Effect of ritodrine tocolysis on fetal cardiac output distribution to the placenta

Background : Adequate placental perfusion is important for fetal development and well-being, but the effect of tocolysis on placental perfusionisunclear. Theaimofthisstudywastoevaluatechangesin fetal cardiac output distribution to the placenta following ritodrine tocolysis. Methods : This retrospective study involved 244 ultrasound findings in 142 singleton cases of appropriate for gestational age fetuses. The fetal cardiac output distribution to the placenta was de-finedandcalculatedasthepercentageofumbilicalveinflowvolume (UVFV) based on the combined cardiac output (CCO). Ultrasound findings of 28 patients in the ritodrine group and 114 patients in the control group were compared using the unpaired t -test and Mann-Whitney U-test. Results : The CCO and UVFV increased as gestation progressed. Ontheotherhand,distributiontotheplacentawascon-stant at approximately 15% from 28 to 35 weeks of gestation. Compared with the control group, the ritodrine group showed a significant increase in fetal heart rate, and the CCO also increased. The increase in UVFV in the ritodrine group was attributed to a significant increase in both the umbilical vessel diameter and blood flow velocity. As a result, distribution to the placenta in the ritodrine group was constant at about 20% and had a 5% increase at each week of gestation compared to the control group. Conclusions : To conclude, ritodrine tocolysis increased the fetal cardiac output distribution to the placenta. Additional research is required to determine whether tocolysisimprovestheplacentalperfusioninfetalgrowthrestriction duetoreducedplacentalperfusion


Introduction
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.

Study population
This was a retrospective cross-sectional study.The study participants and the exclusion criteria are shown in Fig. 1.Given the risk of preterm labor, bed rest or ritodrine administration was started upon admission.Bed rest is advised when there is cervical length shortening; whereas, ritodrine is administered when there are evident uterine contractions.A ritodrine infusion in 5% glucose was initiated at a dose of 50 µg/min and was increased to a maximum of 200 µg/min until the maternal symptoms subsided.Gestational ages were determined based on the crown-rump lengths before 12 weeks of gestation or the mother's last regular menstrual period.

Sonography
The participants' pregnancies were examined during a 30min ultrasound session.All examinations were performed by a single sonographer using a Voluson E8 ultrasound system (GE Healthcare Japan Corporation, Tokyo, Japan) equipped with a RAB4-8-D probe (GE Healthcare Japan Corporation, Tokyo, Japan) set on low frequency.
All fetal blood vessel diameters were measured twice, and the average values were calculated.The inner diameter (D) of the aorta and the pulmonary artery was measured perpen-dicular to the vessel wall between the open semilunar valves in the zoomed images.The sample volume was placed at the ostia of the aorta and the pulmonary artery, and the maximum velocity during systole was recorded for 2-3 s during fetal quiescence.The angle correction was kept as low as possible.The systolic time-velocity integral (TVI) and heart rate (HR) were calculated from the average of three cardiac cycles.The left and right ventricular outputs were calculated as π•(D/2)2•TVI•HR, and CCO was calculated as the sum of the left and right ventricular outputs.For UVFV, the diameter of the intra-abdominal umbilical vein (D) was measured before that of the first portal branches perpendicular to the vessel wall.The time-averaged maximum velocity (TAMXV) was recorded over 5-10 s with the angle correction oriented along the axis of the vessel when fetal breathing movements were not observed.The UVFV was calculated as π•(D/2)2•TAMXV•1/2.The distribution to the placenta was defined and calculated as the percentage of UVFV based on the CCO.Fetal weights were estimated during ultrasound examinations [5].

Statistical analyses
All data were expressed as means and standard deviations.
The assumption of normality was checked for each variable.Continuous variables were compared using the unpaired ttest or u-test, and categorical variables were compared using the Fisher's exact or the Chi-square test.Statistical significance was set at p < 0.05.Statistical analyses were carried out using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [6], which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).

Results
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 ± 17 d vs. 38 w 2 d ± 13 d, p < 0.001) and a lower birth weight (2323 ± 529 g vs. 2828 ± 47 g, p < 0.001).There was no difference in standard deviation (SD) values based on standard birth weight (0.11 ± 0.79 vs. 0.03 ± 0.75, p = 0.538).Umbilical cord arterial blood pH (7.296 ± 0.068 vs. 7.294 ± 0.067, p = 0.800) and weight of the placenta (584 ± 136 g vs. 578 ± 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.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.

Discussion
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 ritodrineinduced 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.

Conclusions
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.

Fig. 2 .
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.

Table 2 . Comparisons of ultrasound Doppler findings between the two groups at each weeks of gestation.
, estimated fetal body weight; CCO, combined cardiac output; LCO, left cardiac output; LOT HR, left outflow tract heart rate; LOT d, left outflow tract diameter; LOT TVI, loft outflow tract time velocity integral; RCO, right cardiac output; ROT HR, right outflow tract heart rate; ROT d, right outflow tract diameter; ROT TVI, right outflow tract time velocity integral; UVFV, umbilical vein flow volume; UVd, umbilical vein diameter; UVF, umbilical vein flow; UA-PI, umbilical artery-pulsatility index; MCA-PI, middle cerebellum artery-pulsatility index; *, p < 0.05. EFBW