Adequate perfusion of the placenta and fetal organs is necessary for normal fetal growth and well-being. Recent developments in ultrasound technology have enabled the reproducible and accurate recording of flow volumes, providing additional important physiological information about fetal placental perfusion, including combined cardiac output (CCO) and umbilical vein flow volume (UVFV).

CCO is an indicator of myocardial function [1]; however, it is of limited value as it is load load-dependent. UVFV is closely related to the placental cotyledon mass and indicates the oxygen levels and nutrients transferred from the mother to the fetus. Moreover, the evaluation of blood flow distribution can provide important physiological information [2]. Chronic hypoxia caused by limited placental perfusion, associated with placental dysfunction, restricts fetal growth, whereas decreased placental perfusion during slight uterine contractions reduces the oxygen supply, causing late decelerations. In these circumstances, tocolytic drugs and bed rest are often used empirically to prevent the occurrence of slight uterine contractions that may lead to fetal hypoxia [3].

Ritodrine is a beta-sympathomimetic agent used for tocolysis in several countries. Doppler analyses indicated that ritodrine induces favorable changes in placental perfusion. Ritodrine passes through the placenta, enters the fetal circulation, and increases the fetal heart rate, resulting in increased fetal cardiac output. In addition, controlling uterine contractions may improve placental blood flow by reducing placental perfusion pressure [4]. Hence, the favorable effects of ritodrine tocolysis on placental perfusion may be applied to fetal growth restriction associated with placental dysfunction. However, the effects of ritodrine on placental perfusion and the ability of the fetus to handle oxygen deficiencies remain unclear. This study aimed to evaluate changes, following ritodrine tocolysis, in fetal cardiac output distribution to the placenta.

A total of 306 ultrasound evaluations were performed in 177 cases with no obstetric complications other than threatened preterm delivery. We analyzed 244 data items from 142 cases, excluding small and large for gestational age neonates. This included 48 data items in 28 cases in the ritodrine group and 196 data items in 114 cases in the control group. Ultrasound findings were compared between the two groups at each week of gestation (Fig. 1).

Table 1 shows the background of all cases and a comparison between the ritodrine and the control groups. The ritodrine group had a lower gestational age at birth (35 w 2 d $\pm$ 17 d vs. 38 w 2 d $\pm$ 13 d, p 0.001) and a lower birth weight (2323 $\pm$ 529 g vs. 2828 $\pm$ 47 g, p 0.001). There was no difference in standard deviation (SD) values based on standard birth weight (0.11 $\pm$ 0.79 vs. 0.03 $\pm$ 0.75, p = 0.538). Umbilical cord arterial blood pH (7.296 $\pm$ 0.068 vs. 7.294 $\pm$ 0.067, p = 0.800) and weight of the placenta (584 $\pm$ 136 g vs. 578 $\pm$ 91 g, p = 0.517) did not differ between the two groups.

Table 2 shows comparisons of ultrasound Doppler findings between the two groups at each week of gestation. The CCO was significantly higher in the ritodrine group than in the control group during the periods of 28 w 0 d to 29 w 6 d, and 34 w 0 d to 35 w 6 d. Although no significant difference was observed, it suggests that the ritodrine group tended to have a higher CCO than the control group during the periods of 30 w 0 d to 31 w 6 d, and 32 w 0 d to 33 w 6 d. When the left and right ventricular stroke volumes were examined separately, both left cardiac output (LCO) and right cardiac output (RCO) tended to be higher in the ritodrine group than in the control group, but there was no statistical significance. In each period, the increase in cardiac output was associated with a significant increase in HR, with no significant increase in the TVI. The UVFV was significantly increased in the ritodrine group compared with the control group in each period. This was associated with a significant increase in both umbilical vein vessel diameter and umbilical vein blood flow velocity. As a result, distribution to the placenta tended to be significantly higher in the ritodrine group than in the control group, and a statistically significant difference was observed after 30 weeks of gestation. The umbilical artery pulsatility index (PI) was significantly lower in the ritodrine group than in the control group after 32 weeks of gestation. There was no difference in middle cerebral artery PI between the two groups during each period.

Fig. 2 shows the changes in CCO, UVFV, and distribution to the placenta according to the weeks of gestation. CCO and UVFV tended to increase as the gestational weeks increased. On the other hand, distribution to the placenta was constant at about 15% from 28 to 35 weeks of gestation. CCO and UVFV tended to increase significantly in the ritodrine group compared with the control group. As a result, distribution to the placenta significantly increased after 30 weeks of gestation.

Fig. 2.

Comparison of the ultrasound Doppler findings at each week of gestation between the control group and the ritrodine group. (a) Combined cardiac output. (b) Umbilical vein flow volume. (c) Distribution to the placenta. The dotted line indicates the ritodrine group, the solid line indicates the control group, and the error bar indicates the standard deviation. *p 0.05.

