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Biological and structural phenotypes associated with neurodevelopmental outcomes in congenital heart disease.

ABSTRACT: Neurodevelopmental disability (NDD) is recognised as one of the most common comorbidities in children with congenital heart disease (CHD) and is associated with altered brain structure and growth throughout the life course. Causes and contributors underpinning the CHD and NDD paradigm are not fully understood, and likely include innate patient factors, such as genetic and epigenetic factors, prenatal haemodynamic consequences as a result of the heart defect, and factors affecting the fetal-placental-maternal environment, such as placental pathology, maternal diet, psychological stress and autoimmune disease. Additional postnatal factors, including the type and complexity of disease and other clinical factors such as prematurity, peri-operative factors and socioeconomic factors are also expected to play a role in determining the final presentation of the NDD. Despite significant advances in knowledge and strategies to optimise outcomes, the extent to which adverse neurodevelopment can be modified remains unknown. Understanding biological and structural phenotypes associated with NDD in CHD are vital for understanding disease mechanisms, which in turn will advance the development of effective intervention strategies for those at risk. This review article summarises our current knowledge surrounding biological, structural, and genetic contributors to NDD in CHD and describes avenues for future research; highlighting the need for translational studies that bridge the gap between basic science and clinical practice.

SUBMITTER: Verrall CE

PROVIDER: S-EPMC10167385 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Biological and structural phenotypes associated with neurodevelopmental outcomes in congenital heart disease.

Verrall Charlotte E CE Patel Shrujna S Travitz Leksi L Tchieu Jason J Dale Russel C RC Kasparian Nadine A NA Winlaw David S DS Blue Gillian M GM

Translational pediatrics 20230427 4

Neurodevelopmental disability (NDD) is recognised as one of the most common comorbidities in children with congenital heart disease (CHD) and is associated with altered brain structure and growth throughout the life course. Causes and contributors underpinning the CHD and NDD paradigm are not fully understood, and likely include innate patient factors, such as genetic and epigenetic factors, prenatal haemodynamic consequences as a result of the heart defect, and factors affecting the fetal-place ...[more]

PMID: 37181016

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Project description:BackgroundChildren with congenital heart defects have an increased risk of neurodevelopmental disability. The impact of environmental chemical exposures during daily life on neurodevelopmental outcomes in toddlers with congenital heart defects is unknown.MethodsThis prospective study investigated the impacts of early childhood exposure to mixtures of environmental chemicals on neurodevelopmental outcomes after cardiac surgery. Outcomes were assessed at 18 months of age using The Bayley Scales of Infant and Toddler Development-III. Urinary concentrations of exposure biomarkers of pesticides, phenols, parabens, and phthalates, and blood levels of lead, mercury, and nicotine were measured at the same time point. Bayesian profile regression and weighted quantile sum regression were utilized to assess associations between mixtures of biomarkers and neurodevelopmental scores.ResultsOne-hundred and forty infants were enrolled, and 110 (79%) returned at 18 months of age. Six biomarker exposure clusters were identified from the Bayesian profile regression analysis; and the pattern was driven by 15 of the 30 biomarkers, most notably 13 phthalate biomarkers. Children in the highest exposure cluster had significantly lower adjusted language scores by -9.41 points (95%CI: -17.2, -1.7) and adjusted motor scores by -4.9 points (-9.5, -0.4) compared to the lowest exposure. Weighted quantile sum regression modeling for the overall exposure-response relationship showed a significantly lower adjusted motor score (β = -2.8 points [2.5th and 97.5th percentile: -6.0, -0.6]). The weighted quantile sum regression index weights for several phthalates, one paraben, and one phenol suggest their relevance for poorer neurodevelopmental outcomes.ConclusionsLike other children, infants with congenital heart defects are exposed to complex mixtures of environmental chemicals in daily life. Higher exposure biomarker concentrations were associated with significantly worse performance for language and motor skills in this population.

Project description:ImportanceA recent advisory from the American Heart Association delineated the potential benefits of developmental care for hospitalized children with congenital heart disease (CHD) and a critical gap in research evaluating the association of such inpatient programs with neurodevelopmental outcomes.ObjectiveTo investigate associations between the Cardiac Inpatient Neurodevelopmental Care Optimization (CINCO) program interventions, delirium, and neurodevelopment in young children (newborn through age 2 years) hospitalized with CHD.Design, setting, and participantsThis cohort study used quality improvement data from inpatient cardiac units at a tertiary care children's hospital in the US. Participants were children aged 0 to 2 years who were admitted for at least 7 days from September 1, 2018, to September 1, 2023. The CINCO program was implemented on September 1, 2020, in 6-month plan-do-study-act phases.ExposuresThe 5 CINCO interventions were medical and/or nursing order panels, developmental kits, bedside developmental plans, caregiver mental health support handouts, and developmental care rounds.Main outcomes and measuresNumber of days with delirium per patient, which was measured using the Cornell Assessment of Pediatric Delirium (a score higher than 9 indicated delirium). Neurodevelopment was measured using the Bayley Scales of Infant and Toddler Development, Fourth Edition (BSID-4).ResultsThe full sample included 1331 qualifying admissions for 1019 unique pediatric patients (median [range] age at admission, 3.65 [0-34.62] months; 771 males [57.9%]), with a subcohort of 121 unique patients (median [range] age at admission, 0.00 [0-9.85] months; 77 males [63.6%]) whose initial hospitalization occurred before age 10 months and who underwent BSID-4 evaluation at age 12 months or older. The mean (SD) number of days with delirium per patient was stable for 2 years prior to CINCO implementation, decreased by 54.0% between phases 1 and 2 of the CINCO program (from 3.05 [0.60] to 1.38 [0.21]), and then remained stable over time. Each of the 5 CINCO interventions was associated with lower delirium after false discovery rate (FDR) correction (eg, medical and/or nursing order panel: B = -1.376 [95% CI, -1.767 to -0.986]; F2,1273 = 47.767; partial η2 = 0.036; P < .001). Mean (SD) BSID-4 cognitive index scores were stable for 2 years prior to implementation, higher between phases 1 and 2 of the program (from 81.67 [14.14] to 93.92 [19.43]), and then remained stable over time. Four of the 5 interventions were associated with higher BSID-4 cognitive scores after FDR correction (eg, bedside developmental plans: B = 8.585 [95% CI, 2.247-14.923]; F5, 101 = 7.221; partial η2 = 0.067; P = .008). Delirium was associated with lower BSID-4 cognitive scores. There were no associations between delirium and BSID-4 language or motor scores.Conclusions and relevanceThis cohort study found that among hospitalized children with CHD, the implementation of an inpatient developmental care program was associated with reduced incidence of delirium and higher cognitive scores. Pediatric cardiac centers may consider adopting these low-cost, low-risk, generalizable program interventions.

