Early exposure to environmental sounds and the development of cortical auditory evoked potentials of preterm infants during the first three months of life

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In the current study, we investigate the effect of preterm birth on the course of development of auditory cortical areas by evaluating how gestational age (GA) correlates with the latency of the P1 component of the cortical auditory evoked potential (CAEP) of two experimental groups measured at one or three months of age. Results: Our sample consisted of 23 infants delivered at GA ranging from 31.28-41.42 weeks and separated into two groups evaluated transversally at one or three months of corrected age (CA). In the group evaluated at one-month CA, the latency of the component P1 was similar in both terms and infants classified as late-preterm (GA>32 weeks). However, in the group evaluated at three months CA, P1 latency was significantly smaller in preterms. These preliminary results suggest an acceleration of the development of auditory cortical pathways in preterms, probably due to their early exposure to socially relevant auditory stimuli from the external environment. Developmental Neuroscience Pediatrics preterm newborn brain development auditory cortex Figures Figure 1 Figure 2 Introduction The remarkable adaptability of the human brain results from the interplay of both evolutionary and developmental mechanisms. Genetically determined developmental programs set up the stage upon which cortical circuits are sculpted by experience and learning, particularly during the sensitive periods of synaptic plasticity [1-3]. The primary auditory cortex is structurally mature as early as 28 weeks of gestation [4] and already responds electrically to sounds in the low-frequency range associated with speech [5,6]. This could explain why newborns can discriminate their mothers’ voice immediately after birth [7,8]. While our understanding of the prenatal emergence of the cortical organization has traditionally depended on animal-based research, due to ethical concerns, preterm birth offers a unique opportunity to investigate this issue in human subjects as well. The extra period of sensory stimulation afforded by preterms allows the earlier maturation of binocular vision and thalamocortical connectivity to the primary somatosensory cortex [9,10]. Preterm birth is characterized by delivery before 37 weeks of GA [11,12] and the following sub-categories of preterms are proposed, based on GA: extremely preterm (<28 weeks), very preterm (28 to <32 weeks), and moderate to late preterm (32 to 70%) are considered late-preterm (34 to <37 weeks) [14] and they account for about 85 of all births [15]. Since late-preterm births occur during the period when cortical volume increases by 50% (34-40 weeks), there is a pressing need to understand the possible effects of premature exposure to the extrauterine environment in this population [15,16]. The cortical auditory evoked potential (CAEP) is characterized by waveforms with positive and negative deflections occurring between 0-300 ms after sound onset in adults. The earliest components are called P1 and N1 and are already present in newborns [17,18]. The latency of the P1 component shows a steady decrease until it stabilizes in adulthood [19-22] and has been proposed as a biomarker for the maturation of cortical sensory pathways [17,21,23-25,49-55]. In the present study, we evaluate the development of the cortical auditory pathway of late preterms in the first three months of life. Methods Subjects This study was approved by the Research Ethics Committee of the Federal University of Rio Grande do Norte (#340.110) and written informed parental consent was obtained on behalf of all participants. The participants were 23 newborns (GA: 31.28-41.42 weeks) recruited at the Maternity School of the Federal University of Rio Grande do Norte according to the following inclusion criteria: no signs of hearing problems during routine maternity screening, normal Auditory Brainstem Responses (ABR) with a click and normal threshold for ABR tone burst at 500 Hz, 1000Hz and 4000 Hz in both ears, normal Distortion Product Otoacoustic Emissions (DPOAE) and tympanometry result with curve type A in both ears. Table 1 shows the demographic characteristics and birth outcomes of mothers and infants. Procedure and stimuli The design of the study was cross-sectional and the subjects were evaluated at one or three months after birth and were divided into two groups according to their GA: preterm or term. For the CAEP recordings, subjects were accommodated either on a car seat or in the caregivers’ lap within a sound-attenuated room. All tests were performed while infants were in stage 4 of the Neonatal Behavioral Assessment Scale [26]: alert, awake state. We used ER-3A insert phones (Etymotic Research, Inc.) for sound delivery to the right ear and the CAEP recordings were performed with a Smart EP USB Jr system with two channels (Intelligent Hearing Systems, Inc.). The CAEP was recorded on channel A, while channel B was used to register eye movements for off-line artifact removal and to determine the rejection level for each session. Disposable surface electrodes were used for the recording procedures. The CAEP was recorded at the midline (Cz) and referenced to the right mastoid. The ground electrode was placed at the left mastoid. All electrode impedances were less than 3kΩ. A minimum of 150 stimuli was presented and the resulting signal, within an analysis window of -100 ms pre-stimulus and 500ms post-stimulus, was averaged at both 70 dB NA and 0 dB NA after band-pass filtering from 1 to 30 Hz. The gain in both channels was 100,000. The rate of the stimulus was 1.9 sec. Auditory responses were recorded in response to a /da/ speech stimulus with an intensity of 70 dB HL and with an interstimulus interval of 526.00 ms. The /da/ sound was recorded with the software praat (www.praat.org) using a unidirectional microphone in an acoustically isolated room [27]. The latency of component P1 was determined as the first positive peak after 50 ms, following a negative decline. The latency of the P1 component was confirmed independently by two experienced judges. Statistical analysis Only 2-sided tests and nonparametric statistical tests were used due to the non-normal distribution of variables and/or sample size. Sample characteristics were compared using Pearson's chi-square test or Fisher's exact test. Results are expressed as mean ± standard deviation. Samples’ comparison at one- and three-months CA were performed with a two-tailed Mann-Whitney rank sum U test. The relationship between GA and p1 latency was assessed with the Spearman correlation ( r ). The significance level was set at 0.05. Results P1 latency is not correlated with GA at both 1 ( r s = 0.44, p = 0.183) and 3 ( r s = 0.49, p = 0.109) months CA. We computed linear regression lines to fit the P1 latency data (Figure 1A) and though the slopes of regression lines were not significantly different ( p = 0.63) (see Supplementary Table 1), their elevations are significantly different from each other ( p < 0.001) (Figure 1). <> According to Table 1, the demographic characteristics and birth outcomes of terms and preterms are similar, except for birth weight, which is lower in preterms ( p < 0.05). Our sample is composed mostly of moderate to late preterms (GA 32 to <37 weeks), which represent about 10% of all births [28]. Their prematurity ranged from 0.15-5.72 weeks (average 2.78 ± 1.58 weeks). <> For the infants evaluated at one-month, the average latency of the P1 component was not significantly different between terms (309.40 ± 78.32 ms) and preterms (295.30 ± 47.66 ms) ( U = 10, p = 0.4242) (Figure 1B). However, for the group evaluated at three-months, average P1 latency was 240.80 ± 57.67 ms for terms and 171.1 ± 26.44 ms for preterms, respectively (Figure 1B), and significantly lower for the latter ( U = 5, p < 0.05). The grand average CAEP waveforms at one- and three-months are shown in Figures 2A and 2B, respectively. The latency of the P1 component at three-months is smaller than at one-month for the preterm group (176.00 ± 29.16 ms vs 295 ±47.65 ms; U = 1, p = 0.005), but not the term group (247.00 ± 64,64 ms vs. 309.40 ± 78.31 ms; U = 17, p = 0.1111). <> Discussion The maturation of cortical circuits is coordinated by genetic and experience-dependent mechanisms [29]. The susceptibility of developing cortical circuits to environmental factors begins in the womb [30] and this is underscored the capacity of human newborns to immediately interact with their caregivers [7,31,32]. The last trimester of gestation