The neurodevelopmental and mental health outcomes in children with single ventricle physiology and Fontan circula on: a state-of- the-art review and future direc ons Enrico Piccinelli1,2, Gianfranco Butera1, Mara Pila 1, Micol Rebonato1, Roberto Formigari1, Marin Verrengia1, Alberto Testa1, Gianluigi Perri1, Umberto Morbiducci2, Marco Deriu2 and Lorenzo Galle 1 1 Paediatric Cardiology Department, Ospedale Pediatrico Bambino Gesù, Roma, Italy 2 PolitoBIOMed Lab, Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Italy Abstract The survival of pa ents with single ventricle circula on undergoing Fontan opera on has signi cantly improved in the last decades. However, the neurodevelopmental outcome of this pa ents is s ll not sa sfying and far below the healthy controls. The ae ology of neurodevelopment disability and mental health disorders is mul factorial and has a cumula ve and synergic trend over the years. Gene c factors, abnormal fetal circula on, peri and intra-opera ve care, mul ple hospitaliza ons and socioeconomic status play a crucial role in this process. Due to the heterogeneity of anatomies and di erent treatment possibili es there is a need for a personalized, mul disciplinary and transla onal approach focused on the pa ent. The introduc on of new technologies driven by ar cial intelligence and the con nuous integra on of in vivo data and biomedical simula ons into medicine promises signi cant improvements in pathologies diagnosis and treatment thus enhancing the quality of life of pa ents and their families. Keywords 1 Neurodevelopmental outcomes, Single ventricle physiology, Fontan circula on, Future direc ons, Bioengineering 1. Introduc on The Fontan procedure is the nal stage of three opera ons performed to palliate children born with single ventricle physiology. In these pa ents, due to the complex heart anatomy is impossible to repair the heart re-crea ng the physiologic biventricular circula on. The original opera on was described in 1968 by Francis Fontan in pa ents with tricuspid atresia [1]. Various modi ca ons have been developed in the following decades and the extracardiac total cavo-pulmonary connec on (TCPC), is now the most widely used [2]. In this opera on, the systemic venous blood coming from the inferior vena cava (IVC) is diverted through an extracardiac conduit connec ng to the pulmonary arteries (PAs), comple ng the previous performed Glenn connec on of the superior vena cava (SVC) to the PAs. In recent years, the survival of pa ents with single ventricle circula on has signi cantly improved due to the advancements in fetal diagnosis, periopera ve management and medical care [3,4]. Therefore, all the e orts are focused on reducing the long-term morbidity and improving quality of life and neuropsychological outcomes [5,6,7,8]. The literature regarding the neurodevelopmental outcomes in children with single ventricle physiology is redundant and o en controversial and no large randomized trials have been conducted. For this reason, we aim to provide a state-of-the-art review of the neurodevelopment and mental health outcomes of children with single ventricle physiology undergoing Fontan opera on in the modern era and to give insight into future direc ons and tools for neurodevelopment impairment predic on, including ar cial intelligence (AI). DETERMINED 2022: Neurodevelopmental Impairments in Preterm Children — Computa onal Advancements, August 26, 2022, Ljubljana, Slovenia *Corresponding author. email: do or.piccinelli@gmail.com (E. Piccinelli); gianfranco.butera@opbg.net (G. Butera); marco.deriu@polito.it (M. Deriu); lorenzo.galle @opbg.net (L. Galle ) orcid: 0000-0001-6987-2745 (E. Piccinelli) © 2022 Copyright for this paper by its authors. Use permi ed under Crea ve Commons License A ribu on 4.0 Interna onal (CC BY 4.0). CEUR Workshop Proceedings (CEUR-WS.org) 147 ti t ti ti ti tt tti ti ti ti ti ti ft ff ti ti ti ti ti ti ti tti fi ti tt ti ti ti ti ti ti ti ti ti fi ti t ti tt ti ti ti ti ti ti ti fi ti ti ti ti ti ti ti ti ti fi ti ti ti fi ti ti ff ti ti fi fi ti 2. Material and methods Relevant studies were iden ed by PubMed, Embase and Cochrane. No language restric ons were used. The rst search from PubMed, Embase and Cochrane was performed by the rst author of this review and double-checked by the other corresponding authors. The following keywords were used: (neurodevelopment outcome OR mental health OR neurodevelopment disability OR ar cial