4 Discussion

FO is covered by a free flap from the septum primum, which extends into the LA. In the fetus, 80% oxygenated blood flows into the LA via FO after it returns from the placenta through the umbilical vein.⁸ This shunt ensures flow to the LV part of the heart, providing more oxygenated blood to both cerebral and coronary vascular beds. Typically, FO is unrestrictive during pregnancy.^9,10 After birth, pulmonary vascular resistance decreases and systemic vascular resistance increases. This increased pulmonary venous return increases the left atrial filling pressure, ultimately leading to FOF closure.¹⁰ An echo-free zone near the interatrial septum was observed in the fetus using two-dimensional echocardiography and was considered normal FOF, which is thin, mobile, and unrestrictive, with a smooth curvature extending into the LA. The flow velocity through the normal FO is smooth.¹⁰ If the FOF increases halfway or more across the LA, it will be considered RFOF.¹¹ The RFOF incidence rate is 0.2%–1% and varies among different study subjects.¹² In our study, we observed a 0.31% rate of isolated RFOF occurrence in 28,308 normal fetuses. This result is consistent with that of Stewart et al.¹² The exact etiopathogenesis has not yet been explored, but it has been speculated that isolated primary RFOF could be caused by focal dysplasia or intrauterine injuries such as myocarditis.^3,13

Fetal echocardiography is the best method for identifying isolated RFOF. The four-chamber view and FO channel view are most commonly used for diagnosing isolated RFOF. In these views, the atrial septum and FO are perpendicular in 2D imaging and parallel in Doppler flow. Therefore, it is recommended that FO structure be assessed in these views under the guidance of color Doppler echocardiography. Our study displayed two-dimensional echocardiography of the four-chamber view, and demonstrated that the FOF was stiff without its normal flapping motion. The FOF protruded to the LA in diastole, extended more than 50% into the LA, and reached the lateral wall of the LA, which was close to the mitral valve in diastole. In the FO channel and four-chamber views, the hypermobile and RFOF also contracted and extended when responding to the fetal cardiac cycle. As seen from the color Doppler, there was thin right-to-left linear blood flow through the FO and lateral flow displacement around the FO from LA to LV. In addition, a reversal flow across the FO from the left to right shunt was observed. The flap excursion on M-mode is uniphasic, and the pulmonary venous return and mitral orifice flow were not impaired.

In this study, there were 11 cases with a FOF/LA ratio <0.65 and 76 cases with a ratio ≥0.65; of these, 53 showed ventricular disproportion. An FOF/LA ratio cut-off of ≥0.65 indicates a significant or extremely significant association with ventricular disproportion.⁷ Our results indicate that the degree of asymmetry of the ventricle is associated with the degree of protrusion of the septum primum into LA.

Generally, isolated RFOF should be considered when the left and right heart is disproportionate and there are no other cardiac defects. Typically, a smaller left side of the heart is an initial sign of isolated RFOF. It has been reported that isolated RFOF is one of the most common causes of smaller left hearts in fetuses, excluding congenital or structural heart disease; the RV/LV and PA/AO ratios are 1.23–2.12 and 1.04–2.38, respectively.¹ We obtained a similar ratio, RV/LV1.02–2.36, and a PA/AO ratio of 1.02–2.32. According to the study by Hagen et al.,¹⁴ RA dilation is more common than RV dilation because RA is the first chamber to be affected by overload, and RFOF could reduce blood flow across the FO due to increased RA pressure. Tricuspid regurgitation could further increase RA pressure. In our study, 53 RFOF cases (60.9%) showed dilated RA, and 10 cases (11.5%) had moderate or severe tricuspid regurgitation. RFOF decreased blood flow in the left side of the heart, which could decrease LA and LV dimensions, but systolic LV function remains unaffected compared to the right side of the heart.²

Isolated RFOF could be related to ventricular disproportion, especially in type-II and type-III cases. Some fetuses in our study displayed smaller left side of the heart, AO, and AOI. Seven fetuses who could have had coarctation of the aorta (COA) were referred to us. However, none of them had significant COA after their birth, but all had isolated RFOF. A significant amount of systemic venous return is diverted to the RV, depending on RFOF severity. Diminished flow from FO to LV leads to a smaller cavity, while reduced downstream blood flow into the descending aorta further decreased the original AOI. No statistical difference was identified between fetuses with isolated RFOF and fetuses with true fetal COA.^7,15 Isolated RFOF and COA can both cause similar morphological and hemodynamic variations in cardiac structures, but there are more fetuses with isolated RFOF than patients without CoA. In fetuses with isolated RFO, the pulmonary venous return will increase LA pressure, the FOF and atrial septum will be repositioned after birth, and LV filling and forward flow in the aortic arch could increase. This indicates that isolated RFOF could be self-limiting but not pathological.^10,15 Early detection of isolated RFOF in a fetus due to suspected COA or ventricular imbalance can minimize the effects of CoA at birth.¹⁵ The combination of AOI/DA<0.74 and the presence of constricted frame and/or isthmus blood flow disturbance can improve diagnostic accuracy.¹⁶ No cases with AOI/DA<0.74 were observed in our study. In clinical practice, a more rigorous assessment of the solitary RFOF bulge in a four-chamber view could reduce false positives and improve the specificity of prenatal COA diagnosis. The FOF/LA ratio can be calculated by measuring the maximum diameter of the RFOF and LA. If FOF/LA > 0.65, CoA should be diagnosed with caution because its indirect signs could be caused by RFOF.^10,15

In our study, three fetuses had premature atrial contractions and two fetuses had supraventricular tachycardia. The arrhythmia was resolved in both cases. A strong positive association has been reported between RFOF and fetal arrhythmias, the most common of which is the atrial complex of premature (PAC).¹⁷ Papa et al.¹⁸ reported 93 RFOFs in 1223 fetuses, 36% of which were associated with the PAC. They claimed that the pressure exerted on the atria by the redundant primary septum caused the ectopic heart rhythm. After birth, normalization of pulmonary circulation increases LA pressure, which closes FOF and eliminates the cause of these PACs.^17–19

Isolated RFOF occurs in approximately 1/3 of restrictive FO cases in normal fetus hearts.² Isolated RFOF can result in increased and dilated right heart blood flow, congenital heart failure, and fetal hydrops. In our study, there were no obvious cardiac abnormalities after birth, except in two isolated RFOF cases. Case #1 presented with Isolated RFOF with severe tricuspid regurgitation, pleural effusion, and ascites. The fetus was born at 31 weeks of gestation but died five days later. It is speculated that in early FO obstruction, elevated right heart filling pressure could lead to right congestive heart failure, which develops into fetal hydrops and tricuspid regurgitation. Case #2, who had isolated RFOF with moderate pericardial effusion and ascites, was born at 29 weeks of gestation but survived only one day. The presumed cause of death was FO obstruction in the uterus. These two cases represent the potential development of hydrops fetalis and tricuspid regurgitation in the late stages of pregnancy due to FO obstruction. Developments related to antenatal complications should be closely followed, and edema typically completely reverses with timely delivery, when isolated RFOF is the only factor.