is marked by rapid cortical growth [33,34]. While the premature exposure to the extrauterine environment during this period may interfere with the maturation of association areas and increase the risk of neurodevelopmental impairment [35], the rate of cortical maturation is not synchronous across cortical regions [4,36]. In the primary auditory cortex, for instance, developmental changes in cortical microstructure have largely occurred by 28 weeks of gestation [4]. This differential pattern of cortical maturation might explain why non-primary areas are more vulnerable to disruption due to premature exposure to the extrauterine environment [37,38] while primary areas may experience an acceleration in maturation [9,10]. According to our findings (see Figure 1B), the earlier exposure to extrauterine sound stimulation in late-preterm infants probably speeds up the maturation of auditory cortical circuits and improves the efficiency of auditory input processing in this population during the first months of postnatal life [39]. An earlier study [40] had already reported that P1 latency was similar in one-month-old terms and preterms. However, our study is the first to show that P1 latency in a group of three months old infants is shorter in moderate-to-late preterms (see Figure 1B). Previous works had shown that P1 latency steadily decreases from around 250 ms in one-month-old infants towards 100 ms in adults [41,42]. The smaller P1 latency of preterms in the three-month CA group probably reflects the accelerating maturational effects of early exposure to the extrauterine environment, which usually includes speech stimulation [43]. Other studies had already investigated the effect of preterm birth on the maturation of auditory cortical pathways in pre-schoolers using P1 as a biomarker [44-47]. However, the preterms in those studies were classified as extreme/very-preterm and the poor results they observed in comparison to controls may have been influenced by concurrent clinical conditions associated with extreme prematurity [47]. The neural mechanisms associated with the accelerating effects of preterm birth on the maturation of cortical pathways remain to be determined. One possibility is an increase in the effectiveness of thalamocortical connectivity with the primary auditory cortex [1] due to precocious exposure to the external social environment. A similar effect was reported previously in the primary somatosensory cortex of very preterm infants (GA<33 weeks) following the premature exposure to activities such as breastfeeding and bottle-feeding [10]. A previous study [48] had shown that the latencies of components N1 and P2 are shorter in term than in preterm infants at three months of GA. While this result is the opposite we observed in the present work, we suppose this difference stems from the choice of auditory stimuli and the biomarker for physiological maturation. In that study [48], the stimulus was a click while we used speech stimuli (the phoneme /da/). Also, we used the latency of the P1 component as a biomarker, the gold standard for evaluating the maturation of cortical auditory pathways [17,21,23-25,49-55]. Our results are corroborated by other studies that show the advantages of prematurity in auditory recognition memory [56], binocular vision [9], and language comprehension [57]. Thus, even though preterm birth is associated with many neurodevelopmental risks, especially in small for gestational age (SGA) infants [34], the early exposure to socially relevant stimuli can enhance the maturation of sensory pathways [58]. Though our results differ from studies using visual evoked potentials (VEP) that show that preterm birth negatively affects the development of visual pathways [59, 60], the preterm group in those studies was composed of very preterm infants, which may have been SGA at birth. Conclusion The present results reinforce the notion that early exposure to socially relevant environments contributes to the adaptive maturation of sensory pathways. This understanding is of practical importance since preterm birth is on the rise worldwide. Many preterms need to remain hospitalized in neonatal intensive care units (NICU), isolated from their parents, and subject to continuous loud noises or visual deprivation [61]. These conditions can be further detrimental to the maturation of cortical sensory circuits due to their effect on the levels of stress hormones. Fortunately, the young brain is remarkably resilient and can overcome early insults when provided access to appropriate care, stimulation, and follow-up measures [62]. Limitations The main limitations of the present work are 1) the small sample number and 2) the fact that we only considered the role of extrinsic variables (environmental exposure), while it is known that cortical maturation is influenced by intrinsic variables as well. Abbreviations ABR: auditory brainstem response CA: corrected age CAEP: cortical auditory evoked potential DPOAE: Distortion Product Otoacoustic Emissions GA: gestational age NICU: neonatal intensive care unit SGA: small for gestational age VCS: vulnerable child syndrome VEP: visual evoked potential Declarations - Ethics approval and consent to participate This study was approved by the Research Ethics Committee of the Federal University of Rio Grande do Norte (#340.110) and written informed parental consent was obtained on behalf of all participants. - Consent to publish All authors consent to the publication of the manuscript in BMC Research Notes - Availability of data and materials The data that support the findings of this study are available on request from the corresponding author, AP. The data are not publicly available due to ethical restrictions - Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest - Funding Financial support for this work was provided by the Coordination for the Improvement of Higher Education Personnel (CAPES) of the Ministry of Education of Brazil. - Authors' Contributions SB, AP designed the experiments; HGC, ASN, BKC, KA, SB, AP collected data; HGC, ASN, BKC, KA, SB, AP analyzed data; HGC, SB, AP wrote the manuscript - Acknowledgments Not applicable References Barkat TR, Polley DB, Hensch TK. A critical period for auditory thalamocortical connectivity. Nat Neurosci. 2011 Sep;14(9):1189–94. de Araújo Costa Folha OA, Bahia CP, de Aguiar GPS, Herculano AM, Coelho NLG, de Sousa MBC, et al. Effect of chronic stress during adolescence in prefrontal cortex structure and function. Behav Brain Res. 2017 May;326:44–51. Hensch TK. Critical period plasticity in local cortical circuits. Nat Rev Neurosci. 2005 Nov;6(11):877–88. Monson BB, Eaton-Rosen Z, Kapur K, Liebenthal E, Brownell A, Smyser CD, et al. Differential rates of perinatal maturation of human primary and nonprimary auditory cortex. eNeuro. 2018 Jan;5(1):ENEURO.0380-17.2017. Birnholz J, Benacerraf B. The development of human fetal hearing. Science. 1983 Nov 4;222(4623):516–8. Rotteveel JJ, de Graaf R, Stegeman DF, Colon EJ, Visco YM. The maturation of the central auditory conduction in preterm infants until three months post term. V. The auditory cortical response (ACR). Hearing Res. 1987 Jan;27(1):95–110. DeCasper A, Fifer W. Of human bonding: newborns prefer their mothers’ voices. Science. 1980 Jun 6;208(4448):1174–6. Hepper PG, Scott D, Shahidullah S. Newborn and fetal response to maternal voice. J Reprod Infant Psychol. 1993 Jul;11(3):147–53. Jando G, Miko-Barath E, Marko K, Hollody K, Torok B, Kovacs I. Early-onset binocularity in preterm infants reveals experience-dependent visual development in humans. Proc Natl Acad Sci USA. 2012 Jul 3;109(27):11049–52. Toulmin H, Beckmann CF, O’Muircheartaigh J, Ball G, Nongena P, Makropoulos A, et al. Specialization and integration of functional thalamocortical connectivity in the human infant. Proc Natl Acad Sci USA. 2015 May 19;112(20):6485–90. Abbott A. Neuroscience: The brain, interrupted. Nature. 2015 Feb;518(7537):24–6. Goldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. The Lancet. 2008 Jan;371(9606):75–84. Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller A-B, et al. Born Too Soon: The global epidemiology of 15 million preterm births. Reprod Health. 2013;10(Suppl 1):S2. Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller A-B, Narwal R, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. The Lancet. 2012 Jun;379(9832):2162–72. Loftin RW, Habli M, Snyder CC, Cormier CM, Lewis DF, Defranco EA. Late preterm birth. Rev Obstet Gynecol. 2010;3(1):10–9. Adams-Chapman I. Neurodevelopmental outcome of the late preterm infant. Clin Perinatol. 