Maternal plasma angiogenic index-1 (placental growth factor/soluble vascular endothelial growth factor receptor-1) is a biomarker for the burden of placental lesions consistent with uteroplacental underperfusion: a longitudinal case-cohort study

Abstract

Background Placental lesions consistent with maternal vascular underperfusion (MVU) are thought to be pathogenically linked to preeclampsia, small-for-gestational-age newborns, fetal death, and spontaneous preterm labor and delivery; yet, these lesions cannot be diagnosed antenatally. We previously reported that patients with such conditions and lesions have an abnormal profile of the angiogenic placental growth factor (PlGF) and anti-angiogenic factors [e.g., soluble vascular endothelial growth factor receptor-1 (sVEGFR-1)]. Objectives The objectives of this study were to: 1) examine the relationship between the maternal plasma PlGF/sVEGFR-1concentration ratio (referred to herein as angiogenic index-1) and the burden of histologic placental features consistent with MVU; and 2) test the hypothesis that angiogenic index-1 can identify patients in the midtrimester who are destined to deliver before 34 weeks of gestation with multiple (i.e., 3 or more) histologic placental features consistent with MVU. Study Design A two-stage case-cohort sampling strategy was used to select participants from among 4,006 women with a singleton gestation enrolled from 2006 through 2010 in a longitudinal study. Maternal plasma angiogenic index-1 ratios were determined using enzyme-linked immunosorbent assays. Placentas underwent histologic examination according to standardized protocols by experienced pediatric pathologists who were blinded to clinical diagnoses and pregnancy outcomes. The diagnosis of lesions consistent with MVU was made using criteria proposed by the Perinatal Section of the Society for Pediatric Pathology. Weighted analyses were performed to reflect the parent cohort, ‘n*’ is used to reflect weighted frequencies. Results 1) Angiogenic index-1 (PlGF/sVEGFR-1) concentration ratios were determined in 7,560 plasma samples collected from 1,499 study participants; 2) the prevalence of lesions consistent with MVU was 21% (n* = 833.9/3,904) and 27% (n* = 11.4/42.7) of women with 3 or more MVU lesions delivered before 34 weeks of gestation; 3) a low angiogenic index-1 (<2.5th quantile for gestational age) in maternal plasma samples obtained within 48 hours of delivery had a sensitivity of 73% [n* = 8.3/11.4; 95% confidence interval (CI), 47%–98%], a specificity of 94% (n* = 3130.9/3316.2; 95% CI, 94%–95%), a positive likelihood ratio (LR+) of 12.2, and a negative likelihood ratio (LR-) of 0.29 in the identification of patients who delivered placentas with 3 or more MVU lesions at <34 weeks; 4) prospectively, at 20–23 weeks of gestation, a maternal plasma concentration of angiogenic index-1 below the 2.5th quantile identified 70% (n* = 7.2/10.3; 95% CI, 42%–98%) of patients who delivered placentas with 3 or more MVU lesions before 34 weeks [specificity, 97% (n* = 2831.3/2918; 95% CI, 96%–98%); LR+, 23; LR−, 0.31]; and 5) among women without obstetrical complications who delivered at term, angiogenic index-1 was lower in women with compared to those without placental lesions consistent with MVU (p < 0.05). Conclusio...

Antecedents and correlates of blood concentrations of neurotrophic growth factors in very preterm newborns

“…Elevated concentrations of presumed anti-inflammatory protectors of the brain and retina, [55–58] such as erythropoietin and thyroid stimulating hormone, accompany systemic inflammation,[15, 59, 60] which contributes to brain damage. [59–61] Consequently, our second null hypothesis postulates that postnatal systemic inflammation is not associated with top quartile concentrations of NT-4, BDNF, or bFGF.…”

“…[59–61] Consequently, our second null hypothesis postulates that postnatal systemic inflammation is not associated with top quartile concentrations of NT-4, BDNF, or bFGF. Our logistic regression models adjusted for 3 variables, indicated delivery only, birth weight Z-score < −2 only, and both indicated delivery and birth weight Z-score < −2 (Tables 2–4).…”

Failure of physiologic transformation of spiral arteries, endothelial and trophoblast cell activation, and acute atherosis in the basal plate of the placenta

“…We previously proposed that pathology of the placental bed, primarily through ischemia and/or other mechanisms such as a maternal-fetal immune response, may lead to preeclampsia, small for gestational age, preterm labor with intact or ruptured membranes, abruptio placentae, and fetal death; and why a similar insult would result in different clinical phenotypes depends on genetic and environmental factors and time of onset, duration, and extent of the ischemic insult [160]. Korzeniewski et al [161] recently demonstrated that maternal plasma angiogenic index-1 concentration ratios seem to reflect the burden of uteroplacental vasculopathy indicated by histologic examination of the placenta, regardless of clinical diagnosis. The time order between changes in plasma angiogenic index-1 concentration ratios and placental features consistent with maternal vasculopathy, however, remains to be determined.…”

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

“…However, hints have begun to emerge. 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.…”