Maternal hyperoxygenation improves left heart filling in fetuses with atrial septal aneurysm causing impediment to left ventricular inflow

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1 Ultrasound Obstet Gynecol 2015; 45: Published online 4 May 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: /uog Maternal hyperoxygenation improves left heart filling in fetuses with atrial septal aneurysm causing impediment to left ventricular inflow A. CHANNING*, A. SZWAST*, S. NATARAJAN*, K. DEGENHARDT*, Z. TIAN* and J. RYCHIK* *The Fetal Heart Program, Cardiac Center, The Children s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Division of Cardiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA KEYWORDS: atrial septal aneurysm; congenital heart defects; fetal echocardiography; left ventricular hypoplasia; oxygen ABSTRACT Objectives Aneurysm of the atrial septum (AAS) with excessive excursion of septum primum into the left atrium is an uncommon and relatively benign fetal condition associated with impediment to left ventricular (LV) filling and the appearance of a slender, but apex-forming, LV on fetal echocardiography. Impediment to filling can be severe, creating the image of LV hypoplasia with retrograde aortic flow. We hypothesize that maternal hyperoxygenation alters atrial septal position, improves LV filling, and normalizes aortic flow in fetuses with AAS by increasing fetal pulmonary venous return. Methods Fetal echocardiography was performed prior to, and at 10 min of, maternal hyperoxygenation in 12 fetuses with AAS who were referred to our center because of LV hypoplasia. Atrial septal excursion (ASE), LV and right ventricular (RV) sphericity index (SI) and direction of flow in the aortic isthmus, as determined by Doppler, were measured. Results With maternal hyperoxygenation, mean ± SD ASE decreased (0.76 ± 0.17 before maternal hyperoxygenation vs 0.53 ± 0.23 after maternal hyperoxygenation; P < 0.01), consistent with increased pulmonary venous return, LV-SI increased (0.29 ± 0.06 vs 0.42 ± 0.06; P < 0.001), indicating increased LV filling, and the direction of aortic isthmus flow changed from retrograde in all cases prior to maternal hyperoxygenation to antegrade in 10 and to bidirectional in two. RV-SI remained unchanged (0.53 ± 0.13 vs 0.52 ± 0.10; P = 0.7). Conclusions In cases of AAS, short-term maternal hyperoxygenation increases fetal pulmonary venous return, substantially alters LV geometry and promotes antegrade flow in the aortic isthmus. This demonstrates proof-of-concept that maternal hyperoxygenation can improve filling of the left side of the fetal heart in AAS. Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd. INTRODUCTION Aneurysm of the atrial septum (AAS) with excessive excursion of septum primum into the left atrium is an uncommon fetal condition. Severe leftward bowing of an AAS may represent relative restriction to flow across the foramen ovale. Redundant AAS can bow markedly leftward, with atrial septal tissue itself causing impediment to inflow across the mitral valve, creating the appearance of a smaller-than-normal, thin, but apex-forming, left ventricle (LV) on fetal echocardiography. At times, impediment to LV filling can be severe, with identification of retrograde flow in the aortic arch, thus raising suspicion of LV hypoplasia. Despite the appearance of the LV and the altered flow in the arch, AAS is not typically a pathological condition that requires treatment. Redundant atrial tissue may be associated with atrial arrhythmias but is usually not reflective of structural heart disease; the condition is self-limiting. After delivery and the subsequent first breaths of the newborn, pulmonary venous return increases considerably, with repositioning of the atrial septum and a natural increase in LV filling, with normalization of ventricular size. Correspondence to: Dr J. Rychik, Fetal Heart Program, The Children s Hospital of Philadelphia, 34 th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA ( rychik@ .chop.edu) Accepted: 29 September 2014 Copyright 2014 ISUOG. Published by John Wiley & Sons Ltd. ORIGINAL PAPER

2 Maternal hyperoxygenation 665 The observation of fetal AAS with a small, thin, underfilled LV, ultimately manifesting as a completely normal LV after birth, has led us to investigate the possibility of recreating this phenomenon before birth. Maternal hyperoxygenation in the third trimester of pregnancy has been applied in a number of conditions, both from a diagnostic and therapeutic perspective It can promote fetal pulmonary vasodilation, thereby influencing the quantity of pulmonary venous return to the left side of the heart. The aim of this study was to investigate the possibility that fetal physiology can be manipulated to improve LV filling prenatally by exploring whether a short period of maternal hyperoxygenation could transiently improve filling of the