intelligence OR computa onal models) AND (congenital heart disease OR single ventricle OR hypoplas c le heart syndrome OR Fontan circula on). We included only papers from January 2000 up to August 2022. Older papers were excluded, with the excep ons of papers explaining concepts, surgical techniques or to compare the neurodevelopment outcome early a er the introduc on of the Fontan opera on. 3. E ology and risk factors of neurodevelopmental disability The ae ology of neurodevelopmental disability in pa ents with single ventricle physiology is mul factorial and has a cumula ve and synergic trend over the years. In many pa ents with congenital heart disease (CHD) there is a predisposi on to extracardiac and brain congenital anomalies [9]. Indeed, an exome sequencing of 1213 CHD parent-o spring trios iden ed shared gene c contribu ons to CHD and neurodevelopmental disabili es [10]. Moreover, the abnormal fetal circula on typical of univentricular physiologies is o en related to brain dismatura on. Fetuses with hypoplas c le heart syndrome (HLHS) have altered cerebral perfusion and oxygena on due to intracardiac mixing and the retrograde brain perfusion through the ductus arteriosus and the hypoplas c aorta. This abnormal perfusion has a drama c e ect on brain growth and matura on. In fact, even term infants with HLHS have smaller and less mature brains than controls [11]. Fetal brain magne c resonance imaging (MRI) of pa ents with CHD at 25–35 weeks of gesta on demonstrated signi cantly lower matura on scores compared to healthy controls. In par cular germinal matrix, myelina on and superior temporal sulcus scores were signi cantly delayed in this popula on [12]. Moreover, a comprehensive neuropathologic evalua on of 11 elec vely aborted HLHS fetuses revealed chronic di use white ma er injury (WMI) [13]. This brain dysmaturity represents the substrate for further brain injuries during and a er surgery. Stegeman et al. described the pre- and post- opera ve spectrum of brain MRI of pa ents with cri cal CHD, including pa ents with HLHS. Interes ngly, 348 MRI scans con rmed that the most a ected area involved before and a er surgery is the white ma er in 25% and 30% of infants, respec vely. They also noted that 6% of these pa ents presented with arterial ischemic stroke even before surgery. Finally, not only thrombo c lesions were reported but also hemorrhagic injuries especially intraparenchymal cerebral haemorrhage, cerebellar haemorrhage, intraventricular haemorrhage and subdural haemorrhage [14]. Interes ngly, this punctate WMI typical of pa ents with CHD, share a similar injury pa ern to preterm infants [15]. Guo et al. analysed 216 term-born CHD neonates and WMI was iden ed in 86 of them [16]. The comparison between WMI and preterm neonates highlighted that WMI in pa ents with CHD has a speci c topology with a preference for anterior and posterior lesions. Indeed, the central areas are less vulnerable in comparison to the preterm neonates, re ec ng the expected matura on of pre-oligodendrocytes [16]. Despite the improvements in surgical techniques and post-opera ve intensive care, deep hypothermic circulatory arrest (DHCA) nega vely impacts on the neurologic outcome. In many centers, regional low- ow cerebral perfusion (RLFP) is used instead of DHCA to reduce the me of cerebral ischemia. A recent study comparing brain MRI before and a er Norwood opera on highlighted the presence of new or worsened ischemic lesions in 73% of infants, especially periventricular leukomalacia and focal ischemic lesions [17]. Furthermore, a randomized, controlled trial comparing new cerebral injuries on MRI a er surgery using DHCA or antegrade cerebral perfusion in neonates with complex aor c arch obstruc ons including HLHS showed no signi cant di erence between these techniques [18]. When analyzing early neurodevelopmental outcomes a er cardiac surgery, these opera ve factors may be even less important than pre- and post-opera ve factors such as longer postopera ve stay in intensive care, which are associated with lower psychomotor and mental development index [19]. Also socioeconomic status (SES) should be accounted for, because it emerged that children with single ventricle physiology and lower SES have reduced func onal status and ne motor, problem-solving, adap ve behaviour and communica on skills at the age of 6 years in comparison to pa ents with higher SES [20]. Finally, these children usually experience