An isolated RFOF is rare and easily overlooked in prenatal ultrasound examinations. The incidence of isolated RFOF detected by ultrasonography is only 0.6–1.7%[9, 10]. To date, only two cases of prenatal diagnosis have been reported, including one case by Hagen et al. and one by Devadasan et al.. This study systematically analyzed the ultrasonographic features of isolated RFOF for the first time, including atrial and ventricular asymmetry, disproportion between the pulmonary artery and aorta, dysplasia of the aortic arch, narrowing of the aortic isthmus, aneurysmal dilatation of the ductus arteriosus, and premature atrial beats.
This study found that with increasing RFOF severity, the asymmetry of intracardiac structures and the disproportion between the pulmonary artery and aorta became more obvious, the dysplasia of the aortic arch became more serious, and the AID became thinner. These ultrasonographic features are similar to those of CoA (Table 2), which is consistent with the results reported by Vena et al.. Fetal cardiovascular development depends on an increase in blood volume and the impact of blood flow[1, 2]. The main causes of the asymmetric development of intracardiac structures in RFOF are as follows: (1) the high activity of the foramen ovale flap affects the blood flow through the foramen ovale; (2) the protruding foramen ovale flap blocks the inflow of blood through the mitral valve; and (3) the flow of oxygen-rich blood from the ductus venosus is disturbed, causing turbulence[8, 16, 17]. These factors reduce the flow of blood through the left heart system, resulting in hypoplasia of the left heart.
Prenatal ultrasound diagnosis of fetal CoA has a high false positive rate. Perolo et al. reported the results of 10 years of diagnosing fetal cardiac malformation and found that the accuracy of prenatal diagnosis of CHD was as high as 91%. The false positive diagnosis rate was 3.4%, and the main false positive diagnosis was CoA. Stos et al. reported that the diagnostic accuracy for 202 fetuses with severe CoA was only 19% if a PAD/AoD > 1.6 was used as the prediction index. Jung et al. reported 44 fetuses with an isolated right dominant heart (RDH) whose RAD/LAD, RVD/LVD, and PAD/AoD were greater than 1.5. Their results showed that 66% of fetuses with RDH were normal newborns after delivery and that 34% had cardiac disorders, with CoA and an interrupted aortic arch accounting for 27.2% of cases. The false positive diagnosis of CoA may be related to isolated RFOF[8, 10]. RFOF affects the blood flow into the left heart through the foramen ovale, increasing the blood volume through the ductus arteriosus and reducing the blood volume through the aortic arch, finally causing dysplasia of the aortic arch[1, 2, 16]. This may be one of the reasons why RFOF is misdiagnosed as CoA. Another reason is that both RFOF and CoA result in a disproportion between the left and right heart. In fetuses with RFOF, the foramen ovale and ductus arteriosus are closed after birth, and pulmonary vascular resistance decreases considerably. This process changes the blood flow through the pulmonary artery and aorta and increases aortic blood flow, causing the aortic arch to expand and continue to develop. Therefore, fetuses with CoA and RFOF have different prognosis. In summary, the presence of RFOF must be considered for fetuses with suspected CoA on prenatal ultrasound examinations. In this study, the difference in the FOFD/LAD ratio between the RFOF group and the CoA group was statistically significant, which may be helpful in distinguishing between RFOF and CoA.
It should be emphasized that the ultrasonographic features of RFOF are also similar to those of RFO, including atrial and ventricular asymmetry and a narrowed aortic isthmus[6, 7, 9]. The asymmetric growth of intracardiac structures in RFO is mainly due to obstruction of the blood flow through the foramen ovale, and the normal functions of the left heart are mostly taken over by the right heart. Although some studies have previously identified RFOF as RFO, their prognoses are different. The prognosis of fetuses with an RFO is poor, and that of fetuses with an RFO complicated with CHD is even worse[2, 6, 16]. However, the prognosis of fetuses with an isolated RFOF is better. The four fetuses with an isolated RFOF described by Devadasan and Hagen et al.[9, 10] had no adverse outcomes. Fetuses with an isolated RFOF described by Vena et al. also had no adverse perinatal outcomes. Uzun et al. reported 23 cases of RFO without an abnormal heart structure, including 21 cases of RFOF without structural heart disease. Among these cases, two newborns died, including one with VACTERL association and one with Menke syndrome, a posterior urethral valve, and bradycardia. Four newborns presented pulmonary arterial hypertension, all of whom had other abnormalities including hypothyroidism, anemia, edema, Down's syndrome, or hypospadias. The remaining fetuses had no adverse outcomes. In our study, none of the 15 fetuses with an isolated RFOF developed CoA or other adverse outcomes. Therefore, in view of the different prognoses of fetuses with isolated RFOF and RFO, an isolated RFOF should be clinically distinguished from an RFO. When atrial and ventricular asymmetry are found in prenatal ultrasound examinations, whether the foramen ovale flap is redundant or restrictive must be determined, and whether other maternal and fetal complications are present should be noted.
In summary, measurement and calculation of the FOFD/LAD, observation of blood flow through the foramen ovale, and observation of the activity of the foramen ovale flap contribute to the differential diagnosis between RFOF and CoA or RFO.
This study had some limitations, including its retrospective nature. The findings of this study need to be validated in prospective studies in the future. Furthermore, the sample size was relatively small due to the strict selection criteria. According to the means and standard deviations of RAD/LAD, RVD/LVD, PAD/AoD, and aortic isthmus Z–score in our study, assuming an alpha of 0.05 and power of 0.8, the number of subjects needed to detect significant differences between the RFOF and CoA groups would be 106. Hence, we cannot be sure whether the lack of a significant difference was caused by truly no difference or an insufficient sample size. However, based on the study by Vena et al., we tend to favor the former explanation. In addition, according to the means and standard deviations of the FOFD/LAD, with group sample sizes of 15 and 9 in our study, assuming an alpha of 0.05, the statistical power to detect a difference between the RFOF and CoA groups was 1.0, indicating that the conclusion is still reliable.