The neurodevelopmental and mental health outcomes in children with single ventricle physiology and Fontan circula7 on: a state-of- the-art review and future direc7 ons

Abstract

The survival of pa5ents with single ventricle circula5on undergoing Fontan opera5on has significantly improved in the last decades. However, the neurodevelopmental outcome of this pa5ents is s5ll not sa5sfying and far below the healthy controls. The ae5ology of neurodevelopment disability and mental health disorders is mul5factorial and has a cumula5ve and synergic trend over the years. Gene5c factors, abnormal fetal circula5on, peri and intra-opera5ve care, mul5ple hospitaliza5ons and socioeconomic status play a crucial role in this process. Due to the heterogeneity of anatomies and different treatment possibili5es there is a need for a personalized, mul5disciplinary and transla5onal approach focused on the pa5ent. The introduc5on of new technologies driven by ar5ficial intelligence and the con5nuous integra5on of in vivo data and biomedical simula5ons into medicine promises significant improvements in pathologies diagnosis and treatment thus enhancing the quality of life of pa5ents and their families.

Keywords

• 1 Neurodevelopmental outcomes
• Single ventricle physiology
• Fontan circula5on
• Future direc5ons
• Bioengineering

2. Material and methods

Relevant studies were iden5fied by PubMed, Embase and Cochrane. No language restric5ons were used. The first search from PubMed, Embase and Cochrane was performed by the first 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 ar5ficial intelligence OR computa5onal models) AND (congenital heart disease OR single ventricle OR hypoplas5c le` heart syndrome OR Fontan circula5on). We included only papers from January 2000 up to August 2022. Older papers were excluded, with the excep5ons of papers explaining concepts, surgical techniques or to compare the neurodevelopment outcome early a`er the introduc5on of the Fontan opera5on.

3. E7 ology and risk factors of neurodevelopmental disability

The ae5ology of neurodevelopmental disability in pa5ents with single ventricle physiology is mul5factorial and has a cumula5ve and synergic trend over the years. In many pa5ents with congenital heart disease (CHD) there is a predisposi5on to extracardiac and brain congenital anomalies [ 9 ]. Indeed, an exome sequencing of 1213 CHD parent-offspring trios iden5fied shared gene5c contribu5ons to CHD and neurodevelopmental disabili5es [ 10 ]. Moreover, the abnormal fetal circula5on typical of univentricular physiologies is o`en related to brain dismatura5on. Fetuses with hypoplas5c le` heart syndrome (HLHS) have altered cerebral perfusion and oxygena5on due to intracardiac mixing and the retrograde brain perfusion through the ductus arteriosus and the hypoplas5c aorta. This abnormal perfusion has a drama5c effect on brain growth and matura5on. In fact, even term infants with HLHS have smaller and less mature brains than controls [ 11 ]. Fetal brain magne5c resonance imaging (MRI) of pa5ents with CHD at 25–35 weeks of gesta5on demonstrated significantly lower matura5on scores compared to healthy controls. In par5cular germinal matrix, myelina5on and superior temporal sulcus scores were significantly delayed in this popula5on [ 12 ]. Moreover, a comprehensive neuropathologic evalua5on of 11 elec5vely aborted HLHS fetuses revealed chronic diffuse white mac 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 postopera5ve spectrum of brain MRI of pa5ents with cri5cal CHD, including pa5ents with HLHS. Interes5ngly, 348 MRI scans confirmed that the most affected area involved before and a`er surgery is the white mac er in 25% and 30% of infants, respec5vely. They also noted that 6% of these pa5ents presented with arterial ischemic stroke even before surgery. Finally, not only thrombo5c lesions were reported but also hemorrhagic injuries especially intraparenchymal cerebral haemorrhage, cerebellar haemorrhage, intraventricular haemorrhage and subdural haemorrhage [ 14 ]. Interes5ngly, this punctate WMI typical of pa5ents with CHD, share a similar injury pac ern to preterm infants [ 15 ]. Guo et al. analysed 216 term-born CHD neonates and WMI was iden5fied in 86 of them [ 16 ]. The comparison between WMI and preterm neonates highlighted that WMI in pa5ents with CHD has a specific topology with a preference for anterior and posterior lesions. Indeed, the central areas are less vulnerable in comparison to the preterm neonates, reflec5ng the expected matura5on of pre-oligodendrocytes [ 16 ]. Despite the improvements in surgical techniques and post-opera5ve intensive care, deep hypothermic circulatory arrest (DHCA) nega5vely impacts on the neurologic outcome. In many centers, regional low-flow cerebral perfusion (RLFP) is used instead of DHCA to reduce the 5me of cerebral ischemia. A recent study comparing brain MRI before and a`er Norwood opera5on 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 aor5c arch obstruc5ons including HLHS showed no significant difference between these techniques [ 18 ]. When analyzing early neurodevelopmental outcomes a`er cardiac surgery, these opera5ve factors may be even less important than pre- and post-opera5ve factors such as longer postopera5ve 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 func5onal status and fine motor, problem-solving, adap5ve behaviour and communica5on skills at the age of 6 years in comparison to pa5ents with higher SES [ 20 ]. Finally, these children usually experience mul5ple hospitaliza5ons, catheteriza5on and eventually further surgeries. Every addi5onal procedure increases the risk of brain injuries due to anaesthesia, cardiac bypass and cardiac thromboembolism. These pa5ents are naturally predisposed to thromboembolic events and stroke due to liver dysfunc5on or protein-losing enteropathy, which plays a role in the coagula5on-fibrinolysis balance [ 21 ]. The common findings of high haematocrit and pro-inflammatory status also increase the thromboembolic risk. Finally, the blood mix and direct venous-arterial connec5on through interatrial communica5on, single ventricle and Fontan fenestra5on in the different 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 substan5al progress in care, this popula5on s5ll presents with cogni5ve, motor, social and psychological deficits. In the late '80s around 64% of pa5ents with HLHS presented major developmental disabili5es at some point in their stage-pallia5on [ 23 ]. More recent studies and reviews bring different 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, repor5ng no significant difference in Wechsler Intelligence scale from the healthy popula5on [ 25 ]. On the contrary, a recent na5onwide Finnish prospec5ve study of 23 pa5ents with HLHS, 13 with other univentricular physiology, and 40 healthy controls followed un5l 5 years old demonstrated a significantly lower median full-scale IQ at preschool age, in the first two groups in comparison to the healthy controls. This study also confirmed a high rate of brain MRI abnormali5es, mainly ischemic in 82% of the pa5ents 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 significantly lower compared to the general popula5on. Indeed, they obtained lower intelligence test scores, decreased motor func5on, impaired visuospa5al abili5es and more marked behavioral disorders [ 27 ]. Promising data are coming from the recent introduc5on of hybrid approaches for ini5al pallia5on of HLHS, that has shown more favourable neurodevelopment outcomes and quality of life at 2–3 years of age, with cogni5ve, language and motor composite scores on the Bayley-III not significantly different from healthy peers [ 28 ].

