Increased Apoptosis, Altered Oxygen Signaling, and Antioxidant Defenses in First-Trimester Pregnancies with High-Resistance Uterine Artery Blood Flow

Abstract

The mechanisms of deficient placentation in the first trimester remain poorly understood, although apoptosis, hypoxia, and oxidative stress have been implicated. High uterine artery Doppler resistance indexes (RIs) are predictive of placental complications of pregnancy, such as preeclampsia, fetal growth restriction, and stillbirth. We provide evidence that even in the first trimester, pregnancies with high uterine artery Doppler RI demonstrate alterations in placental gene and protein expression. Apoptosis was significantly higher in high RI placental tissue, as determined by Western blot analysis of cleaved poly (ADP-ribose) polymerase and caspase 3. Protein expression of the trophoblast survival factor insulin-like growth factor-2 was significantly lower. Both high and normal RI placentas showed evidence of hypoxia and oxidative stress with expression of hypoxia-inducible factors 1α and 2α, heat shock protein 70, presence of nitrotyrosine residues, and lipid peroxidation. We observed no exaggerated placental hypoxia or oxidative stress associated with high RI pregnancies. High RI placental tissue demonstrated an altered balance of antioxidant enzyme activity. Hypoxia and oxidative stress appear to be a physiological state in early pregnancy; our data did not support the hypothesis that they are associated with deficient placentation in the first trimester. Higher levels of apoptosis, reduced insulin-like growth factor-2 expression, and altered antioxidant defenses may contribute to abnormal placentation and the later development of pregnancy complications, such as preeclampsia, fetal growth restriction, and stillbirth.

Preeclampsia: a gestational cardiorenal syndrome

“…However, more recent evidence has demonstrated that uterine artery Doppler waveforms better reflect maternal systemic vascular resistance rather than local uterine artery resistance (Kalafat et al 2018;Perry et al 2018c). The latter data would indicate that maternal uterine perfusion dictates the degree of placental invasion rather than the other way round -a hypothesis which is consistent with cellular and mechanistic studies of trophobalsat function (Leslie et al 2015;Wallace et al 2015;James-Allan et al 2018;Charolidi et al 2019).…”

“…The latter data would indicate that maternal uterine perfusion dictates the degree of placental invasion rather than the other way round – a hypothesis which is consistent with cellular and mechanistic studies of trophobalsat function (Leslie et al . ; Wallace et al . ; James‐Allan et al .…”

Reply

“…For example, coronary artery occlusion causes myocardial damage – not the reverse. Our finding that abnormal first‐trimester uterine artery Doppler indices are invariably associated with defects in trophoblast oxygenation, cellular damage and function irrespective of pregnancy outcome, supports this hypothesis. Furthermore, we would like to point out that, in most cases of late‐onset pre‐eclampsia, mid‐trimester uterine artery Doppler indices are normal, becoming abnormal only in late pregnancy, just prior to development of pre‐eclampsia.…”

Role of early second-trimester uterine artery Doppler screening to predict small-for-gestational-age babies in nulliparous women

“…3 Interestingly, higher levels of apoptosis and altered antioxidant defenses have been observed in placentas from pregnancies with high-resistance uterine artery flow. 24 However, a quantitative systematic review of early clinical studies using likelihood ratio as a measure of diagnostic accuracy concluded that uterine artery Doppler flow velocity has limited diagnostic accuracy in predicting preeclampsia, fetal growth restriction, and perinatal death. 16 In a recent, large retrospective study (N=23,894 participants), uterine artery PI at 19 to 24 weeks gestation was associated with high detection rates for SGA neonates (<5 th percentile) at a ten percent false positive rate.…”