Maternal tadalafil treatment does not increase uterine artery blood flow or oxygen delivery in the pregnant ewe

Abstract

Increasing placental perfusion (PP) could improve outcomes of growth-restricted fetuses. One way of increasing PP may be by using phosphodiesterase (PDE)-5 inhibitors, which induce vasodilatation of vascular beds. We used a combination of clinically relevant magnetic resonance imaging (MRI) techniques to characterize the impact that tadalafil infusion has on maternal, placental and fetal circulations. At 116-117 days' gestational age (dGA; term, 150 days), pregnant ewes (n = 6) underwent fetal catheterization surgery. At 120-123 dGA ewes were anaesthetized and MRI scans were performed during three acquisition windows: a basal state and then ∼15-75 min (TAD 1) and ∼75-135 min (TAD 2) post maternal administration (24 mg; intravenous bolus) of tadalafil. Phase contrast MRI and T₂ oximetry were used to measure blood flow and oxygen delivery. Placental diffusion and PP were assessed using the Diffusion-Relaxation Combined Imaging for Detailed Placental Evaluation-'DECIDE' technique. Uterine artery (UtA) blood flow when normalized to maternal left ventricular cardiac output (LVCO) was reduced in both TAD periods. DECIDE imaging found no impact of tadalafil on placental diffusivity or fetoplacental blood volume fraction. Maternal-placental blood volume fraction was increased in the TAD 2 period. Fetal $D_{O_2}$ and ${\dot{V}}_{O_2}$ were not affected by maternal tadalafil administration. Maternal tadalafil administration did not increase UtA blood flow and thus may not be an effective vasodilator at the level of the UtAs. The increased maternal-placental blood volume fraction may indicate local vasodilatation of the maternal intervillous space, which may have compensated for the reduced proportion of UtA $D_{O_2}$ .

Keywords: fetal MRI; fetal development; fetal growth restriction; haemodynamics; magnetic resonance imaging; placental perfusion; tadafer; tadalafil.

FIGURE 1

Maternal (filled symbols) and fetal (open symbols) MAP (triangles), HR (squares) and plasma tadalafil concentrations (diamonds) across the basal, TAD 1 and TAD 2 MRI acquisition periods. Maternal MAP is significantly lower during both TAD 1 and TAD 2 periods in comparison to baseline. Data analysed by repeated measures one‐way ANOVA with a Bonferroni correction for multiple comparisons. Data presented as means ± SD. P ≤ 0.05.

FIGURE 2

Representative anatomical‐magnitude (a) and phase (b) images of the maternal ascending aorta utilized for the determination of maternal left ventricular cardiac output (LVCO) unindexed (c) and indexed (d) to maternal weight across basal (open circles), TAD 1 (grey filled circles) and TAD 2 (black filled circles) periods. Data presented as individual data points with means ± SD superimposed. Data analysed by a repeated measures one‐way ANOVA with Bonferroni's correction for multiple comparisons.

FIGURE 3

Uterine artery blood flow indexed to maternal weight (a), normalized to LVCO (b) and the change from basal state of uterine artery $D_{{\mathrm{O}}_2}$ as a proportion of available $D_{{\mathrm{O}}_2}$ (c). Data presented as individual data points with means ± SD superimposed. Data analysed by a repeated measures one‐way ANOVA with Bonferroni's correction for multiple comparisons. Letters represent statistical differences between groups whereby different letters depict statistical significance; *statistically different from baseline P ≤ 0.05.

FIGURE 4

Representative placentome image showing regions of interest for placentome DECIDE (a) and the corresponding diffusivity (b), pseudo‐diffusivity (c), placentome fetal blood volume fraction (d), placentome maternal blood volume fraction (e), T₂ of the placentome fetal blood fraction (f) and converted feto‐placental $S_{{\mathrm{O}}_2}$ (g) during basal, TAD 1 and TAD 2 periods. Data presented as individual data points with means ± SD superimposed. Data analysed by a repeated measures one‐way ANOVA with Bonferroni's correction for multiple comparisons. Letters represent statistical differences between groups whereby different letters depict statistical significance; *statistically different from baseline P ≤ 0.05.

FIGURE 5

Representative anatomical magnitude (a) with corresponding phase (b) image of the umbilical vein and umbilical vein blood flow (c), fetal $D_{{\mathrm{O}}_2}$ (d), fetal ${\dot{V}}_{{\mathrm{O}}_2}$ (e) and fetal oxygen extraction fraction (f) during the basal, TAD 1 and TAD 2 periods. Data presented as individual data points with means ± SD superimposed. Data analysed by a repeated measures one‐way ANOVA with Bonferroni's correction for multiple comparisons. Letters represent statistical differences between groups whereby different letters depict statistical significance; *statistically different from baseline P ≤ 0.05.