mul ple 148 fi ft ff ff fl ti ti ti fi ti ti ti ti ti ti ti ft fi ti ti ti ti ff ti fi ti ti ti ti ti ti ti ti ti ti ti fi ti ti ti ft fi ti ff ff tt ti tt ti ti ti ft ti ti ti ti ft ti ti fi ti fi fl ti ti ti ti ft ti ti fi ti ti ti ti ti ft ti ti ti fi ti ti ti fi ti ti ft ti fi ti ti tt ft ti hospitaliza ons, catheteriza on and eventually further surgeries. Every addi onal procedure increases the risk of brain injuries due to anaesthesia, cardiac bypass and cardiac thromboembolism. These pa ents are naturally predisposed to thromboembolic events and stroke due to liver dysfunc on or protein-losing enteropathy, which plays a role in the coagula on- brinolysis balance [21]. The common ndings of high haematocrit and pro-in ammatory status also increase the thromboembolic risk. Finally, the blood mix and direct venous-arterial connec on through interatrial communica on, single ventricle and Fontan fenestra on in the di erent stages raise the risk of stroke [22]. 4. Neurodevelopmental outcomes in Childhood In the last decades, the neurodevelopmental outcome of children with single ventricle physiology has improved. However, despite substan al progress in care, this popula on s ll presents with cogni ve, motor, social and psychological de cits. In the late '80s around 64% of pa ents with HLHS presented major developmental disabili es at some point in their stage-pallia on [23]. More recent studies and reviews bring di erent and controversial results [24]. Goldberg et al. assessed the neurodevelopmental outcome of 51 preschool children with HLHS and other single ventricle physiologies palliated with the Fontan procedure, repor ng no signi cant di erence in Wechsler Intelligence scale from the healthy popula on [25]. On the contrary, a recent na onwide Finnish prospec ve study of 23 pa ents with HLHS, 13 with other univentricular physiology, and 40 healthy controls followed un l 5 years old demonstrated a signi cantly lower median full-scale IQ at preschool age, in the rst two groups in comparison to the healthy controls. This study also con rmed a high rate of brain MRI abnormali es, mainly ischemic in 82% of the pa ents with HLHS and in 56% of children with other single ventricle anatomies [26]. When a broad range of neuropsychological outcome variables was extended from children to young adults with single ventricle physiology, they scored signi cantly lower compared to the general popula on. Indeed, they obtained lower intelligence test scores, decreased motor func on, impaired visuospa al abili es and more marked behavioral disorders [27]. Promising data are coming from the recent introduc on of hybrid approaches for ini al pallia on of HLHS, that has shown more favourable neurodevelopment outcomes and quality of life at 2–3 years of age, with cogni ve, language and motor composite scores on the Bayley-III not signi cantly di erent from healthy peers [28]. Interes ngly, when compared to preschool children with CHD undergoing biventricular repair, pa ents with single ventricle following the Fontan pathway presented with similar neurodevelopmental outcomes and full-scale IQ. However, the Fontan group performed worse in terms of processing speed, a en on, and impulsivity [29]. Even more controversial is the sub-analysis of the HLSH group versus other func onal single ventricle anatomies. According to Goldberg et al. the HLHS group had signi cantly lower Wechsler Intelligence scores than the non-HLHS group but no signi cant di erence in the behavioural scores [25], while Gaynor et al. found no signi cant di erence in the neurodevelopmental outcomes among the two groups [29]. Finally, a studies focusing on speci c neurocogni ve aspects,, analysing the de cits in visual-percep ve skills and execu ve func on highlighted that the Fontan group didn't di er signi cantly from the control group for the Test of Visual-Perceptual Skills summary but had worse results on all scales of both the copy and immediate recall trials of the Rey–Osterrieth Complex Figure [30,31]. Regarding the execu ve func on, pa ents with single ventricle physiology displayed de cits in exibility and problem-solving [31]. 