This study revealed two major findings. First, pregnant women with FGR had significantly lower UtA blood flow than normal pregnant women. Second, in the tadalafil-treated FGR group, the UtA blood flow increased more than that in controls.
In this study, pregnant women with FGR had significantly lower UtA blood flow than controls. Of the few studies evaluating abnormal pregnancy using MRI, Hwuang reported that total UtA blood flow decreased in small for gestational age (SGA) infants and women with preeclampsia and that this result was linked to poor pregnancy outcomes [24]. Konje et al. reported that women who delivered FGR infants had 12.5% and 36.7% lower UtA blood flow as compared to healthy controls at 20 and 38 weeks, respectively, using the ultrasound technique [25]. Thus, the results of our study and previous studies support a relationship between the decrease in UtA blood flow and the retardation of fetal growth. However, the mechanisms underlying such a relationship remains unknown. A previous study demonstrated that UtA blood flow assessed by Doppler ultrasound and O2 delivery estimated by blood sample were twofold greater at 20 weeks gestational age in Andean women genetically adapted to high altitude than in European women at high altitude and that those increase in UtA blood flow and O2 delivery was paralleled by greater fetal size [26]. This observation leads to the hypothesis that preserved UtA blood flow during pregnancy might play a role in protecting fetal O2 supply and growth. We previously demonstrated that placental oxygenation significantly reduced in the FGR group than in controls [27,28]. Since efficient oxygen extraction requires sufficient fetal blood flow in the intervillus and chorionic villi, it is likely that fetal blood flow and chorionic villus changes in FGR reduce oxygen extraction efficiency [29]. Additionally, the days to delivery were significantly shorter in the FGR group than in controls in the present study; this might be owing to insufficient blood flow between the uterus and placenta due to placental abnormalities; therefore, placental insufficiency is considered a cause of preterm delivery [30–32]. Thus, measurement of UtA blood flow might allow for early detection of FGR and associated poor pregnancy outcomes such as preterm birth. Further study is warranted.
Tadalafil-treated FGR patients showed an increase in EFBW and UtA blood flow more than that in controls. The mechanism of action of tadalafil is supposedly dilation of vascular smooth muscles in the uterine spiral artery, leading to placental vasodilation and improved oxygen and nutrient supply to the fetus, and our results are consistent with this theory [16]. We demonstrated that tadalafil improved the width of maternal blood sinuses in the labyrinth zone of the placenta in a mouse model of preeclampsia but did not significantly alter fetal capillaries [14]. Sekimoto et al. revealed that the murine-reduced uterine perfusion pressure model showed an increased sFlt-1 protein level in the placenta, and tadalafil corrected it to control levels. It probably decreases vascular resistance in the placental vascular bed and increases blood flow, leading to improved placental circulation and reduction in placental ischemia. Resultantly, they showed that tadalafil improved placental hypoxia through corrected enhanced HIF1a expression [12]. However, sildenafil citrate improved pre-constricted placental arterial perfusion in a human placental model, whereas tadalafil showed no response. Possibly, tadalafil does not cross the human placental barrier or is degraded by trophoblasts [33]. This proves that tadalafil is safe for the fetus; Maki et al. also reported that tadalafil reduced fetal and FGR-related infant deaths and significantly prolonged gestational length in patients with GA < 32 weeks [11]. Improvement in placental insufficiency owing to increased UtA blood flow with tadalafil administration might have contributed to these results.
The present study demonstrated that the inter- and intraobserver errors were very small. MRI is a non-invasive modality, free from radiation exposure and allow for the objective evaluation of uterine arteries blood flow without administrating gadolinium contrast medium, even in patients difficult to examine with ultrasound examination. Hwuang et al. reported the possibility of using 4D-flow MRI performed at 3T to assess the anatomy and hemodynamics of uterine arteries in women in the second and third trimesters of pregnancy [34]. While their method has been proven to be highly reproducible, the study by Sussman et al. evaluated uterine arteries with 2D PC-MRI more accurately than that with 4D-flow MRI [35]. Our method can be considered useful in that it was found to be as good as or better than the study by Sussman et al. in reproducibility.
The strength of our study lies in demonstrating the feasibility of measuring uterine arterial blood flow using 2D PC-MRI, which has traditionally been challenging. We further investigated the effect of tadalafil on FGR using this approach that ensured high intra- and interobserver reproducibility. This robust methodology increases the reliability of our findings. Furthermore, the technique we used has the potential to evaluate the effects of other drugs. This study has some limitations. Firstly, the sample size was small for the pregnant women with tadalafil treatment in this study. Those patients were recruited in a single center during short period between a Phase II and Phase IIb clinical trials. As Phase IIb clinical trial is underway at the moment, it is unable to recruit further patients into this study. Secondly, The diagnosis of FGR in the present study follow the Japanese criteria [21]. Globally, FGR without congenital anomalies is determined using Delhi procedure [36]. Nonetheless, 13 of the 14 patients (93%) recruited in this study met this criterion.
In conclusion, UtA blood flow in pregnant women with FGR was significantly lower than that in healthy pregnant women. Tadalafil improves UtA blood flow in pregnant women with FGR, which is expected to extend the number of weeks of gestation and improve placental function in these patients. A placebo-controlled randomized controlled trial as a multicenter-validation clinical trial (Phase IIb) is underway, the results of which are awaited.