Project description:BackgroundDe novo genic and copy number variants are enriched in patients with congenital heart disease, particularly those with extra-cardiac anomalies. The impact of de novo damaging variants on outcomes following cardiac repair is unknown.MethodsWe studied 2517 patients with congenital heart disease who had undergone whole-exome sequencing as part of the CHD GENES study (Congenital Heart Disease Genetic Network).ResultsTwo hundred ninety-four patients (11.7%) had clinically significant de novo variants. Patients with de novo damaging variants were 2.4 times more likely to have extra-cardiac anomalies (P=5.63×10-12). In 1268 patients (50.4%) who had surgical data available and underwent open-heart surgery exclusive of heart transplantation as their first operation, we analyzed transplant-free survival following the first operation. Median follow-up was 2.65 years. De novo variants were associated with worse transplant-free survival (hazard ratio, 3.51; P=5.33×10-04) and longer times to final extubation (hazard ratio, 0.74; P=0.005). As de novo variants had a significant interaction with extra-cardiac anomalies for transplant-free survival (P=0.003), de novo variants conveyed no additional risk for transplant-free survival for patients with these anomalies (adjusted hazard ratio, 1.96; P=0.06). By contrast, de novo variants in patients without extra-cardiac anomalies were associated with worse transplant-free survival during follow-up (hazard ratio, 11.21; P=1.61×10-05) than that of patients with no de novo variants. Using agnostic machine-learning algorithms, we identified de novo copy number variants at 15q25.2 and 15q11.2 as being associated with worse transplant-free survival and 15q25.2, 22q11.21, and 3p25.2 as being associated with prolonged time to final extubation.ConclusionsIn patients with congenital heart disease undergoing open-heart surgery, de novo variants were associated with worse transplant-free survival and longer times on the ventilator. De novo variants were most strongly associated with adverse outcomes among patients without extra-cardiac anomalies, suggesting a benefit for preoperative genetic testing even when genetic abnormalities are not suspected during routine clinical practice. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01196182.

Project description:PurposeTo characterize temporal trends and outcomes of delivery hospitalization with maternal congenital heart disease (CHD).Materials and methodsFor this repeated cross-sectional analysis, deliveries to women aged 15-54 years with maternal CHD were identified in the 2000-2018 National Inpatient Sample. Temporal trends in maternal CHD were analyzed using joinpoint regression to estimate the average annual percentage change (AAPC) with 95% CIs. The relationship between maternal CHD and several adverse maternal outcomes was analyzed with log-linear regression models. Risk for adverse outcomes in the setting of maternal CHD was further characterized based on additional diagnoses of cardiac comorbidity including congestive heart failure, arrhythmia, valvular disease, pulmonary disorders, and history of thromboembolism.ResultsOf 73,109,790 delivery hospitalizations, 51,841 had a diagnosis of maternal CHD (7.1 per 10,000). Maternal CHD rose from 4.2 to 10.9 per 10,000 deliveries (AAPC 4.8%, 95% CI 4.2%, 5.4%). Maternal CHD deliveries with a cardiac comorbidity diagnosis also increased from 0.6 to 2.6 per 10,000 from 2000 to 2018 (AAPC 8.4%, 95% CI 6.3%, 10.6%). Maternal CHD was associated with severe maternal morbidity (adjusted risk ratios [aRR] 4.97, 95% CI 4.75, 5.20), cardiac severe maternal morbidity (aRR 7.65, 95% CI 7.14, 8.19), placental abruption (aRR 1.30, 95% 1.21, 1.38), preterm delivery (aRR 1.47, 95% CI 1.43, 1.51), and transfusion (aRR 2.28, 95% CI 2.14, 2.42). Risk for severe morbidity (AAPC 4.7%, 95% CI 2.5%, 6.9%) and cardiac severe morbidity (AAPC 4.7%, 95% CI 2.5%, 6.9%) increased significantly among women with maternal CHD over the study period. The presence of cardiac comorbidity diagnoses was associated with further increased risk.ConclusionMaternal CHD is becoming more common among US deliveries. Among deliveries with maternal CHD, risk for severe morbidity is increasing. These findings support that an increasing burden of risk from maternal CHD in the obstetric population.

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Biological and structural phenotypes associated with neurodevelopmental outcomes in congenital heart disease.

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Biological and structural phenotypes associated with neurodevelopmental outcomes in congenital heart disease.

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