Regardless of the weeks of gestation, the ritodrine group showed a significant increase in fetal HR and tended to increase cardiac output as compared with the control group. The ventricular outflow tract diameter and TVI were almost the same between the two groups. The increase in UVFV in the ritodrine group was attributed to a significant increase in both umbilical vein diameter and blood flow velocity. As a result, distribution to the placenta was constant at approximately 20% in the ritodrine group and increased by approximately 5% compared with the control group between 28 and 35 weeks of gestation.

Ritodrine tocolysis significantly increased CCO, UVFV, and placental distribution of fetal blood flow. Ritodrine administration also increased fetal HR, which contributed to the increase in CCO. A previous study showed that ritodrine tocolysis significantly increased fetal HR and LCO [4]. Although that study did not consider vessel diameter, ritodrine did not change the ventricular outflow tract diameter and TVI in this study.

In this study, ritodrine tocolysis increased the umbilical venous diameter and UVFV. UVFV usually increases only with increasing vessel diameter according to gestational age [7, 8]. Furthermore, fetal breathing movements increase the umbilical vein’s blood flow, diameter, and blood flow velocity [9], but they do not affect fetal HR or umbilical arterial blood flow waveform. We believe that UVFV was augmented by ritodrine tocolysis. However, it remains unclear whether the vessel diameter dilation was caused by ritodrine directly or by passive dilation as a consequence of increased blood flow. We propose that the increase in UVFV resulted from a decrease in placental villous vascular resistance due to ritodrine-induced vasodilation.

Other investigators have described reductions in the Doppler indices associated with the umbilical artery, following ritodrine tocolysis [10, 11]. In this study, the uterine artery PI decreased in the ritodrine group in cases with more gestational weeks. These findings suggest that ritodrine acts as a vasodilator of the fetal vasculature. It has also been reported that ritodrine increases the extensibility and volume of large blood vessels and reduces peripheral vascular resistance [12]. We expect that lower peripheral vascular resistance in the fetus contributes to an increase in the distribution of cardiac output to the placenta.

The distribution to the placenta decreases in patients with fetal growth restriction and placental dysfunction [2]. In growth-restricted fetuses, absolute and relative UVFV are lower [13, 14], while CCO is relatively normal, which seems to augment the recirculation of the umbilical blood within the fetal body. Hence, bed rest and tocolytic drugs may be used empirically for patients with fetal growth restriction [3]. The findings of this study showed that ritodrine tocolysis increased the distribution of cardiac output to the placentas of fetuses that were developing normally. Whether ritodrine tocolysis can increase the distribution of cardiac output to the placenta in patients with fetal growth restriction and placental dysfunction remains unclear. However, if the distribution to the placenta can also be augmented in these patients, it may be possible to increase oxygen delivery to the fetal tissue. The clinical question is whether tocolytic drugs improve distribution to the placenta, which is reduced in FGR, and whether it leads to improvement in chronic hypoxia. We think it is necessary to consider these in future research. In fetal physiology, ritodrine increases cardiac output due to fetal tachycardia, but tocolytic drugs other than ritodrine may not increase cardiac output. If UVFV increases without an increase in cardiac output, the rate of increase in distribution to the placenta will be higher. We think it is important to understand how distribution to the placenta changes with tocolytic drugs other than ritodrine.

We acknowledge that evaluation of the distribution to the placenta is not possible for all outpatients who undergo routine pregnancy check-ups using ultrasound; hence, there was a potential for selection bias. While we limited the level of error by using a single sonographer, the lack of repeatable measurements was a limitation of our study.

In summary, ritodrine tocolysis increases the distribution of fetal cardiac output to the placenta, which is largely attributable to a greater increase in UVFV compared to CCO. We believe that tocolytic drugs increase the distribution to the placenta and improve the low-oxygen concentrations that are present in growth-restricted fetuses.

UVFV, umbilical vein flow volume; CCO, combined cardiac output; TVI, time-velocity integral; TAMXV, time-averaged maximum velocity.

RS designed the research study and analyzed the data. RS, TS, and KM performed the operation and collected the data. KM supervised the study. All authors contributed to editorial changes in the manuscript. All the authors approved the final version of the manuscript.

The study was conducted in accordance with the Declaration of Helsinki, and the protocol for this study was approved by the ethics committee of Gifu University Hospital, Gifu, Japan (approval number: 29-380). This was a retrospective study, and the data used for statistical analyses were collected from medical records. All laboratory tests were performed on patients as a routine practice. The Ethics Committee did not require written informed consent from each patient, but instead required printed information (post-out) to be provided about the study. All participants were given the opportunity to refuse inclusion of their data in the study.

We gratefully acknowledge the work of past and present members of our department, and our precious family for the understanding they showed for our work.

This research received no external funding.

The authors declare no conflict of interest.