2006 Dec;33(4):947–64. Cunningham J, Nicol T, Zecker S, Kraus and N. Speech-evoked neurophysiologic responses in children with learning problems: development and behavioral correlates of perception: Ear and Hearing. 2000 Dec;21(6):554–68. Melo  de, Biaggio EPV, Rechia IC, Sleifer P. Potenciais evocados auditivos corticais em neonatos nascidos a termo e pré-termo. CoDAS. 2016 Oct 13;28(5):491–6. Moore DR. Auditory development and the role of experience. Br Med Bull. 2002 Oct 1;63(1):171–81. Shafer VL, Yu YH, Datta H. The development of English vowel perception in monolingual and bilingual infants: Neurophysiological correlates. J Phon. 2011 Oct;39(4):527–45. Shafer VL, Yu YH, Wagner M. Maturation of cortical auditory evoked potentials (Caeps) to speech recorded from frontocentral and temporal sites: Three months to eight years of age. Int J Psychophysiol. 2015 Feb;95(2):77–93. Sharma A, Gilley PM, Dorman MF, Baldwin R. Deprivation-induced cortical reorganization in children with cochlear implants. Int J Audiol. 2007 Jan;46(9):494–9. Eggermont JJ, Ponton CW. Auditory-evoked potential studies of cortical maturation in normal hearing and implanted children: correlations with changes in structure and speech perception. Acta Oto-Laryngol. 2003 Feb;123(2):249–52. Sharma A, Martin K, Roland P, Bauer P, Sweeney MH, Gilley P, et al. P1 latency as a biomarker for central auditory development in children with hearing impairment. J Am Acad Audiol. 2005 Sep 1;16(8):564–73. Mikó-Baráth E, Markó K, Budai A, Török B, Kovacs I, Jandó G. Maturation of cyclopean visual evoked potential phase in preterm and full-term infants. Invest Ophthalmol Vis Sci. 2014 Apr 21;55(4):2574. Brazelton TB, Nugent JK. Neonatal behavioral assessment scale (Clinics in developmental medicine). [Internet]. Mac Keith Press.; 2011 [cited 2020 May 28]. Available from: http://search.ebscohost.com/login.aspx?direct=true&scope=site&db=nlebk&db=nlabk&AN=503755 Banhara MR. Potenciais auditivos de longa latência: N1, P2, N2, P300, evocados por estímulo de fala em usuários de implante coclear [Internet] [Mestrado em Fisiopatologia Experimental]. [São Paulo]: Universidade de São Paulo; 2007 [cited 2020 May 28]. Available from: http://www.teses.usp.br/teses/disponiveis/5/5160/tde-17102014-111320/ United States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS). Natality public-use data on CDC WONDER Online Database, for years 2016-2018 (Expanded) [Internet]. CDC Wonder. United States Department of Health and Human Services (US DHHS); 2019 [cited 2020 May 27]. Available from: https://wonder.cdc.gov/natality-expanded-current.html Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci. 2006 Sep;7(9):697–709. Sanes DH, Bao S. Tuning up the developing auditory CNS. Curr Op Neurobiol. 2009 Apr;19(2):188–99. Partanen E, Kujala T, Naatanen R, Liitola A, Sambeth A, Huotilainen M. Learning-induced neural plasticity of speech processing before birth. Proc Natl Acad Sci USA. 2013 Sep 10;110(37):15145–50. Webb AR, Heller HT, Benson CB, Lahav A. Mother’s voice and heartbeat sounds elicit auditory plasticity in the human brain before full gestation. Proc Natl Acad Sci USA. 2015 Mar 10;112(10):3152–7. Kostović I, Jovanov-Milošević N. The development of cerebral connections during the first 20–45 weeks’ gestation. Sem Fetal Neonat Med. 2006 Dec;11(6):415–22. Malik S, Vinukonda G, Vose LR, Diamond D, Bhimavarapu BBR, Hu F, et al. Neurogenesis continues in the third trimester of pregnancy and is suppressed by premature birth. J Neurosci. 2013 Jan 9;33(2):411–23. Katz J, Lee ACC, Kozuki N, Black RE. Mortality risk among term and preterm small for gestational age infants. In: Embleton ND, Katz J, Ziegler EE, editors. Nestlé Nutrition Institute Workshop Series [Internet]. S. Karger AG; 2015 [cited 2020 May 28]. p. 29–35. Available from: https://www.karger.com/Article/FullText/365800 Ball G, Srinivasan L, Aljabar P, Counsell SJ, Durighel G, Hajnal JV, et al. Development of cortical microstructure in the preterm human brain. Proc Natl Acad Sci USA. 2013 Jun 4;110(23):9541–6. Polin RA, Fox WW, Abman SH. Fetal and neonatal physiology: expert consult (2-volume set). London: Elsevier Health Sciences; 2011. Zhang Y, Inder TE, Neil JJ, Dierker DL, Alexopoulos D, Anderson PJ, et al. Cortical structural abnormalities in very preterm children at 7years of age. NeuroImage. 2015 Apr;109:469–79. Lebenberg J, Mangin J-F, Thirion B, Poupon C, Hertz-Pannier L, Leroy F, et al. Mapping the asynchrony of cortical maturation in the infant brain: A MRI multi-parametric clustering approach. NeuroImage. 2019 Jan;185:641–53. Didoné D, Garcia M, da Silveira A. Long latency auditory evoked potential in term and premature infants. Int Arch Otorhinolaryngol. 2013 Nov 7;18(01):016–20. Moore JK, Linthicum FH. The human auditory system: A timeline of development. Int J Audiol. 2007 Jan;46(9):460–78. Sharma A, Dorman MF, Spahr AJ. A sensitive period for the development of the central auditory system in children with cochlear implants: implications for age of implantation: Ear Hearing. 2002 Dec;23(6):532–9. Vouloumanos A, Werker JF. Listening to language at birth: evidence for a bias for speech in neonates. Dev Sci. 2007 Mar;10(2):159–64. Green M, Solnit AJ. Reactions to the threatened loss of a child: a vulnerable child syndrome. Pediatric management of the dying child, part iii. Pediatrics. 1964 Jul;34:58–66. Hövel H, Partanen E, Huotilainen M, Lindgren M, Rosén I, Fellman V. Auditory event-related potentials at preschool age in children born very preterm. Clin Neurophysiol. 2014 Mar;125(3):449–56. Hövel H, Partanen E, Tideman E, Stjernqvist K, Hellström-Westas L, Huotilainen M, et al. Auditory event-related potentials are related to cognition at preschool age after very preterm birth. Pediatr Res. 2015 Apr;77(4):570–8. Suppiej A, Cainelli E, Cappellari A, Ermani M, Sartori S, Bisiacchi PS. Neonatal cortical auditory evoked potentials are affected by clinical conditions occurring in early prematurity: J Clin Neurophysiol. 2015 Oct;32(5):419–23. Pasman JW, Rotteveel JJ, de Graaf R, Stegeman DF, Visco YM. The effect of preterm birth on brainstem, middle latency and cortical auditory evoked responses (BMC AERs). Early Hum Dev. 1992 Dec;31(2):113–29. Ceponiene R, Rinne T, Näätänen R. Maturation of cortical sound processing as indexed by event-related potentials. Clin Neurophysiol. 2002 Jun;113(6):870–82. Kihara M, Hogan AM, Newton CR, Garrashi HH, Neville BR, de Haan M. Auditory and visual novelty processing in normally-developing Kenyan children. Clin Neurophysiol. 2010 Apr;121(4):564–76. Kushnerenko E, Ceponiene R, Balan P, Fellman V, Huotilainen M, Näätänen R. Maturation of the auditory event-related potentials during the first year of life: Neuroreport. 2002 Jan;13(1):47–51. Ohlrich ES, Barnet AB. Auditory evoked responses during the first year of life. Clin Neurophysiol. 1972 Feb;32(2):161–9. Ponton CW, Eggermont JJ, Kwong B, Don M. Maturation of human central auditory system activity: evidence from multi-channel evoked potentials. Clin Neurophysiol. 2000 Feb;111(2):220–36. Silva LAF, Magliaro FCL, Carvalho ACM de, Matas CG. Maturação dos potenciais evocados auditivos de longa latência em crianças ouvintes: análise do complexo P1-N1-P2-N2. CoDAS [Internet]. 2017 Sep 4;29(4). Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S2317-17822017000400314&lng=pt&tlng=pt Wunderlich JL, Cone-Wesson BK. Maturation of CAEP in infants and children: A review. Hearing Res. 2006 Feb;212(1–2):212–23. deRegnier R-A, Wewerka S, Georgieff MK, Mattia F, Nelson CA. Influences of postconceptional age and postnatal experience on the development of auditory recognition memory in the newborn infant. Dev Psychobiol. 2002;41(3):216–25. Gonzalez-Gomez N, Nazzi T. Phonotactic acquisition in healthy preterm infants: Phonotactic acquisition in preterm infants. Dev Sci. 2012 Nov;15(6):885–94. Fenoglio A, Georgieff MK, Elison JT. Social brain circuitry and social cognition in infants born preterm. J Neurodevelop Disord. 2017 Dec;9(1):27. Sayeur MS, Vannasing P, Tremblay E, Lepore F, McKerral M, Lassonde M, et al. Visual development and neuropsychological profile in preterm children from 6 months to school age. J Child Neurol. 2015 Aug;30(9):1159–73. Tremblay E, Vannasing P, Roy M-S, Lefebvre F, Kombate D, Lassonde M, et al. Delayed early primary visual pathway development in premature infants: high density electrophysiological evidence. PLoS ONE. 2014 Sep 30;9(9):e107992. Wachman EM, Lahav A. The effects of noise on preterm infants in the NICU. Archives of Disease in Childhood - Fetal and Neonatal Edition. 2011 Jul 1;96(4):F305–9. Caldas IFR, Garotti MF, Shiramizu VKM, Pereira A. The socio-communicative development of preterm infants is resistant to the negative effects of parity on maternal responsiveness. Front Psychol. 