Maternal circulating angiogenic factors in twin and singleton pregnancies

Abstract

Objective The purpose of this study was to compare longitudinally sampled maternal angiogenic proteins between singleton and twin pregnancies. Study Design Placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin (sEng) from healthy pregnant women were quantified at 10, 18, 26 and 35 weeks’ gestation (n=91), and during the third trimester (31–39 weeks) and at delivery (33–41 weeks; n=41). Geometric means and 95% confidence intervals were calculated for gestational age adjusted angiogenic protein concentrations and compared between matched twin and singleton pregnancies. Results Maternal sFlt-1 concentrations and the sFlt-1/PlGF ratio were higher in twins than singletons across pregnancy and at delivery, with the greatest differences at week 35 [sFlt-1: 36916 vs. 10151 pg/mL; p<0.0001; sFlt-1/PlGF: 168.4 vs. 29.0; p<0.0001]. Maternal concentrations of s-endoglin also were higher in the third trimester and delivery. Maternal PlGF concentrations were lower in twin than singleton pregnancies at week 35 only [219.2 vs. 350.2 pg/mL; p<0.0001]. Placental weight appeared to be inversely correlated with maternal sFlt-1/PlGF ratio at the end of the pregnancy in both twins and singletons. Conclusions Higher maternal anti-angiogenic proteins in twin than singleton pregnancies does not appear to be due to greater placental mass in the former, and may be one explanation for the increased risk of preeclampsia in women carrying multiple gestations. Determining whether women with a history of multiple gestations have an altered cardiovascular disease and breast cancer risk, like those with a history of preeclampsia, is warranted.

Angiogenic imbalance and diminished matrix metalloproteinase-2 and -9 underlie regional decreases in uteroplacental vascularization and feto-placental growth in hypertensive pregnancy

“…The placental and uterine angiogenic imbalance paralleled the reduced placental and fetal growth, uteroplacental vascularization, and MMP levels/activity in the proximal, middle and distal regions of the RUPP vs Preg uterus. These findings are consistent with reports that sFlt-1 levels are greater in villous explants from preeclamptic than normal Preg women [83], and that sFlt-1 increases while PIGF decreases in twin vs singleton pregnancies [45] and in twin pregnancies with suspected preeclampsia [44, 49]. 3) The levels of sFlt-1 were further increased, PlGF was further decreased, and sFlt-1/PlGF ratio was further increased in the distal vs proximal and middle regions of the RUPP uterus.…”

“…Also, VEGF levels are controlled at the maternal-fetal interface, partly through feedback modulation of sFlt-1, in order to prevent damage to the placenta or fetus by excess VEGF [86], and dysregulation of this feedback mechanism may prevent compensatory MMP upregulation and uteroplacental vascularization and lead to further restriction of placental and fetal growth. This is supported by reports that serum levels of sFlt-1 and the sFlt-1/PlGF ratio are markedly increased while PlGF levels are markedly decreased in twin pregnancies with preeclampsia compared with twin pregnancies with an uneventful pregnancy outcome [44, 45]. 2) Other anti-angiogenic factors may be released and affect regional MMP levels and uteroplacental vascularization in HTN-Preg.…”

“…The risk of preeclampsia increases in twin and multiple pregnancy [44, 45, 49], where relative increases in placental ischemia and inadequate uteroplacental vascularization [46] could further affect placental and fetal development. Studies in RUPP and hypoxic pregnant rats have supported placental ischemia/hypoxia as an initiating mechanism of HTN-Preg and IUGR [10, 15, 17].…”

“…Uteroplacental and vascular remodeling may require critical physiological adjustments in twin or multiple pregnancy [43–45]. Regional differences in uteroplacental blood flow could affect the pregnancy outcome, and may be a factor in the increased risk of preeclampsia in twin or multiple pregnancy [46–49].…”

“…Regional differences in uteroplacental blood flow could affect the pregnancy outcome, and may be a factor in the increased risk of preeclampsia in twin or multiple pregnancy [46–49]. Also, circulating levels of angiogenic and anti-angiogenic factors are altered in twin vs singleton pregnancies [45] and in twin pregnancies with suspected preeclampsia [44, 49]. However, the extent of uteroplacental vascularization and the molecular mechanisms regulating uteroplacental remodeling in normal multiple pregnancy versus multiple pregnancy complicated with preeclampsia are unclear.…”