Interpretation
Previous studies on LGA populations have described impaired cognitive function from children to adulthood10,23,24, as well as low academic scores8,25,26 and associations with other neurological disorders11,27-30. Although all these studies investigated a large period of life, according to our knowledge no one addressed perinatal CNS consequences of being born LGA. The findings disclosed here may help shedding light on the existent disparity in neurodevelopmental studies conducted with LGA populations. We suggest that mixed LGA cases with normal and altered neural encoding of speech sounds may have obscure results in previous work, yielding the incongruities observed.
Pathophysiological mechanisms leading to this neurofunctional alteration at birth in LGA neonates remain unexplored. LGA neonates have greater adipose tissue compared to their AGA pairs37, displaying a higher neonatal BMI index (see Table 2 and Figure 4) . Higher neonatal adiposity has been associated with higher pro-inflammatory cytokines such as IL-1β, IL-6, and IFN-γ and IL-1Rα and IL-470 which, in turn, may unleash a sustaining neuroinflammatory state after overcoming the blood-brain barrier71, with adverse consequences on structural and functional neural networks involved in cognitive skills72-75. One of these main brain affections is on white matter. During pregnancy, between 24 and 40 weeks of gestational age (GA), pre-oligodendrocytes actively develop to their mature form of myelinating glial cells (i.e., oligodendrocytes)76. During this period, preoligodendrocytes are susceptible to many risk factors, including inflammation, which can compromise the myelinization process77. The vast mounting evidence linking child and adult high body mass with low white matter integrity78, together with the possible disruption of myelinization processes due to neuroinflammation, suggests white matter affections in LGA neonates at birth. Since a significant relationship between FFR–F0 strength and white matter mean diffusivity underlying primary auditory cortex has been found79, we suggest that the neural effects caused from neonatal adiposity via proinflammatory products could impair the fine-grained CNS microstructure required for fast processing of speech sounds, hence leading to a weaker neural encoding of the stimulus fundamental frequency observed here in LGA neonates. Further studies should clarify the potential different contributions of subcutaneous versus visceral fat to the observed effects on FFR.
On the other hand, since high maternal pre-pregnancy BMI80 and GWG81 have been associated with an inflammatory in utero environment, which is linked with offspring’s neurodevelopmental impairment, an association between each of these maternal characteristics and our electrophysiological data was expected, which could not be confirmed though. The small sample size and the few pregnant women with a high pre-pregnancy body mass index may be behind these negative results. Yet, the fact that a significant correlation between electrophysiological data was found with the neonatal BMI index but not with the maternal BMI or GWG indices indicates a neonatal proinflammatory state as a result of an immune response from the neonate’s own adipose tissue which may not have been exclusively mother-induced82.
From a clinical point of view, the association between being born LGA and the risk to develop metabolic and cardiovascular diseases and obesity, both linked to behavioral problems and poor academic achievement11,83, demand further studies focusing on babies and infants born with high birth weight. The promotion of effective early detection and intervention plans to maximize an appropriate development and to reduce the negative consequences of obesity in the public health is required. Taking into account that language is crucial to acquire knowledge and that poor reading ability leads to academic failure, greater incidence of social and emotional problems, and lower economic outcomes84, we suggest that the detection of disrupted early mechanisms necessary for literacy abilities, such as the neural encoding of speech sounds pitch could be relevant for this population. Pitch, as a language attribute, has a key role for word segmentation85, conveys emotional information86,87 and facilitates speaker recognition88. Thus, pitch processing is deemed as essential in establishing the first social interactions, and, indeed, for language acquisition89,90.
The possibility to record FFR with similar equipment used for hearing screening and already existing analysis routines allow a fast, objective, and cheap translation of present results. Thus, a disrupted FFR could provide crucial information to pediatricians to determine follow-up monitoring with an interdisciplinary group to promote appropriate neurocognitive development.