2018 Feb 2;9:43. Table TABLE 1 Total Sample N =23 Preterm n =12 Term n =11 n (%) p value Maternal age 1 0.05 > 35 y.o. 4(33.33) 1(33.33) 3(33.33) Education 3 Less than middle-school 17(94.44) 8(100.00) 9(90.00) > 0.05 More than middle-school 1(5.56) 0(0.00) 1(10.00) Sex of child Male 10(43.48) 6(46.16) 4(40.00) > 0.05 Female 13(56.52) 7(53.84) 6(60.00) Gestational age 31 to < 37 weeks 13(56.52) 13(100.0) 0(0.00) 37 weeks 10(43.48) 0(0.00) 10(100.0) Birth weight 5 < 2,500 g 10(50.00) 10(83.33) 0(0.00) 2,500 g 10(50.00) 2(16,67) 8(100.00) Family income (in minimum wages) 6 0.05 1 to 5 8(50.00) 4(57.15) 4(44.45) Socioeconomic Status 7,8 A, B, and C 6(30.00) 1(9.10) 5(55.55) 0.05 Yes 10 8(57.15) 3(50.00) 5(62.50) 1 11 missing values; 2 y.o.: years old; 3 5 missing values; 4 31.28 weeks; 5 3 missing values; 6 8 missing values; 7 3 missing values; 8 Brazil Economic Classification Criteria (www.abep.org/criterio-brasil); 9 9 missing values; 10 all infants stayed in NICU for 2 days Supplementary Files SUPPLEMENTARYTABLE1.docx Cite Share Download PDF Status: Published Journal Publication published 26 Jun, 2020 Read the published version in BMC Research Notes → Version 2 posted Editorial decision: Accept 02 Jun, 2020 Editor assigned by journal 30 May, 2020 Submission checks completed at journal 29 May, 2020 Editor invited by journal 29 May, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-13251","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research note","associatedPublications":[],"authors":[{"id":626773,"identity":"24abe0b9-1817-48ad-bf87-bbb6a9fcb347","order_by":0,"name":"Hannalice Gottschalck Cavalcanti","email":"","orcid":"","institution":"Universidade Federal da Paraiba","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hannalice","middleName":"Gottschalck","lastName":"Cavalcanti","suffix":""},{"id":626774,"identity":"2c2efb30-08fd-4d77-9934-6e0a39e777d9","order_by":1,"name":"Aryelly Dayane da Silva Nunes","email":"","orcid":"","institution":"Universidade Federal do Rio Grande do Norte","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Aryelly","middleName":"Dayane da Silva","lastName":"Nunes","suffix":""},{"id":626775,"identity":"4d335be4-aff0-48f2-b0f4-23f04f3f8f65","order_by":2,"name":"Brenda Karla Silva da Cunha","email":"","orcid":"","institution":"Universidade Federal do Rio Grande do Norte","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Brenda","middleName":"Karla Silva da","lastName":"Cunha","suffix":""},{"id":626776,"identity":"65d1faa7-3405-489f-a7bc-685e234a072a","order_by":3,"name":"Kátia de Freitas Alvarenga","email":"","orcid":"","institution":"Universidade de Sao Paulo Campus de Ribeirao Preto","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kátia","middleName":"de Freitas","lastName":"Alvarenga","suffix":""},{"id":626777,"identity":"93f5bc19-b199-442b-b7f9-c6c6745c53b5","order_by":4,"name":"Sheila Andreoli Balen","email":"","orcid":"","institution":"Universidade Federal do Rio Grande do Norte","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Sheila","middleName":"Andreoli","lastName":"Balen","suffix":""},{"id":626778,"identity":"0f2a71d8-4aca-4788-9ef1-ca762bc1141e","order_by":5,"name":"Antonio Pereira","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxUlEQVRIiWNgGAWjYNACAwYGfgbGB0DWARK0SDYwG5CiBaTrALFa+Gc3H/vwoeCevPGNZLYHPxju5BPUInHnWPLMGQbFhttuJLMb9jA8s2wgqOdGjjEzj0EC47Yb+cckeBgOGxDUIX8j/zPzH4ME+80zktkk/xCjxeBGDjMzg0FC4gaJZDZpomwxvHPMmLHHICF5xpnH7MYyBs8Ia5G73fyY4cefBNv+9mS2h28q7hDWwiCBYLKB45RULaNgFIyCUTAKsAAAe9M77Ii00bsAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-0808-1058","institution":"Universidade Federal do Pará","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Pereira","suffix":""}],"badges":[],"createdAt":"2020-02-04 13:21:09","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.2.22677/v2","doiUrl":"https://doi.org/10.21203/rs.2.22677/v2","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13104-020-05129-8","type":"published","date":"2020-06-26T12:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":1260022,"identity":"08a99e1a-9529-42c5-93e9-21941af523a0","added_by":"auto","created_at":"2020-06-05 01:09:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":40400,"visible":true,"origin":"","legend":"(A) P1 latencies recorded at one- and three-months CA as a function of GA. Linear regression lines are superimposed on the raw data for the CAEP recordings at one- or three-months CA, respectively; (B) Latency of the P1 component of the CAEP of preterm (GA\u003c37 weeks) and term (GA≥37 weeks) infants recorded at one- or three-months CA. Lines represent the median. * p\u003c0.05","description":"","filename":"1.PNG","url":"https://assets-eu.researchsquare.com/files/rs-13251/v2/1.PNG"},{"id":1260023,"identity":"f2a7c52b-9bcc-473c-8b57-63c23173f6d9","added_by":"auto","created_at":"2020-06-05 01:09:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":74656,"visible":true,"origin":"","legend":"Grand average waveforms of the CAEP of the term and preterm groups recorded at one- (A) and three-months (B) CA. The arrows indicate the P1 component.","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-13251/v2/2.png"},{"id":13536084,"identity":"e8461f2d-52bf-44f9-bfdd-42da2db11b46","added_by":"auto","created_at":"2021-09-17 01:31:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":380768,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-13251/v2/73e28c24-0a15-4e84-9727-d75c48084ed8.pdf"},{"id":1260025,"identity":"d2c67974-daa6-47af-9617-986ca7c94265","added_by":"auto","created_at":"2020-06-05 01:09:41","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13269,"visible":true,"origin":"","legend":"","description":"","filename":"SUPPLEMENTARYTABLE1.docx","url":"https://assets-eu.researchsquare.com/files/rs-13251/v2/SUPPLEMENTARYTABLE1.docx"}],"financialInterests":"","formattedTitle":"Early exposure to environmental sounds and the development of cortical auditory evoked potentials of preterm infants during the first three months of life","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe remarkable adaptability of the human brain results from the interplay of both evolutionary and developmental mechanisms. Genetically determined developmental programs set up the stage upon which cortical circuits are sculpted by experience and learning, particularly during the sensitive periods of synaptic plasticity [1-3]. The primary auditory cortex is structurally mature as early as 28 weeks of gestation [4] and already responds electrically to sounds in the low-frequency range associated with speech [5,6]. This could explain why newborns can discriminate their mothers\u0026rsquo; voice immediately after birth [7,8].\u003c/p\u003e\n\u003cp\u003eWhile our understanding of the prenatal emergence of the cortical organization has traditionally depended on animal-based research, due to ethical concerns, preterm birth offers a unique opportunity to investigate this issue in human subjects as well. The extra period of sensory stimulation afforded by preterms allows the earlier maturation of binocular vision and thalamocortical connectivity to the primary somatosensory cortex [9,10].\u003c/p\u003e\n\u003cp\u003ePreterm birth is characterized by delivery before 37 weeks of GA [11,12] and the following sub-categories of preterms are proposed, based on GA: extremely preterm (\u0026lt;28 weeks), very preterm (28 to \u0026lt;32 weeks), and moderate to late preterm (32 to \u0026lt;37 weeks) [13]. Most preterm births (\u0026gt;70%) are considered late-preterm (34 to \u0026lt;37 weeks) [14] and they account for about 85 of all births [15]. Since late-preterm births occur during the period when cortical volume increases by 50% (34-40 weeks), there is a pressing need to understand the possible effects of premature exposure to the extrauterine environment in this population [15,16].\u003c/p\u003e\n\u003cp\u003eThe cortical auditory evoked potential (CAEP) is characterized by waveforms with positive and negative deflections occurring between 0-300 ms after sound onset in adults. The earliest components are called P1 and N1 and are already present in newborns [17,18]. The latency of the P1 component shows a steady decrease until it stabilizes in adulthood [19-22] and has been proposed as a biomarker for the maturation of cortical sensory pathways [17,21,23-25,49-55]. In the present study, we evaluate the development of the cortical auditory pathway of late preterms in the first three months of life.