Neurodevelopment. Congenital heart disease (CHD) refers to a broad group of structural abnormalities of the heart that are present at birth and affect approximately 1% of all live births. Over the past two decades, advances in neonatal surgery and perioperative care have dramatically increased survival rates. Yet this success has revealed an important challenge, and focus has gradually shifted from the heart alone to the brain. A growing body of evidence has shown that children with CHD are at increased risk for neurodevelopmental disorders, including delayed language acquisition, executive dysfunction, and visuospatial processing difficulties. In a recent publication, we took advantage of a unique biorepository to explore how early differences can be identified on the molecular level that may inform later neurodevelopmental features. Here is what we found.
Figure 1. Placental weight and fetal growth stratification with corresponding methylation pathways. The nine-block classification system (left) combines placental weight (x-axis, low to high) and fetal-to-placental weight ratio (y-axis, high to low) to categorize neonatal growth patterns. In our cohort, analyses focused on three groups: light placenta with heavy infant (Group A), light placenta with balanced infant growth (Group D), and balanced placenta and infant (Group E, highlighted in red). DNA methylation differences across these groups revealed pathway-specific alterations (right), with gene-set enrichment analyses pointing to biological processes relevant for neurodevelopmental vulnerability in congenital heart disease.
Understanding development. It may sound strange at first to redefine congenital heart disease as an “unexplained brain disorder”, but please let me explain. There have been tremendous advances in cardiac surgery and neonatal care, and a significant number of individuals with CHD now reach adulthood. However, it has long been observed that individuals with CHD are at increased risk for a wide range of neurodevelopmental disorders. There are well-known factors contributing to this risk. A significant subset of individuals with CHD has genetic syndromes such as 22q or Trisomy 21. In addition, neonates with CHD are at risk for a range of medical complications that affect the brain, such as perioperative strokes and acute seizures. For a child neurologist consulting in the cardiac intensive care unit (CICU), these are the obvious features that we can identify. However, all these factors combined explain less than 50% of the developmental outcomes in individuals with CHD. Particularly when it comes to neurodevelopmental issues presenting outside the neonatal period—such as autism, learning differences, or ADHD—most of the risk remains unexplained.
Biorepository. For our study by Jacobwitz and collaborators, we took advantage of a unique dataset. Obtaining long-term follow-up in neonates is challenging enough, but having biosamples obtained at birth of a cohort of individuals with CHD jointly with developmental outcomes measures several years later is something that I would have considered virtually impossible only a few years ago. In prior posts, I have referred to biobanks as the “gold of the 21st century,” and the uniqueness of this data resource and the questions that it allows us to ask are a good reminder of the crucial nature of biobanking for future biomedical insight. Yes, we can send genetic testing, but we are only seeing the tip of the iceberg. Biobanking is what enabled gene discovery and made the subsequent development of personalized therapies happen in the first place. But before I dive into some of our findings, let me introduce two more concepts critical to understanding fetal development: neuroplacentology and the fetal to placental ratio (F/P ratio).
Neuroplacentology. In neurogenetics, we don’t think about the placenta all that much. Families often ask about the impact of perinatal events, where we can often be reassuring given unremarkable neuroimaging findings that exclude severe perinatal injuries. For the clinical questions we are facing in children with genetic epilepsies and neurodevelopmental disorders, past information about placental health often does not factor in. In the emerging field of “neuroplacentology,” researchers try to understand how pathology of the placenta may relate to later neurodevelopment outside of defined genetic syndromes or severe perinatal events. Evidence is still emerging for neonatology more broadly, and several studies suggest that placental lesions may contribute to adverse neurodevelopmental outcomes in preterm infants, neonatal encephalopathy, and fetal growth restriction. However, findings remain inconsistent due to variability in lesion classification, outcome measures, and follow-up duration. In contrast, the evidence is more robust in congenital heart disease (CHD), where placental abnormalities are frequently identified and have been correlated with smaller neonatal brain volume. CHD infants with additional placental dysfunction face higher mortality and longer hospital stays, likely due to impaired placental oxygenation and reduced fetal cerebral oxygen delivery.
F/P ratio. The fetal-to-placental (F/P) weight ratio is a simple yet powerful indicator of placental efficiency. It compares the weight of the baby (fetus) to the weight of the placenta at birth and reflects how well the placenta supported fetal growth during pregnancy. A higher F/P ratio suggests that the placenta was relatively small for the size of the baby, which might indicate a stressed system that was pushed to its limit. Conversely, a low F/P ratio where the placenta is disproportionately large compared to the baby may signal suboptimal placental function or underlying pathology. Both extremes are associated with adverse outcomes, including in neonates with congenital heart disease (CHD).
Methylation. In our study by Jacobwitz and collaborators, we tried to understand how placental health relates to early brain development in neonates with CHD. Using DNA methylation profiling of umbilical cord or postnatal blood, we explored whether we find differences in individuals with balanced compared to unbalanced F/P ratio. Basically, we asked the question whether unbalanced F/P ratios leave an epigenetic echo that might tell us about subtle differences in brain development. We included 45 neonates, including 23 individuals with balanced F/P ratios (Group E) and 22 individuals with unbalanced F/P ratios. The unbalanced F/P ratios were further divided in 11 neonates with Group A (light placenta, heavy infant) and 11 neonates with Group D (light placenta, balanced infant growth). If the letters seem confusing, the group naming follows the 3×3 schema proposed by Matsuda et al., and other groups were too small in this cohort to be included in the analysis.
Gene set differences. The short-term outcomes in all three groups were roughly the same, as we did not find group differences in the Bayley-3 scores at 18 months. However, this is when many neurodevelopmental conditions such as ADHD or milder learning differences cannot yet be detected. However, despite development at 18 months remaining comparable, blood methylation patterns at birth showed significant differences. The most unexpected finding emerged when we mapped the differentially methylated loci to biological pathways. The enriched pathways were strongly associated with neurodevelopment, including axon guidance, neuronal migration, synaptic assembly, and neurotransmitter release. These are not pathways typically associated with placental biology, but rather with cortical development. These findings suggest that umbilical cord or early postnatal blood methylation patterns, when interpreted in the context of F/P ratios, may provide an early molecular indicator of neurodevelopmental risk, even before birth. This creates the possibility of identifying high-risk infants prenatally, thereby opening the door to earlier neuroprotective interventions.
What You Need to Know. In neonates with congenital heart disease, stratifying umbilical cord blood methylation data by normalized fetal-to-placental weight ratios reveals epigenetic signatures enriched for neurodevelopmental pathways, including axon guidance, synaptic organization, and neuronal migration. These findings suggest that fetal-to-placental weight ratios may be an early molecular indicator of neurodevelopmental risk, providing a foundation for risk stratification.