5. Mental health and psychiatric disorders Children and adolescents with CHD have a higher risk of developing mental health disorders due to mul ple hospitaliza ons and interven ons, stressful life events, social and cultural factors [32-34]. A recent large compara ve cross-sec onal study from the Texas Children’s Hospital including 1164 pa ents with CHD from 4 to 17 years old highlighted that 18.2% of this popula on had a diagnosis or medica on for anxiety or depression, signi cantly higher than healthy peers. In par cular children with complex single ventricle hearts had around 7 mes higher odds of developing anxiety and/or depression [35]. DeMaso et al. from Boston Children’s Hospital con rmed that adolescents with single ventricle CHD who underwent the Fontan procedure have higher odds to receive a psychiatric diagnosis compared with healthy peers (65% vs. 22%). Speci cally, they presented with increased risk of anxiety disorders and A en on de cit hyperac vity disorder (ADHD) [36]. The same group also highlighted that early-term-born adolescents with single 149 ff ti ti ti fi ti ff ti ti ti ti ti fi ti ti fi ff ti ti fl ti ti ti fi fi fi fi ti ti ti fi fi ti ti ff ff ti ti fi fi fi ti ti fi ti fl ti ti ti ti ff ti ti ti ti ff ti ti ti tt ti ti fi ti fi fi ti ti ti fi fi ti ti tt ti ti ti ti fi fi ti ti ti ti ti ti ventricle anatomy (born between 37 and 38 weeks gesta on) were more likely to develop ADHD during their life when compared to full-term birth peers with the same physiology [37]. Depressive symptoms are also common in pa ents with single ventricle physiology, as shown by Pike et al. who correlated this condi on to signs of chronic injury at MRI in speci c brain areas controlling cogni on, anxiety, and depression [38]. However, despite all the neurodevelopmental and psychiatric issues and the mul ple opera ons and interven ons, the quality of life (QoL) of these pa ents is self-perceived normal, even when compared to healthy controls [39,40]. Similar conclusions come from a more recent study highligh ng that a higher level of educa on and full- me occupa on posi vely in uences pa ents' quality of life [41]. 6. Biomedical technologies and future direc ons Considering the anatomical inter-variability and the plethora of possible treatment strategies for pa ents with single ventricle physiology, the way forward to obtain be er outcomes and longer life expectancy is a mul disciplinary and integrated approach tailored on the single pa ent: personalised surgical approach as well as ad-hoc peri and post-opera ve care, combined with a ordable short and long-term predic on tools is the future challenge. A transla onal approach, combining biomedical engineering methodologies and advanced imaging technologies may address this topic, improving the surgical results and the neurodevelopmental outcomes. In this regard, Computa onal Fluid Dynamics (CFD) to simulate the hemodynamics in pa ents with single ventricle physiology models has been already applied successfully e.g. to predict the best surgical solu on in the di erent pallia on stages [42-46]. More in detail, CFD was largely adopted to assess the ow e ciency of the systemic-pulmonary shunt, at the ventricular and neo- aor c level and in the Fontan circula on quan fying energy losses and how the la er correlate with the clinical outcome. The capability of exploring di erent hemodynamic scenarios adop ng pa ent-speci c computa onal models where virtual surgical connec ons can be pre-opera vely tested can be extremely useful for surgical and clinical decision-making. The availability of in silico but also in vitro models of possible surgical op ons supports the iden ca on of the best surgical pathway, stressing the di erences in the local hemodynamics, e.g. analyzing the impact that compe ve ows might have in terms of energe cs of the system. For instance, in Norwood I opera on, a model-based approach may support the pa ent- speci c selec on between the two most commonly used shunts: the Blalock-Taussig shunt and the Sano shunt. In fact, di erent variables contribute to the performance of these shunts, e.g. their size, length and posi ons, a ec ng the ne balance between systemic and pulmonary blood ow [47,48]. This is an important issue among surgeons and paediatric cardiologists as there is s ll debate about performing one or the other shunt considering that the transplanta on-free survival at 12 months is signi cantly be er with the Sano shunt but there is no signi cant di erence a er one year between the two groups [49,50]. Moreover, biomedical simula ons may predict the possibility of thrombus forma on in the Fontan circula on eventually responsible for stroke in case of conduit fenestra on [51]. The analysis of the di erent ow