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003eSubjects\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Research Ethics Committee of the Federal University of Rio Grande do Norte (#340.110) and written informed parental consent was obtained on behalf of all participants. The participants were 23 newborns (GA: 31.28-41.42 weeks) recruited at the Maternity School of the Federal University of Rio Grande do Norte according to the following inclusion criteria: no signs of hearing problems during routine maternity screening, normal Auditory Brainstem Responses (ABR) with a click and normal threshold for ABR tone burst at 500 Hz, 1000Hz and 4000 Hz in both ears, normal Distortion Product Otoacoustic Emissions (DPOAE) and tympanometry result with curve type \u003cem\u003eA \u003c/em\u003ein both ears. Table 1 shows the demographic characteristics and birth outcomes of mothers and infants.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eProcedure and stimuli\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe design of the study was cross-sectional and the subjects were evaluated at one or three months after birth and were divided into two groups according to their GA: preterm or term. For the CAEP recordings, subjects were accommodated either on a car seat or in the caregivers\u0026rsquo; lap within a sound-attenuated room. All tests were performed while infants were in stage 4 of the Neonatal Behavioral Assessment Scale [26]: alert, awake state.\u003c/p\u003e\n\u003cp\u003eWe used ER-3A insert phones (Etymotic Research, Inc.) for sound delivery to the right ear and the CAEP recordings were performed with a Smart EP USB Jr system with two channels (Intelligent Hearing Systems, Inc.). The CAEP was recorded on channel A, while channel B was used to register eye movements for off-line artifact removal and to determine the rejection level for each session. Disposable surface electrodes were used for the recording procedures. The CAEP was recorded at the midline (Cz) and referenced to the right mastoid. The ground electrode was placed at the left mastoid. All electrode impedances were less than 3k\u0026Omega;. A minimum of 150 stimuli was presented and the resulting signal, within an analysis window of -100 ms pre-stimulus and 500ms post-stimulus, was averaged at both 70 dB NA and 0 dB NA after band-pass filtering from 1 to 30 Hz. The gain in both channels was 100,000. The rate of the stimulus was 1.9 sec.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Auditory responses were recorded in response to a /da/ speech stimulus with an intensity of 70 dB HL and with an interstimulus interval of 526.00 ms. The /da/ sound was recorded with the software praat (www.praat.org) using a unidirectional microphone in an acoustically isolated room [27]. The latency of component P1 was determined as the first positive peak after 50 ms, following a negative decline. The latency of the P1 component was confirmed independently by two experienced judges.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOnly 2-sided tests and nonparametric statistical tests were used due to the non-normal distribution of variables and/or sample size. Sample characteristics were compared using Pearson's chi-square test or Fisher's exact test. Results are expressed as mean \u0026plusmn; standard deviation. Samples\u0026rsquo; comparison at one- and three-months CA were performed with a two-tailed Mann-Whitney rank sum U test. The relationship between GA and p1 latency was assessed with the Spearman correlation (\u003cem\u003er\u003c/em\u003e). The significance level was set at 0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eP1 latency is not correlated with GA at both 1 (\u003cem\u003er\u003csub\u003es\u003c/sub\u003e\u003c/em\u003e = 0.44, \u003cem\u003ep\u003c/em\u003e = 0.183) and 3 (\u003cem\u003er\u003csub\u003es\u003c/sub\u003e\u003c/em\u003e = 0.49, \u003cem\u003ep\u003c/em\u003e = 0.109) months CA.\u0026nbsp; We computed linear regression lines to fit the P1 latency data (Figure 1A) and though the slopes of regression lines were not significantly different (\u003cem\u003ep \u003c/em\u003e= 0.63) (see Supplementary Table 1), their elevations are significantly different from each other (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001) (Figure 1).\u003c/p\u003e\n\u003cp\u003e\u0026lt;\u0026lt;FIGURE 1\u0026gt;\u0026gt;\u003c/p\u003e\n\u003cp\u003eAccording to Table 1, the demographic characteristics and birth outcomes of terms and preterms are similar, except for birth weight, which is lower in preterms (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05). Our sample is composed mostly of moderate to late preterms (GA 32 to \u0026lt;37 weeks), which represent about 10% of all births [28]. Their prematurity ranged from 0.15-5.72 weeks (average 2.78 \u0026plusmn; 1.58 weeks).\u003c/p\u003e\n\u003cp\u003e\u0026lt;\u0026lt;TABLE 1\u0026gt;\u0026gt;\u003c/p\u003e\n\u003cp\u003eFor the infants evaluated at one-month, the average latency of the P1 component was not significantly different between terms (309.40 \u0026plusmn; 78.32 ms) and preterms (295.30 \u0026plusmn; 47.66 ms) (\u003cem\u003eU\u003c/em\u003e = 10, \u003cem\u003ep\u003c/em\u003e = 0.4242) (Figure 1B). However, for the group evaluated at three-months, average P1 latency was 240.80 \u0026plusmn; 57.67 ms for terms and 171.1 \u0026plusmn; 26.44 ms for preterms, respectively (Figure 1B), and significantly lower for the latter (\u003cem\u003eU \u003c/em\u003e= 5, \u003cem\u003ep \u003c/em\u003e\u0026lt; 0.05). The grand average CAEP waveforms at one- and three-months are shown in Figures 2A and 2B, respectively. The latency of the P1 component at three-months is smaller than at one-month for the preterm group (176.00 \u0026plusmn; 29.16 ms vs 295 \u0026plusmn;47.65 ms; \u003cem\u003eU\u003c/em\u003e = 1, \u003cem\u003ep\u003c/em\u003e = 0.005), but not the term group (247.00 \u0026plusmn; 64,64 ms vs. 309.40 \u0026plusmn; 78.31 ms; \u003cem\u003eU\u003c/em\u003e = 17, \u003cem\u003ep\u003c/em\u003e = 0.1111).\u003c/p\u003e\n\u003cp\u003e\u0026lt;\u0026lt;FIGURE 2\u0026gt;\u0026gt;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe maturation of cortical circuits is coordinated by genetic and experience-dependent mechanisms [29]. The susceptibility of developing cortical circuits to environmental factors begins in the womb [30] and this is underscored the capacity of human newborns to immediately interact with their caregivers [7,31,32].\u003c/p\u003e\n\u003cp\u003eThe last trimester of gestation is marked by rapid cortical growth [33,34]. While the premature exposure to the extrauterine environment during this period may interfere with the maturation of association areas and increase the risk of neurodevelopmental impairment [35], the rate of cortical maturation is not synchronous across cortical regions [4,36]. In the primary auditory cortex, for instance, developmental changes in cortical microstructure have largely occurred by 28 weeks of gestation [4]. This differential pattern of cortical maturation might explain why non-primary areas are more vulnerable to disruption due to premature exposure to the extrauterine environment [37,38] while primary areas may experience an acceleration in maturation [9,10]. According to our findings (see Figure 1B), the earlier exposure to extrauterine sound stimulation in late-preterm infants probably speeds up the maturation of auditory cortical circuits and improves the efficiency of auditory input processing in this population during the first months of postnatal life [39].\u003c/p\u003e\n\u003cp\u003eAn earlier study [40] had already reported that P1 latency was similar in one-month-old terms and preterms. However, our study is the first to show that P1 latency in a group of three months old infants is shorter in moderate-to-late preterms (see Figure 1B). Previous works had shown that P1 latency steadily decreases from around 250 ms in one-month-old infants towards 100 ms in adults [41,42]. The smaller P1 latency of preterms in the three-month CA group probably reflects the accelerating maturational effects of early exposure to the extrauterine environment, which usually includes speech stimulation [43].\u003c/p\u003e\n\u003cp\u003eOther studies had already investigated the effect of preterm birth on the maturation of auditory cortical pathways in pre-schoolers using P1 as a biomarker [44-47]. However, the preterms in those studies were classified as extreme/very-preterm and the poor results they observed in comparison to controls may have been influenced by concurrent clinical conditions associated with extreme prematurity [47].