Corpus luteum number and the maternal renin-angiotensin-aldosterone system as determinants of utero-placental (vascular) development: the Rotterdam Periconceptional Cohort

Background: Pregnancies with > 1 corpus luteum (CL) display a hyperdynamic circulation and an increased risk of small-for-gestational age deliveries. Among the factors released by the CL is prorenin, the inactive precursor of renin. Since the renin-angiotensin-aldosterone system (RAAS) is involved in early hemodynamic pregnancy adaptation, we linked both CL number and first-trimester concentrations of prorenin (as an indicator of RAAS activity) and the aldosterone/renin ratio (as an indicator of angiotensin-independent aldosterone effectiveness) to non-invasive markers of utero-placental (vascular) development, measured longitudinally from the first trimester onwards. Methods: A total of 201 women, who conceived naturally or after in-vitro fertilization treatment (with 0 (n = 8), 1 (n = 143), or > 1 (n = 51) CL), were selected from the Rotterdam Periconceptional Cohort. Maternal RAAS components were determined at 11 weeks gestation. Placental volume and utero-placental vascular volume were measured from transvaginal 3D ultrasound scans at 7, 9 and 11 weeks gestation, pulsatility and resistance indices of the uterine arteries were assessed by pulsed wave Doppler ultrasounds at 7, 9, 11, 13, 22 and 32 weeks gestation. At birth placental weight was obtained using standardized procedures. Results: Pregnancies without a CL show lower uterine artery indices throughout gestation than 1 CL and > 1 CL pregnancies, while parameters of placental development are comparable among the CL groups. After adjustment for patient- and treatment-related factors, first-trimester prorenin concentrations are positively associated with uterine artery pulsatility and resistance indices (β 0.06, 95% CI 0.01;0.12, p = 0.04 and β 0.10, 95% CI 0.01;0.20, p = 0.04, respectively), while high prorenin concentrations are negatively associated with first-trimester utero-placental vascular volume (β -0.23, 95% CI -0.44;-0.02, p = 0.04) and placental weight (β -93.8, 95%CI -160.3;-27.4, p = 0.006). In contrast, the aldosterone/renin ratio is positively associated with first-trimester placental volume (β 0.12, 95% CI 0.01;0.24, p = 0.04). Conclusions: The absence of a CL, resulting in low prorenin concentrations, associates with low uterine artery pulsatility and resistance, while high prorenin concentrations associate with a low utero-placental vascular volume and weight. These data support a scenario in which excess prorenin, by upregulating angiotensin II, increases uterine resistance, thereby preventing normal placental (vascular) development, and increasing the risk of small-for-gestational age deliveries. Simultaneously, high aldosterone concentrations, by ensuring volume expansion, exert the opposite.