left side of the fetal heart in cases of AAS. Our objectives were to determine whether maternal hyperoxygenation, through the process of improved LV filling, leads to (1) alteration in atrial septal position within the left atrium, (2) altered geometry of the LV and (3) normalization of flow direction in the aorta of a fetus with AAS and an underfilled LV. METHODS In this retrospective single-institution cohort study, the fetal echocardiographic database of The Fetal Heart Program at The Children s Hospital of Philadelphia was reviewed to identify all fetuses referred for evaluation of qualitative LV hypoplasia or small left-sided cardiac structures. Those that were found to have AAS from right to left, diagnosed between September 2008 and May 2013, were included. Fetuses with AAS who had undergone maternal hyperoxygenation testing during echocardiography were evaluated; maternal hyperoxygenation testing was part of our growing clinical experience in using this method of therapy for diagnostic purposes in a variety of prenatal conditions. We used the subsequent findings for clinical decision-making and confirming our suspicions of an absence of structural heart disease. Fetuses were excluded if AAS was not part of their diagnosis. Permission for the study was granted from the Institutional Review Board (Children s Hospital of Philadelphia Institutional Review Board No ). Fetal echocardiograms were performed using the standardized American Society of Echocardiography protocol on a Siemens Acuson Sequoia (Mountain View, CA, USA) ultrasound system, coupled with a 6C2 or an 8 V3 transducer 18. Echocardiographic measurements were obtained from videoclips (S1 S6) taken prior to and at 10 min of maternal hyperoxygenation with 100% FiO 2 via a non-rebreather face mask at 8 L of flow, effectively providing 60% FiO 2. The women remained on oxygen during image acquisition (maximum duration, 30 min total). Doppler flow patterns of the fetal middle cerebral artery (MCA), ductus arteriosus (DA) and umbilical artery (UA) were acquired during fetal apnea, according to methods published previously 19,20. For each examination, gestational age, pulsatility index (PI) for MCA, UA and RA A Figure 1 Diagram depicting measurements for determination of atrial septal excursion index, defined as maximum excursion of septum primum from plane of atrial septum towards left atrial (LA) free wall (A) divided by distance from plane of origin of atrial septum towards left atrial free wall (B). RA, right atrium. DA (defined as (peak systolic velocity end-diastolic velocity)/time-averaged mean velocity), atrial septal excursion (ASE) index, ventricular sphericity index (SI) and direction of flow at the aortic isthmus, determined by Doppler, were recorded. Assessment of the effect of maternal hyperoxygenation on the position of the atrial septum within the left atrium was performed by determining the ASE index before and during maternal hyperoxygenation. In the apical four-chamber view, the maximum extent of bowing of the atrial septum towards the left atrial free wall was measured and divided by the diameter of the left atrium, measured from the base of the atrial septum to the free wall of the left atrium (Figure 1). Marked leftward bowing of the atrial septum yields a high ASE index. With maternal hyperoxygenation, greater filling of the left atrium through increased pulmonary venous return might lead to repositioning of the atrial septum away from the left atrial free wall, moving it closer to the right atrium and thus decreasing the ASE index. Geometry of the LV was assessed by measuring the right ventricular (RV) and LV-SI, a measure of the degree of roundness of the ventricle. In the apical four-chamber view, the long axis of the ventricles was measured at end-diastole, from the plane of the atrioventricular valve to the ventricular cavity apex. The short-axis cavity width of the ventricle was then determined by identifying the 50% mid-portion of the ventricular cavity length and measuring the diameter of the ventricle width at that plane, from septum to free wall. The short axis was then divided by the long axis to calculate the SI 21. A thin underfilled ventricle would have a low SI (low ratio of width to length), while improved filling would create a more rounded globular ventricle with a higher SI. Finally, the direction of flow in the aortic isthmus was determined by comparing color-flow and pulsed Doppler tracings obtained before and at 10 min of maternal hyperoxygenation. Postnatal data of each fetus that received care at our institution were obtained, including results of the first and subsequent postnatal echocardiograms and interventions performed, B LA

