Thinking Outside the “Flow-Mediated” Box: An Analysis of Aortic Dilation in 100 Fetuses with Tetralogy of Fallot Compared to Matched Controls

Background Aortic dilation in tetralogy of Fallot (TOF) is primarily attributed to increased aortic flow in utero . An alternative hypothesis is abnormal neural crest cell migration, with unequal septation of the truncus arteriosus resulting in a larger aorta and inherently hypoplastic pulmonary artery (PA). If so, we hypothesize the aorta to PA ratio (Ao:PA) in TOF is stable throughout gestation, and the total sum of dimensions of the great arteries is similar to controls. Methods We performed a single-center retrospective study of all fetuses with TOF (2014-2020) and gestational age-matched controls. We compared sums of diameters, circumferences, and cross-sectional areas of the aorta and PA and evaluated the Ao:PA across gestation in TOF with pulmonary stenosis (TOF-PS) and atresia (TOF-PA). We analyzed data with two-tailed t-tests and Pearson’s correlation. Results There were 100 fetuses with TOF (36% TOF-PA) with median gestational age of 31 weeks [IQR 26.5, 34.4] and median maternal age of 34 years [IQR 30, 37]. There were no differences in sums of great artery dimensions between TOF-PS and controls. In TOF-PA, sums were significantly lower than controls. The Ao:PA was stable throughout gestation. Conclusions The aorta in fetal TOF is large but grows proportionally throughout gestation, with a sum of great artery dimensions similar to controls. TOF-PA appears to be distinct from TOF-PS (with overall smaller dimensions), and is a group that warrants further investigation. In conclusion, our findings do not support the flow-mediated model of aortic dilation in TOF, and instead suggest an intrinsic developmental mechanism. What’s New? What are the clinical implications? ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NA; Not a clinical trial. ### Funding Statement This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The protocol for this study was approved by Stanford University's Institutional Review Board Panel on Medical Human Subjects (protocol #50981). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Not Applicable Author MND had full access to all data in the study and attests to its integrity and the data analysis.