INTRODUCTION
Abnormal fetal growth is associated with adverse short and long-term
outcomes1,2. Neonates born at the lower end of the
birth weight continuum have a high risk of morbidity and
mortality3,4 including poor neurobehavioral
outcomes5-7. Yet, a non-linear association between
birth weight and adverse outcomes has been
reported8-11, disclosing a reverse J-shaped/U
relationship. As worldwide obesity ratios are
rising12-17, research focusing on the upper birth
weight end, typically defined as large-for-gestational-age (LGA,
>90th percentile), is increasing.
Neonates born LGA are at increased
risk of mortality, obesity, type 2 diabetes, cardiovascular diseases,
and metabolic
syndrome18-22.
However, evidence regarding neurodevelopmental outcomes is limited and
inconsistent. In addition, the lack of consensus on terminology and
criteria, with different cutoff values and the use of absolute birth
weight or its normalization by gestational age hampers generalization.
Elevated birth weight was associated, from childhood to adulthood with
impaired cognitive function10,23,24, poor educational
attainments8,25,26, and with cerebral
palsy27, autism28, attention
difficulties29, social disorder
symptoms30 and externalizing
behaviors11. However, other studies found no
association31,32, or even a positive
relationship33,34, with better development and higher
educational outcomes for LGA compared to adequate-for-gestational-age
(AGA).
A further limitation is that
previous studies focused on children to adults, leaving unexplored the
early years of life –a crucial period for
neurodevelopment–. Biologically
plausible models suggest a higher risk for poor cognitive outcomes in
LGA compared to the general population11,35. Fetal
growth is influenced by complex interactions between fetal genes and
intrauterine environment, so that several studies have suggested that an
adverse fetal environment translates into being
LGA36-38. But perinatal central nervous system (CNS)
dysfunctionality in LGA neonates remains unexplored. One approach,
recently used to disclose functional CNS affections at birth in FGR
neonates39, is through recordings of the
frequency-following response (FFR), a variant of the auditory brainstem
response (ABR) elicited to speech sounds.
FFRs provide a snapshot into the neurophysiological encoding of the
periodic sound features of the human language across the auditory
system40-42. FFR is disrupted in children affected by
dyslexia, reading impairment and autism43-47, and
predicts literacy skills one year ahead48, supporting
its sensitivity to neurodevelopmental outcomes. Recordings of the
neonatal FFR have been successfully carried out in the general
population49-53 and under several pathological
conditions such as hyperbilirubinemia54 and
FGR39. Here we tested in a case-control sample of 50
neonates, whether being born LGA would lead to an altered neural
processing of speech sounds.