3 666 Channing et al. as well as management data within the first month of postnatal life. Statistical analysis Descriptive characteristics were analyzed using the mean and standard deviation values for normally distributed data. Baseline differences in measurements prior to and during maternal hyperoxygenation were compared using Student s t-test for paired samples. P-values < 0.05 were considered significant. RESULTS Sixteen fetuses referred because of LV hypoplasia between September 2008 and May 2013 were found to have AAS with a slender, but apex-forming, LV on fetal echocardiography. Of these 16 fetuses, four had not undergone maternal hyperoxygenation testing; 12 underwent maternal hyperoxygenation testing during a fetal echocardiogram between 26.3 and 37.7 (mean, 35 ± 3) weeks gestation. These 12 patients were included as the final subjects of the study. Echocardiography findings are listed in Table 1. At 10 min of maternal hyperoxygenation, the ASE index had decreased significantly and LV-SI had increased significantly; however, there was no alteration in RV-SI. The direction of aortic isthmus flow changed from retrograde in all 12 cases before maternal hyperoxygenation to antegrade in 10 cases and to bidirectional in two (Figures 2 4). There was no change in qualitative ventricular function, no development of atrioventricular valve regurgitation and no evidence of ductal constriction with maternal hyperoxygenation, as assessed visually by two-dimensional and color-flow Doppler. Four patients underwent pulsed Doppler interrogation of the DA before and during maternal hyperoxygenation. The mean DA-PI in room air, prior to maternal hyperoxygenation, in these four patients was 2.39 ± 0.40 and the mean DA-PI during maternal hyperoxygenation was 2.51 ± 0.43 (P = 0.41). During maternal hyperoxygenation, Doppler interrogation data for UA flow were obtained in 7/12 subjects and for MCA flow in 9/12 subjects for comparison with values prior to maternal hyperoxygenation. The mean UA-PI in room air in the seven subjects was 1.02 ± 0.16 and mean UA-PI during maternal hyperoxygenation was 1.07 ± 0.11 (P = 0.052). The mean MCA-PI in room air in the nine subjects was 1.60 ± 0.61 and mean MCA-PI during maternal hyperoxygenation was 1.78 ± 0.47 (P = 0.23). Postnatal data were available for 11/12 fetuses; one fetus was delivered at another hospital. At birth, the LV appeared normal in size in all subjects, with no concerns about adequacy. Two patients exhibited evidence of coarctation of the aorta. Upon review of the fetal echocardiograms during maternal hyperoxygenation, one of these two had a change of aortic isthmus flow from retrograde to antegrade, with a significant increase in aortic isthmus peak velocity to > 1.5 m/s, and development of an antegrade diastolic run-off pattern. This neonate underwent cardiac catheterization 6 days postpartum to allow better identification of aortic arch anatomy following closure of the DA, which demonstrated coarctation by angiography. The patient subsequently underwent coarctectomy 7 days postpartum with extended end-to-end anastomosis via a left thoracotomy. The second patient had a similar change in direction of flow with maternal hyperoxygenation, from retrograde to antegrade, as seen in the other cases but without a change in velocity characteristics. Postnatal echocardiography revealed evidence of arch hypoplasia and subsequently the neonate underwent homograft patch augmentation of the aortic arch 10 days postpartum. All other patients had a normal postnatal course without clinical evidence of congenital heart disease. DISCUSSION Our report demonstrates proof-of-concept that fetal cardiovascular physiology can be manipulated through short-term maternal hyperoxygenation, leading to improved filling of fetal LV in cases with benign AAS. Restrictive AAS with marked bowing provides a natural human model of LV volume depletion in the setting of a structurally normal LV. We demonstrate that maternal hyperoxygenation increases left-sided pulmonary venous return, thereby repositioning the atrial septum. As expected, RV geometry does not change with maternal hyperoxygenation, as right-sided filling should not be affected. However, LV geometry does change, with increased left-sided pulmonary venous return leading to the appearance of a more spherical and more filled LV. As a consequence of increased filling and stroke volume, a greater blood volume is delivered into the aorta and the Table 1 Echocardiographic findings of 12 fetuses with aneurysm of the atrial septum before and at 10 min of maternal hyperoxygenation (MH) Echocardiographic finding Before MH At 10 min of MH P* Atrial septal excursion index 0.76 ± ± 0.23 < 0.01 Left ventricular sphericity index 0.29 ± ± 0.06 < Right ventricular sphericity index 0.53 ± ± Direction of flow at aortic isthmus Retrograde in 12 Antegrade in 10; bidirectional in 2 Data are given as mean ± SD. *Comparison of paired measurements using Student s t-test: P < 0.05 was considered statistically significant. Determined by color-flow and pulsed Doppler interrogation.