Interes5ngly, when compared to preschool children with CHD undergoing biventricular repair, pa5ents 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, ac en5on, and impulsivity [ 29 ]. Even more controversial is the sub-analysis of the HLSH group versus other func5onal single ventricle anatomies. According to Goldberg et al. the HLHS group had significantly lower Wechsler Intelligence scores than the non-HLHS group but no significant difference in the behavioural scores [ 25 ], while Gaynor et al. found no significant difference in the neurodevelopmental outcomes among the two groups [ 29 ].

Finally, a studies focusing on specific neurocogni5ve aspects,, analysing the deficits in visual-percep5ve skills and execu5ve func5on highlighted that the Fontan group didn't differ significantly 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 execu5ve func5on, pa5ents with single ventricle physiology displayed deficits in flexibility 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 mul5ple hospitaliza5ons and interven5ons, stressful life events, social and cultural factors [ 32-34 ]. A recent large compara5ve cross-sec5onal study from the Texas Children’s Hospital including 1164 pa5ents with CHD from 4 to 17 years old highlighted that 18.2% of this popula5on had a diagnosis or medica5on for anxiety or depression, significantly higher than healthy peers. In par5cular children with complex single ventricle hearts had around 7 5mes higher odds of developing anxiety and/or depression [ 35 ]. DeMaso et al. from Boston Children’s Hospital confirmed 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%). Specifically, they presented with increased risk of anxiety disorders and Ac en5on deficit hyperac5vity disorder (ADHD) [ 36 ]. The same group also highlighted that early-term-born adolescents with single ventricle anatomy (born between 37 and 38 weeks gesta5on) 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 pa5ents with single ventricle physiology, as shown by Pike et al. who correlated this condi5on to signs of chronic injury at MRI in specific brain areas controlling cogni5on, anxiety, and depression [ 38 ].

However, despite all the neurodevelopmental and psychiatric issues and the mul5ple opera5ons and interven5ons, the quality of life (QoL) of these pa5ents is self-perceived normal, even when compared to healthy controls [ 39,40 ]. Similar conclusions come from a more recent study highligh5ng that a higher level of educa5on and full-5me occupa5on posi5vely influences pa5ents' quality of life [ 41 ].