\u003c/p\u003e\n\u003cp\u003eThe neural mechanisms associated with the accelerating effects of preterm birth on the maturation of cortical pathways remain to be determined. One possibility is an increase in the effectiveness of thalamocortical connectivity with the primary auditory cortex [1] due to precocious exposure to the external social environment. A similar effect was reported previously in the primary somatosensory cortex of very preterm infants (GA\u0026lt;33 weeks) following the premature exposure to activities such as breastfeeding and bottle-feeding [10].\u003c/p\u003e\n\u003cp\u003eA previous study [48] had shown that the latencies of components N1 and P2 are shorter in term than in preterm infants at three months of GA. While this result is the opposite we observed in the present work, we suppose this difference stems from the choice of auditory stimuli and the biomarker for physiological maturation. In that study [48], the stimulus was a click while we used speech stimuli (the phoneme /da/). Also, we used the latency of the P1 component as a biomarker, the gold standard for evaluating the maturation of cortical auditory pathways [17,21,23-25,49-55].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur results are corroborated by other studies that show the advantages of prematurity in auditory recognition memory [56], binocular vision [9], and language comprehension [57]. Thus, even though preterm birth is associated with many neurodevelopmental risks, especially in small for gestational age (SGA) infants [34], the early exposure to socially relevant stimuli can enhance the maturation of sensory pathways [58]. Though our results differ from studies using visual evoked potentials (VEP) that show that preterm birth negatively affects the development of visual pathways [59, 60], the preterm group in those studies was composed of very preterm infants, which may have been SGA at birth.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe present results reinforce the notion that early exposure to socially relevant environments contributes to the adaptive maturation of sensory pathways. This understanding is of practical importance since preterm birth is on the rise worldwide. Many preterms need to remain hospitalized in neonatal intensive care units (NICU), isolated from their parents, and subject to continuous loud noises or visual deprivation [61]. These conditions can be further detrimental to the maturation of cortical sensory circuits due to their effect on the levels of stress hormones. Fortunately, the young brain is remarkably resilient and can overcome early insults when provided access to appropriate care, stimulation, and follow-up measures [62].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe main limitations of the present work are 1) the small sample number and 2) the fact that we only considered the role of extrinsic variables (environmental exposure), while it is known that cortical maturation is influenced by intrinsic variables as well.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eABR: auditory brainstem response\u003c/p\u003e\n\u003cp\u003eCA: corrected age\u003c/p\u003e\n\u003cp\u003eCAEP: cortical auditory evoked potential\u003c/p\u003e\n\u003cp\u003eDPOAE: Distortion Product Otoacoustic Emissions\u003c/p\u003e\n\u003cp\u003eGA: gestational age\u003c/p\u003e\n\u003cp\u003eNICU: neonatal intensive care unit\u003c/p\u003e\n\u003cp\u003eSGA: small for gestational age\u003c/p\u003e\n\u003cp\u003eVCS: vulnerable child syndrome\u003c/p\u003e\n\u003cp\u003eVEP: visual evoked potential\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e- Ethics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Research Ethics Committee of the Federal University of Rio Grande do Norte (#340.110) and written informed parental consent was obtained on behalf of all participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e- Consent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors consent to the publication of the manuscript in BMC Research Notes\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e- Availability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author, AP. The data are not publicly available due to ethical restrictions\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e- Competing interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e- Funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFinancial support for this work was provided by the Coordination for the Improvement of Higher Education Personnel (CAPES) of the Ministry of Education of Brazil.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e- Authors' Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSB, AP designed the experiments; HGC, ASN, BKC, KA, SB, AP collected data; HGC, ASN, BKC, KA, SB, AP analyzed data; HGC, SB, AP wrote the manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e- Acknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBarkat TR, Polley DB, Hensch TK. A critical period for auditory thalamocortical connectivity. Nat Neurosci. 2011 Sep;14(9):1189\u0026ndash;94.\u003c/li\u003e\n\u003cli\u003ede Ara\u0026uacute;jo Costa Folha OA, Bahia CP, de Aguiar GPS, Herculano AM, Coelho NLG, de Sousa MBC, et al. Effect of chronic stress during adolescence in prefrontal cortex structure and function. Behav Brain Res. 2017 May;326:44\u0026ndash;51.\u003c/li\u003e\n\u003cli\u003eHensch TK. Critical period plasticity in local cortical circuits. Nat Rev Neurosci. 2005 Nov;6(11):877\u0026ndash;88.\u003c/li\u003e\n\u003cli\u003eMonson BB, Eaton-Rosen Z, Kapur K, Liebenthal E, Brownell A, Smyser CD, et al. Differential rates of perinatal maturation of human primary and nonprimary auditory cortex. eNeuro. 2018 Jan;5(1):ENEURO.0380-17.2017.\u003c/li\u003e\n\u003cli\u003eBirnholz J, Benacerraf B. The development of human fetal hearing. Science. 1983 Nov 4;222(4623):516\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eRotteveel JJ, de Graaf R, Stegeman DF, Colon EJ, Visco YM. The maturation of the central auditory conduction in preterm infants until three months post term. V. The auditory cortical response (ACR). Hearing Res. 1987 Jan;27(1):95\u0026ndash;110.\u003c/li\u003e\n\u003cli\u003eDeCasper A, Fifer W. Of human bonding: newborns prefer their mothers\u0026rsquo; voices. Science. 1980 Jun 6;208(4448):1174\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eHepper PG, Scott D, Shahidullah S. Newborn and fetal response to maternal voice. J Reprod Infant Psychol. 1993 Jul;11(3):147\u0026ndash;53.\u003c/li\u003e\n\u003cli\u003eJando G, Miko-Barath E, Marko K, Hollody K, Torok B, Kovacs I. Early-onset binocularity in preterm infants reveals experience-dependent visual development in humans. Proc Natl Acad Sci USA. 2012 Jul 3;109(27):11049\u0026ndash;52.\u003c/li\u003e\n\u003cli\u003eToulmin H, Beckmann CF, O\u0026rsquo;Muircheartaigh J, Ball G, Nongena P, Makropoulos A, et al. Specialization and integration of functional thalamocortical connectivity in the human infant. Proc Natl Acad Sci USA. 2015 May 19;112(20):6485\u0026ndash;90.\u003c/li\u003e\n\u003cli\u003eAbbott A. Neuroscience: The brain, interrupted. Nature. 2015 Feb;518(7537):24\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eGoldenberg RL, Culhane JF, Iams JD, Romero R. Epidemiology and causes of preterm birth. The Lancet. 2008 Jan;371(9606):75\u0026ndash;84.\u003c/li\u003e\n\u003cli\u003eBlencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller A-B, et al. Born Too Soon: The global epidemiology of 15 million preterm births. Reprod Health. 2013;10(Suppl 1):S2.\u003c/li\u003e\n\u003cli\u003eBlencowe H, Cousens S, Oestergaard MZ, Chou D, Moller A-B, Narwal R, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. The Lancet. 2012 Jun;379(9832):2162\u0026ndash;72.\u003c/li\u003e\n\u003cli\u003eLoftin RW, Habli M, Snyder CC, Cormier CM, Lewis DF, Defranco EA. Late preterm birth. Rev Obstet Gynecol. 2010;3(1):10\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eAdams-Chapman I. Neurodevelopmental outcome of the late preterm infant. Clin Perinatol. 2006 Dec;33(4):947\u0026ndash;64.\u003c/li\u003e\n\u003cli\u003eCunningham J, Nicol T, Zecker S, Kraus and N. Speech-evoked neurophysiologic responses in children with learning problems: development and behavioral correlates of perception: Ear and Hearing. 2000 Dec;21(6):554\u0026ndash;68.\u003c/li\u003e\n\u003cli\u003eMelo \u0026Acirc; de, Biaggio EPV, Rechia IC, Sleifer P. Potenciais evocados auditivos corticais em neonatos nascidos a termo e pr\u0026eacute;-termo. CoDAS. 2016 Oct 13;28(5):491\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eMoore DR. Auditory development and the role of experience. Br Med Bull. 2002 Oct 1;63(1):171\u0026ndash;81.\u003c/li\u003e\n\u003cli\u003eShafer VL, Yu YH, Datta H. The development of English vowel perception in monolingual and bilingual infants: Neurophysiological correlates. J Phon. 2011 Oct;39(4):527\u0026ndash;45.