condi ons, ow stagna on and gra size may an cipate the need for more strict an coagula on to avoid cerebral accidents. The advantage of these technologies is not only in terms of op miza on and personaliza on of treatment for these pa ents but will also allow a be er resource distribu on that can be invested in other aspects of their complex care. On the other side, a strict follow-up of these pa ents would guarantee the prompt recogni on of neurocogni ve impairment and mental health disorders, allowing the early start of the neurodevelopmental interven ons and psychological and educa onal support [52]. Numerous tools to improve execu ve func on have been proposed for pa ents with ADHD and children with learning disabili es, with promising results [53,54]. Nevertheless, there is insu cient experience in the eld of CHD. A preliminary experience with the Cogged interven on, consis ng of home-based 45-minutes training sessions for 5-8 weeks, demonstrated to improve the self-regulatory control abili es of adolescents with CHD, but with no e ects on other execu ve func ons or behavioral outcomes [55]. Finally, AI is expanding in the medical eld, and in CHD as well. From the viewpoint of the clinician, ar cial intelligence can be seen as a diagnos c and therapeu c technology that enabling the analysis of very large pools of data, allows the discovery of pa erns not immediately obvious [56]. Among the AI applica ons of speci c interest here we men on its integra on with fetal echocardiography for the extrac on of undiscovered image features, a promising approach which can markedly improve image acquisi on and op miza on, automated measurements, classi ca on of diagnoses etc [57]. This is of relevance because prenatal diagnosis of CHD is crucial in parents' decision-making regarding the 150 ff ti ti ti ti fi ti ti fi ti ti ti ti ti ti ti ti ti ti ti fl ti ff ti ti ti ti ff ff ti ti ti ti ti ti fi ti ti fi fl ti ti ti fl ti ti ti fi ffi ti ti ti fi ti ti ti ff fi ti ti ti ti ti ff fl ti ff ti ti ti ft ti ti tt ft fi ti ti ti ti ti ff ti tt ti ti ti ti ti fi ti ti ti ti fl ffi ti ti ti ti fl ti ti tt ti ti ti fi ti tt ti ti fi ff ti ti ti tt ti ti fi con nua on of pregnancy, based on the consolidated knowledge that neonates with postnatally diagnosed CHD have increased mortality and worse neurodevelopment outcomes before and a er surgery [58-60]. Within AI, machine learning models can be as important in predic ng the adverse outcomes for congenital heart surgery as in improving social interac on and suppor ve educa on in pa ents with worse neurodevelopmental outcome a er surgery [61,62]. 7. Conclusion More than 50 years a er the introduc on of the Fontan procedure, surgical and periopera ve care developments have improved medium and long-term survival of pa ents with single ventricle physiology. Nevertheless, the neurodevelopmental and mental health outcome is s ll not sa sfying, despite a clear understanding of poten al risk factors. The way forward is a personalized, mul disciplinary and transla onal approach with the integra on of imaging technologies with biomedical simula ons (such as the already employed CFD models) and AI (applied e.g. for image segmenta on, geometry sampling and even genera on of synthe c data). It is expected that such a mul disciplinary framework will lead to a signi cant improvement in the objec ve quality of life of these pa ents and their families. 8. Acknowledgements None 9. Funding The present research work has been developed as part of the PARENT project, funded by the European Union’s Horizon 2020 research and innova on program under the Marie Sklodowska-Curie-Innova ve Training Network 2020, Grant Agreement N° 956394 (h ps://parenth2020. com/). 10. References 1. Fontan FBE. Surgical repair of tricuspid atresia. Thorax. 1971;26:240–248. 2. Marcelle C, Corno A, Giannico S, et al. Inferior vena cava-pulmonary artery extracardiac conduit. A new form of right heart bypass. J Thorac Cardiovasc Surg. 1990;100(2):228–232. 3. Rychik J, Atz AM, Celermajer DS, et al. Evalua on and management of the child and adult with Fontan circula on: a scien c statement from the American heart associa on. Circula on. (2019) 140:e234– 84. 4. Wernovsky G. The paradigm shi toward surgical interven on for neonates with hypoplas c le heart syndrome. Arch Pediatr Adolesc Med 2008;162:849-54. 5. Anderson PAW, Sleeper LA, Mahony L, et al. 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