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.