\u003c/li\u003e\n\u003cli\u003eShafer VL, Yu YH, Wagner M. Maturation of cortical auditory evoked potentials (Caeps) to speech recorded from frontocentral and temporal sites: Three months to eight years of age. Int J Psychophysiol. 2015 Feb;95(2):77\u0026ndash;93.\u003c/li\u003e\n\u003cli\u003eSharma A, Gilley PM, Dorman MF, Baldwin R. Deprivation-induced cortical reorganization in children with cochlear implants. Int J Audiol. 2007 Jan;46(9):494\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eEggermont JJ, Ponton CW. Auditory-evoked potential studies of cortical maturation in normal hearing and implanted children: correlations with changes in structure and speech perception. Acta Oto-Laryngol. 2003 Feb;123(2):249\u0026ndash;52.\u003c/li\u003e\n\u003cli\u003eSharma A, Martin K, Roland P, Bauer P, Sweeney MH, Gilley P, et al. P1 latency as a biomarker for central auditory development in children with hearing impairment. J Am Acad Audiol. 2005 Sep 1;16(8):564\u0026ndash;73.\u003c/li\u003e\n\u003cli\u003eMik\u0026oacute;-Bar\u0026aacute;th E, Mark\u0026oacute; K, Budai A, T\u0026ouml;r\u0026ouml;k B, Kovacs I, Jand\u0026oacute; G. Maturation of cyclopean visual evoked potential phase in preterm and full-term infants. Invest Ophthalmol Vis Sci. 2014 Apr 21;55(4):2574.\u003c/li\u003e\n\u003cli\u003eBrazelton TB, Nugent JK. Neonatal behavioral assessment scale (Clinics in developmental medicine). [Internet]. Mac Keith Press.; 2011 [cited 2020 May 28]. Available from: http://search.ebscohost.com/login.aspx?direct=true\u0026amp;scope=site\u0026amp;db=nlebk\u0026amp;db=nlabk\u0026amp;AN=503755\u003c/li\u003e\n\u003cli\u003eBanhara MR. Potenciais auditivos de longa lat\u0026ecirc;ncia: N1, P2, N2, P300, evocados por est\u0026iacute;mulo de fala em usu\u0026aacute;rios de implante coclear [Internet] [Mestrado em Fisiopatologia Experimental]. [S\u0026atilde;o Paulo]: Universidade de S\u0026atilde;o Paulo; 2007 [cited 2020 May 28]. Available from: http://www.teses.usp.br/teses/disponiveis/5/5160/tde-17102014-111320/\u003c/li\u003e\n\u003cli\u003eUnited States Department of Health and Human Services (US DHHS), Centers for Disease Control and Prevention (CDC), National Center for Health Statistics (NCHS). Natality public-use data on CDC WONDER Online Database, for years 2016-2018 (Expanded) [Internet]. CDC Wonder. United States Department of Health and Human Services (US DHHS); 2019 [cited 2020 May 27]. Available from: https://wonder.cdc.gov/natality-expanded-current.html\u003c/li\u003e\n\u003cli\u003eNithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci. 2006 Sep;7(9):697\u0026ndash;709.\u003c/li\u003e\n\u003cli\u003eSanes DH, Bao S. Tuning up the developing auditory CNS. Curr Op Neurobiol. 2009 Apr;19(2):188\u0026ndash;99.\u003c/li\u003e\n\u003cli\u003ePartanen E, Kujala T, Naatanen R, Liitola A, Sambeth A, Huotilainen M. Learning-induced neural plasticity of speech processing before birth. Proc Natl Acad Sci USA. 2013 Sep 10;110(37):15145\u0026ndash;50.\u003c/li\u003e\n\u003cli\u003eWebb AR, Heller HT, Benson CB, Lahav A. Mother\u0026rsquo;s voice and heartbeat sounds elicit auditory plasticity in the human brain before full gestation. Proc Natl Acad Sci USA. 2015 Mar 10;112(10):3152\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eKostović I, Jovanov-Milo\u0026scaron;ević N. The development of cerebral connections during the first 20\u0026ndash;45 weeks\u0026rsquo; gestation. Sem Fetal Neonat Med. 2006 Dec;11(6):415\u0026ndash;22.\u003c/li\u003e\n\u003cli\u003eMalik S, Vinukonda G, Vose LR, Diamond D, Bhimavarapu BBR, Hu F, et al. Neurogenesis continues in the third trimester of pregnancy and is suppressed by premature birth. J Neurosci. 2013 Jan 9;33(2):411\u0026ndash;23.\u003c/li\u003e\n\u003cli\u003eKatz J, Lee ACC, Kozuki N, Black RE. Mortality risk among term and preterm small for gestational age infants. In: Embleton ND, Katz J, Ziegler EE, editors. Nestl\u0026eacute; Nutrition Institute Workshop Series [Internet]. S. Karger AG; 2015 [cited 2020 May 28]. p. 29\u0026ndash;35. Available from: https://www.karger.com/Article/FullText/365800\u003c/li\u003e\n\u003cli\u003eBall G, Srinivasan L, Aljabar P, Counsell SJ, Durighel G, Hajnal JV, et al. Development of cortical microstructure in the preterm human brain. Proc Natl Acad Sci USA. 2013 Jun 4;110(23):9541\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003ePolin RA, Fox WW, Abman SH. Fetal and neonatal physiology: expert consult (2-volume set). London: Elsevier Health Sciences; 2011.\u003c/li\u003e\n\u003cli\u003eZhang Y, Inder TE, Neil JJ, Dierker DL, Alexopoulos D, Anderson PJ, et al. Cortical structural abnormalities in very preterm children at 7years of age. NeuroImage. 2015 Apr;109:469\u0026ndash;79.\u003c/li\u003e\n\u003cli\u003eLebenberg J, Mangin J-F, Thirion B, Poupon C, Hertz-Pannier L, Leroy F, et al. Mapping the asynchrony of cortical maturation in the infant brain: A MRI multi-parametric clustering approach. NeuroImage. 2019 Jan;185:641\u0026ndash;53.\u003c/li\u003e\n\u003cli\u003eDidon\u0026eacute; D, Garcia M, da Silveira A. Long latency auditory evoked potential in term and premature infants. Int Arch Otorhinolaryngol. 2013 Nov 7;18(01):016\u0026ndash;20.\u003c/li\u003e\n\u003cli\u003eMoore JK, Linthicum FH. The human auditory system: A timeline of development. Int J Audiol. 2007 Jan;46(9):460\u0026ndash;78.\u003c/li\u003e\n\u003cli\u003eSharma A, Dorman MF, Spahr AJ. A sensitive period for the development of the central auditory system in children with cochlear implants: implications for age of implantation: Ear Hearing. 2002 Dec;23(6):532\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eVouloumanos A, Werker JF. Listening to language at birth: evidence for a bias for speech in neonates. Dev Sci. 2007 Mar;10(2):159\u0026ndash;64.\u003c/li\u003e\n\u003cli\u003eGreen M, Solnit AJ. Reactions to the threatened loss of a child: a vulnerable child syndrome. Pediatric management of the dying child, part iii. Pediatrics. 1964 Jul;34:58\u0026ndash;66.\u003c/li\u003e\n\u003cli\u003eH\u0026ouml;vel H, Partanen E, Huotilainen M, Lindgren M, Ros\u0026eacute;n I, Fellman V. Auditory event-related potentials at preschool age in children born very preterm. Clin Neurophysiol. 2014 Mar;125(3):449\u0026ndash;56.\u003c/li\u003e\n\u003cli\u003eH\u0026ouml;vel H, Partanen E, Tideman E, Stjernqvist K, Hellstr\u0026ouml;m-Westas L, Huotilainen M, et al. Auditory event-related potentials are related to cognition at preschool age after very preterm birth. Pediatr Res. 2015 Apr;77(4):570\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eSuppiej A, Cainelli E, Cappellari A, Ermani M, Sartori S, Bisiacchi PS. Neonatal cortical auditory evoked potentials are affected by clinical conditions occurring in early prematurity: J Clin Neurophysiol. 2015 Oct;32(5):419\u0026ndash;23.\u003c/li\u003e\n\u003cli\u003ePasman JW, Rotteveel JJ, de Graaf R, Stegeman DF, Visco YM. The effect of preterm birth on brainstem, middle latency and cortical auditory evoked responses (BMC AERs). Early Hum Dev. 1992 Dec;31(2):113\u0026ndash;29.\u003c/li\u003e\n\u003cli\u003eCeponiene R, Rinne T, N\u0026auml;\u0026auml;t\u0026auml;nen R. Maturation of cortical sound processing as indexed by event-related potentials. Clin Neurophysiol. 2002 Jun;113(6):870\u0026ndash;82.\u003c/li\u003e\n\u003cli\u003eKihara M, Hogan AM, Newton CR, Garrashi HH, Neville BR, de Haan M. Auditory and visual novelty processing in normally-developing Kenyan children. Clin Neurophysiol. 2010 Apr;121(4):564\u0026ndash;76.\u003c/li\u003e\n\u003cli\u003eKushnerenko E, Ceponiene R, Balan P, Fellman V, Huotilainen M, N\u0026auml;\u0026auml;t\u0026auml;nen R. Maturation of the auditory event-related potentials during the first year of life: Neuroreport. 2002 Jan;13(1):47\u0026ndash;51.\u003c/li\u003e\n\u003cli\u003eOhlrich ES, Barnet AB. Auditory evoked responses during the first year of life. Clin Neurophysiol. 1972 Feb;32(2):161\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003ePonton CW, Eggermont JJ, Kwong B, Don M. Maturation of human central auditory system activity: evidence from multi-channel evoked potentials. Clin Neurophysiol. 2000 Feb;111(2):220\u0026ndash;36.\u003c/li\u003e\n\u003cli\u003eSilva LAF, Magliaro FCL, Carvalho ACM de, Matas CG. Matura\u0026ccedil;\u0026atilde;o dos potenciais evocados auditivos de longa lat\u0026ecirc;ncia em crian\u0026ccedil;as ouvintes: an\u0026aacute;lise do complexo P1-N1-P2-N2. CoDAS [Internet]. 2017 Sep 4;29(4). Available from: http://www.scielo.br/scielo.php?script=sci_arttext\u0026amp;pid=S2317-17822017000400314\u0026amp;lng=pt\u0026amp;tlng=pt\u003c/li\u003e\n\u003cli\u003eWunderlich JL, Cone-Wesson BK. Maturation of CAEP in infants and children: A review. Hearing Res. 2006 Feb;212(1\u0026ndash;2):212\u0026ndash;23.