4 Maternal hyperoxygenation 667 Figure 2 Color-flow Doppler imaging (short-axis mediastinal view) in a fetus with aneurysm of the atrial septum. At baseline room air (a), there is normal direction of posterior-directed flow in the ductus arteriosus (DA) (red), but anterior-directed retrograde flow (blue) is noted in the transverse aortic arch (TRV AA). With maternal hyperoxygenation (b), normal antegrade flow (red) is noted in both aortic arch and DA. Note time interval between baseline and maternal hyperoxygenation recordings circled in top right corners. Figure 3 Color-flow Doppler imaging (long-axis aortic arch view) in a fetus with aneurysm of the atrial septum. At baseline room air (a), there is abnormal anterior-directed retrograde flow (red) in the transverse aortic arch (AA) (arrow). With maternal hyperoxygenation (b) normal antegrade flow (blue) is noted in the AA. Note time interval between baseline and maternal hyperoxygenation recordings circled in top right corners. Figure 4 Pulsed-wave Doppler interrogation of aortic arch (AA) flow in a fetus with aneurysm of the atrial septum, demonstrating retrograde flow at baseline (a) and antegrade flow with maternal hyperoxygenation (b). TRV, transverse.

5 668 Channing et al. direction of aortic isthmus flow is either normalized or improved. In our small series, short-term administration of maternal hyperoxygenation was safe, with no negative effects noted. Specifically, there was no evidence of constriction of the DA. Maternal hyperoxygenation has been used diagnostically and therapeutically in a variety of conditions. In the normal human fetus, a short period of maternal hyperoxygenation results in effective pulmonary vasodilation when administered in the third trimester of pregnancy 3. Relaxation of the pulmonary vasculature is possible, with a decrease in pulmonary vascular impedance, as measured by Doppler techniques. A lack of pulmonary vasoreactivity was shown to be poorly prognostic, predictive of fatal lung hypoplasia in conditions of potential lung under development 4. Investigators have used maternal hyperoxygenation to study intrauterine growth restriction, congenital diaphragmatic hernia, fetal lung hypoplasia and maternal pre-eclampsia Improvements in fetal circulatory Doppler flow patterns were demonstrated in growth-restricted fetuses that received maternal hyperoxygenation 17. Treatment of growth-restricted fetuses with maternal oxygen has also been reported, with a decrease in perinatal mortality; however, overall evidence is weak and the practice is not widely accepted currently 22. In addition, maternal hyperoxygenation has been studied in fetal congenital heart conditions, but in a limited manner. Our group has used this therapy to test for pulmonary vasoreactivity and to assess the health of the pulmonary vasculature in fetuses with hypoplastic left heart syndrome and an intact or highly restrictive atrial septum. Absence of the anticipated decrease in pulmonary artery PI is associated with the need for urgent intervention at birth and poor outcome 1. Maternal hyperoxygenation has now become a standard diagnostic tool used in echocardiographic assessment of all fetuses with hypoplastic left heart syndrome at our institution. One case series included 15 fetuses with a variety of forms of left-sided small heart structures and found that daily treatment with sustained periods of maternal hyperoxygenation potentially could accelerate growth of the left side of the heart safely 2. Maternal hyperoxygenation in fetal congenital heart disease holds promise as a diagnostic tool; however, further study is needed. In our series, two patients were noted to have coarctation of the aorta after birth. In one, increased volume load to the left side led to an abnormally elevated peak systolic velocity across the aortic isthmus, with a change in Doppler flow pattern contour, from one of normal appearance to that of an increased diastolic run-off, consistent with coarctation of the aorta. One can speculate that perhaps normalization of volume of flow revealed a relative narrowing that, under volume-depleted conditions of a restrictive atrial