establishment of a successful and functional utero-placental circulation (81–86). A deficiency in angiogenic factors was first implicated in the pathogenesis of preeclampsia (87–95) and subsequently discovered to play a role in SGA/fetal growth restriction (93, 96), fetal death(97, 98), spontaneous preterm labor (99), Ballantyne syndrome (100), twin-to-twin transfusion syndrome (101), etc. During the course of prospective studies, we observed that some patients with a high concentration of endoglin (an anti-angiogenic factor) had a spontaneous preterm delivery (99).…”