6. Biomedical technologies and future direc7 ons

Considering the anatomical inter-variability and the plethora of possible treatment strategies for pa5ents with single ventricle physiology, the way forward to obtain bec er outcomes and longer life expectancy is a mul5disciplinary and integrated approach tailored on the single pa5ent: personalised surgical approach as well as ad-hoc peri and post-opera5ve care, combined with affordable short and long-term predic5on tools is the future challenge. A transla5onal approach, combining biomedical engineering methodologies and advanced imaging technologies may address this topic, improving the surgical results and the neurodevelopmental outcomes. In this regard, Computa5onal Fluid Dynamics (CFD) to simulate the hemodynamics in pa5ents with single ventricle physiology models has been already applied successfully e.g. to predict the best surgical solu5on in the different pallia5on stages [ 42-46 ]. More in detail, CFD was largely adopted to assess the flow efficiency of the systemic-pulmonary shunt, at the ventricular and neoaor5c level and in the Fontan circula5on quan5fying energy losses and how the lac er correlate with the clinical outcome. The capability of exploring different hemodynamic scenarios adop5ng pa5ent-specific computa5onal models where virtual surgical connec5ons can be pre-opera5vely tested can be extremely useful for surgical and clinical decision-making. The availability of in silico but also in vitro models of possible surgical op5ons supports the iden5fica5on of the best surgical pathway, stressing the differences in the local hemodynamics, e.g. analyzing the impact that compe55ve flows might have in terms of energe5cs of the system. For instance, in Norwood I opera5on, a model-based approach may support the pa5entspecific selec5on between the two most commonly used shunts: the Blalock-Taussig shunt and the Sano shunt. In fact, different variables contribute to the performance of these shunts, e.g. their size, length and posi5ons, affec5ng the fine balance between systemic and pulmonary blood flow [ 47,48 ]. This is an important issue among surgeons and paediatric cardiologists as there is s5ll debate about performing one or the other shunt considering that the transplanta5on-free survival at 12 months is significantly bec er with the Sano shunt but there is no significant difference a`er one year between the two groups [ 49,50 ].

Moreover, biomedical simula5ons may predict the possibility of thrombus forma5on in the Fontan circula5on eventually responsible for stroke in case of conduit fenestra5on [ 51 ]. The analysis of the different flow condi5ons, flow stagna5on and gra` size may an5cipate the need for more strict an5coagula5on to avoid cerebral accidents. The advantage of these technologies is not only in terms of op5miza5on and personaliza5on of treatment for these pa5ents but will also allow a bec er resource distribu5on that can be invested in other aspects of their complex care.

On the other side, a strict follow-up of these pa5ents would guarantee the prompt recogni5on of neurocogni5 ve impairment and mental health disorders, allowing the early start of the neurodevelopmental interven5ons and psychological and educa5onal support [ 52 ]. Numerous tools to improve execu5ve func5on have been proposed for pa5ents with ADHD and children with learning disabili5es, with promising results [ 53,54 ]. Nevertheless, there is insufficient experience in the field of CHD. A preliminary experience with the Cogged interven5on, consis5ng of home-based 45-minutes training sessions for 5-8 weeks, demonstrated to improve the self-regulatory control abili5es of adolescents with CHD, but with no effects on other execu5ve func5ons or behavioral outcomes [ 55 ].

Finally, AI is expanding in the medical field, and in CHD as well. From the viewpoint of the clinician, ar5ficial intelligence can be seen as a diagnos5c and therapeu5c technology that enabling the analysis of very large pools of data, allows the discovery of pac erns not immediately obvious [ 56 ]. Among the AI applica5ons of specific interest here we men5on its integra5on with fetal echocardiography for the extrac5on of undiscovered image features, a promising approach which can markedly improve image acquisi5on and op5miza5on, automated measurements, classifica5on of diagnoses etc [ 57 ]. This is of relevance because prenatal diagnosis of CHD is crucial in parents' decision-making regarding the con5nua5on 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 predic5ng the adverse outcomes for congenital heart surgery as in improving social interac5on and suppor5ve educa5on in pa5ents with worse neurodevelopmental outcome a`er surgery [61,62].

7. Conclusion

More than 50 years a`er the introduc5on of the Fontan procedure, surgical and periopera5ve care developments have improved medium and long-term survival of pa5ents with single ventricle physiology. Nevertheless, the neurodevelopmental and mental health outcome is s5ll not sa5sfying, despite a clear understanding of poten5al risk factors. The way forward is a personalized, mul5disciplinary and transla5onal approach with the integra5on of imaging technologies with biomedical simula5ons (such as the already employed CFD models) and AI (applied e.g. for image segmenta5on, geometry sampling and even genera5on of synthe5c data). It is expected that such a mul5disciplinary framework will lead to a significant improvement in the objec5ve quality of life of these pa5ents 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 innova5on program under the Marie Sklodowska-Curie-Innova5ve Training Network 2020, Grant Agreement N° 956394 (hc ps://parenth2020. com/). 10. References

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