aneurysm, was not readily evident. This raises the possibility of studying the utility of maternal hyperoxygenation as a diagnostic tool for identification of coarctation of the aorta in fetuses with ventricular size disproportion 23. It should be stated that, although we observed coarctation in two of our patients with AAS, there is no known association between AAS and coarctation. Our study is limited by a small sample size and, consequently, we may have insufficient power to detect deleterious changes in our parameters with maternal hyperoxygenation testing. Furthermore, quantitative measurements were made without blinding as to whether the patient was on or off oxygen. There is, however, objective evidence that the direction of flow at the aortic isthmus improved in all cases, which can be explained only by increased forward flow through the LV. Moreover, we cannot be certain of the degree to which we truly raised fetal oxygen content. Cordocentesis has been performed in growth-restricted and normal fetuses that were given maternal hyperoxygenation, with a substantial rise observed in fetal oxygen partial pressure in the umbilical vein 13. Additional studies support the notion that increased fetal oxygenation can be achieved effectively by administering supplemental oxygen to the mother 16, We demonstrated proof-of-concept that the left side of the fetal heart can be volume-loaded through maternal hyperoxygenation. This raises a number of intriguing questions. Can sustained administration of maternal oxygen lead to chronic volume loading that may influence a change in cardiac structure over time? Might patients with structural borderline small LV, which may be non-viable as a systemic ventricle after birth, benefit from volume loading before birth in order to encourage growth? Furthermore, could increased aortic flow and increased fetal oxygen delivery through sustained maternal hyperoxygenation potentially influence brain maturation and mitigate the neurocognitive deficits associated with congenital heart disease? In summary, maternal hyperoxygenation can be used safely to manipulate fetal physiology to understand better complex congenital heart disease in the fetus. Our results demonstrate proof-of-concept that fetal physiology can be manipulated with improvements in LV filling through short-term maternal hyperoxygenation in cases of AAS. Maternal hyperoxygenation increases pulmonary venous return, which increases filling of the left atrium and leads to alteration in atrial septal position, greater filling of the LV and normalization, or improvement, of flow direction in the aorta. Continued investigation into the use of maternal hyperoxygenation for evaluating fetal cardiovascular physiology or its sustained use as possible treatment is warranted. ACKNOWLEDGMENTS We acknowledge the efforts and sonographic skills of Margaret McCann and Debra Soffer in evaluation of these patients. J. R. is supported by the Robert and Dolores Harrington Endowed Chair in Pediatric Cardiology at The Children s Hospital of Philadelphia, Philadelphia, PA, USA.

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Note red color of flow indicating antegrade flow in the ductus arteriosus, while there is blue color flow indicating retrograde flow in the adjacent aorta. Videoclip S4 Color-flow Doppler imaging in three vessels and trachea view at upper mediastinum during maternal hyperoxygenation. There is now antegrade flow (red color) in the aorta. Videoclip S5 Color-flow Doppler imaging of fetal aortic arch with mother in room air. There is red flow in the distal aortic arch isthmus region, indicating retrograde flow. Note color scale Nyquist limit is relatively high at 70 cm/s. Videoclip S6 Color-flow Doppler imaging of fetal aortic arch during maternal hyperoxygenation. Flow in the distal aortic arch isthmus region is now blue, indicating antegrade flow. Note color scale Nyquist is set at a similarly high level as in room-air assessment, indicating that color change is unlikely to be related to any aliasing, but rather is due to a true change in direction. Pulsed-wave Doppler interrogation confirms change in flow direction.