In an era where metabolic and neurological disorders in neonates pose substantial therapeutic challenges, the ketogenic diet (KD) has emerged as a cautiously explored option, particularly for select neonatal populations suffering from refractory seizure disorders and rare metabolic conditions. Traditionally reserved for older children and adults, the application of KD in newborns—and especially in those born prematurely—has remained limited, largely due to concerns surrounding nutritional adequacy, metabolic stability, and gestational immaturity. However, a groundbreaking new study spearheaded by Katsoudas and colleagues in the Journal of Perinatology has illuminated not only the potential benefits of this high-fat, low-carbohydrate regimen in these vulnerable patients but also the formidable complexities involved in its clinical implementation.
The ketogenic diet works by fundamentally altering the brain’s energy metabolism, shifting the primary fuel source from glucose to ketone bodies produced from fat metabolism. This metabolic shift has been shown to reduce neuronal excitability and seizure frequency, mechanisms of particular relevance in disorders such as pyruvate dehydrogenase deficiency (PDHD), where impaired carbohydrate metabolism culminates in severe lactic acidosis and refractory epilepsy. Yet, translating this neuroprotective metabolic state from theory into practice within the neonatal intensive care unit (NICU) setting, particularly for premature infants, remains largely uncharted territory.
Katsoudas et al. provide an extensive review of recent advances in the field, highlighting both the promise and pitfalls of ketogenic therapy during this critical developmental window. They emphasize that the neonatal brain exhibits distinct metabolic demands compared to older children, rendering it exquisitely sensitive to shifts in substrate availability. Early postnatal life is characterized by rapid growth, brain maturation, and dynamic shifts in energy metabolism that complicate the initiation and maintenance of KD. Premature neonates born before 37 weeks gestation present an even more fragile metabolic milieu, with immature enzymatic pathways and organ systems amplifying the risk of adverse effects such as hypoglycemia, ketoacidosis, and nutritional deficiencies.
Within this complex landscape, the authors center their discussion on a seminal case report involving a preterm infant born at 34 weeks with a confirmed diagnosis of pyruvate dehydrogenase deficiency. PDHD is a rare mitochondrial disorder disrupting the entry of pyruvate into the tricarboxylic acid (TCA) cycle, resulting in accumulation of lactate and severe neurological impairment including intractable seizures. Conventional anticonvulsant therapies often fail to provide adequate control, thereby necessitating alternative strategies. The report exquisitely documents the multidisciplinary approach required to deploy the ketogenic diet in this neonate, including rigorous metabolic monitoring, individualized caloric and micronutrient supplementation, and careful titration of macronutrient ratios.
A key insight underscored in the case is the delicate balancing act clinicians must perform to mimic the metabolic benefits of keto-adaptation without precipitating metabolic crises. The initiation phase required gradual ramping of the ketogenic ratio, vigilantly monitoring for hypoglycemia and metabolic acidosis using serial blood gases, beta-hydroxybutyrate levels, and lactate measurements. Moreover, the infant’s prematurity mandated supplemental parenteral nutrition support to prevent growth faltering, highlighting the challenge of achieving both metabolic ketosis and optimal neurodevelopmental support. Despite these hurdles, the sustained application of KD yielded meaningful clinical improvements, with a notable reduction in seizure burden and stabilization of biochemical markers.
Mechanistically, the neuroprotective effects of KD in PDHD are attributable to its provision of an alternative fuel—ketone bodies—which can bypass the metabolic blockades inherent to impaired pyruvate dehydrogenase complex activity. Ketones not only fuel the brain directly but may also enhance mitochondrial biogenesis, reduce oxidative stress, and modulate neurotransmitter systems to restore excitatory-inhibitory balance. This confluence of effects suggests that KD may modify disease pathophysiology at a fundamental level, transcending mere symptom suppression. Such mechanistic insights lend robust scientific rationale to expanding KD use in neonatal metabolic encephalopathies.
Nevertheless, the study also candidly discusses the significant clinical pitfalls of ketogenic therapy in neonates. The risk of micronutrient deficiencies, particularly in vitamins B complex, D, calcium, and selenium, requires vigilant supplementation protocols. Furthermore, the potential for exacerbating existing metabolic derangements such as acidosis, hypoglycemia, and lipid abnormalities necessitates comprehensive, round-the-clock ICU monitoring. The authors stress that specialized neonatal ketogenic protocols must be developed, incorporating continuous glucose and ketone monitoring alongside anthropometric assessments to ensure growth and development are not compromised.
Importantly, this work extends the discourse beyond metabolic disease and epilepsy alone, implicating possible KD utility in neonatal neuroprotection more broadly. Emerging evidence suggests that ketone metabolism supports myelination, synaptogenesis, and neuronal survival during critical windows of brain plasticity. Thus, the team’s findings invite further investigation into how ketogenic strategies might attenuate neurological morbidity following hypoxic-ischemic encephalopathy, inborn errors of metabolism, or traumatic brain injury in neonates.
In addressing practical challenges, the authors discuss the technicalities of formulating ketogenic feeds appropriate for neonates, who require liquid-based, easily absorbable nutrient delivery. The balance between medium-chain triglycerides and long-chain fats, the role of ketone esters, and the integration of breast milk or formula constituents into KD remain active areas of inquiry. Furthermore, the psychological impact on parents and caregivers, as well as integration of dietitians and neonatologists into cohesive care teams, highlight the critical importance of an interdisciplinary approach.
Ultimately, this report represents a paradigm shift by validating the feasibility and safety of KD, even in preterm neonates, when applied judiciously within specialized centers. The decreasing seizure frequency, metabolic stabilization, and potential neurodevelopmental benefits observed justify further clinical trials and mechanistic studies. The authors call for establishment of standardized neonatal ketogenic protocols, multicenter registries, and translational research to optimize therapeutic outcomes and minimize risks.
As neonatal medicine advances, the ketogenic diet holds transformative promise as a metabolic intervention. Katsoudas and colleagues’ pioneering work opens the door to redefining nutritional therapies for some of the most challenging neonatal brain disorders. Through precision medicine approaches balancing metabolic demands and neurodevelopmental trajectories, KD may soon become an integral component of neonatal intensive care, bringing hope to families facing devastating metabolic diseases.
In conclusion, while ketogenic therapy in neonates remains an emerging frontier, this landmark study elucidates the therapeutic rationale, implementation nuances, and outcomes associated with its pioneering use in preterm infants with complex metabolic conditions. The intersection of metabolic biochemistry, neonatal critical care, and individualized nutrition management culminates in a bold reimagining of how we harness diet to modulate brain disease from the earliest stages of life. This evolving field invites rigorous investigation and promises to redefine neonatal neurotherapeutics in the years to come.
Subject of Research: Ketogenic diet application in neonates with metabolic and seizure disorders, with a focus on pyruvate dehydrogenase deficiency in preterm infants.
Article Title: Ketogenic diet in neonates: effects, pitfalls, and a paradigm from a preterm newborn affected by pyruvate dehydrogenase deficiency.
Article References: Katsoudas, S., Umana, L.A., Clarke, R. et al. Ketogenic diet in neonates: effects, pitfalls, and a paradigm from a preterm newborn affected by pyruvate dehydrogenase deficiency. J Perinatol (2025). https://doi.org/10.1038/s41372-025-02427-6
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