\u003c/li\u003e\n\u003cli\u003edeRegnier R-A, Wewerka S, Georgieff MK, Mattia F, Nelson CA. Influences of postconceptional age and postnatal experience on the development of auditory recognition memory in the newborn infant. Dev Psychobiol. 2002;41(3):216\u0026ndash;25.\u003c/li\u003e\n\u003cli\u003eGonzalez-Gomez N, Nazzi T. Phonotactic acquisition in healthy preterm infants: Phonotactic acquisition in preterm infants. Dev Sci. 2012 Nov;15(6):885\u0026ndash;94.\u003c/li\u003e\n\u003cli\u003eFenoglio A, Georgieff MK, Elison JT. Social brain circuitry and social cognition in infants born preterm. J Neurodevelop Disord. 2017 Dec;9(1):27.\u003c/li\u003e\n\u003cli\u003eSayeur MS, Vannasing P, Tremblay E, Lepore F, McKerral M, Lassonde M, et al. Visual development and neuropsychological profile in preterm children from 6 months to school age. J Child Neurol. 2015 Aug;30(9):1159\u0026ndash;73.\u003c/li\u003e\n\u003cli\u003eTremblay E, Vannasing P, Roy M-S, Lefebvre F, Kombate D, Lassonde M, et al. Delayed early primary visual pathway development in premature infants: high density electrophysiological evidence. PLoS ONE. 2014 Sep 30;9(9):e107992.\u003c/li\u003e\n\u003cli\u003eWachman EM, Lahav A. The effects of noise on preterm infants in the NICU. Archives of Disease in Childhood - Fetal and Neonatal Edition. 2011 Jul 1;96(4):F305\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eCaldas IFR, Garotti MF, Shiramizu VKM, Pereira A. The socio-communicative development of preterm infants is resistant to the negative effects of parity on maternal responsiveness. Front Psychol. 2018 Feb 2;9:43.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp style=\"border: none;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-family: 'Arial',sans-serif;\"\u003eTABLE 1\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse; border: none;\" width=\"621\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 17.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border-top: black; border-left: white; border-bottom: black; border-right: white; border-style: solid; border-width: 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 17.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: solid black 1.0pt; border-left: none; border-bottom: solid black 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 17.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eTotal Sample\u003cbr /\u003e\u003cem\u003eN\u003c/em\u003e=23\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: solid black 1.0pt; border-left: none; border-bottom: solid black 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 17.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003ePreterm\u003cbr /\u003e\u003cem\u003en\u003c/em\u003e=12\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: solid black 1.0pt; border-left: none; border-bottom: solid black 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 17.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eTerm\u003cbr /\u003e\u003cem\u003en\u003c/em\u003e=11\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: solid black 1.0pt; border-left: none; border-bottom: solid black 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 17.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 217.7pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" colspan=\"3\" width=\"290\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cem\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003en\u003c/span\u003e\u003c/em\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e(%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cem\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003ep\u003c/span\u003e\u003c/em\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e value\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eMaternal age\u003c/span\u003e\u003csup\u003e\u003cspan style=\"font-size: 11.0pt;\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 17.0pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026lt; 34 y.o.\u003csup\u003e2\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e8(66.67)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e2(66,67)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e6(66.67)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026gt; 0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 17.0pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026gt; 35 y.o.\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center; tab-stops: center 39.45pt;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e4(33.33)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e1(33.33)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e3(33.33)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eEducation\u003c/span\u003e\u003csup\u003e\u003cspan style=\"font-size: 11.0pt;\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 17.0pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eLess than middle-school\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e17(94.44)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e8(100.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e9(90.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026gt; 0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 17.0pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eMore than middle-school\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e1(5.56)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e0(0.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e1(10.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eSex of child\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 17.0pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eMale\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e10(43.48)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e6(46.16)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e4(40.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026gt; 0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 17.0pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eFemale\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e13(56.52)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e7(53.84)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e6(60.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eGestational age\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 17.0pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e31 to \u0026lt; 37 weeks\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e13(56.52)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e13(100.0)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e0(0.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026lt;0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 17.0pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026gt; 37 weeks\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e10(43.48)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e0(0.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e10(100.0)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eBirth weight\u003c/span\u003e\u003csup\u003e5\u003c/sup\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026lt; 2,500 g\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e10(50.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e10(83.33)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e0(0.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026lt;0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026gt; 2,500 g\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e10(50.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e2(16,67)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e8(100.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eFamily income (in minimum wages)\u003csup\u003e6\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; \u0026lt; 1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e8(50.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e3(42.85)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e5(55.55)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026gt;0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; 1 to 5\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e8(50.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e4(57.15)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e4(44.45)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eSocioeconomic Status\u003csup\u003e7,8\u003c/sup\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 17.0pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eA, B, and C\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e6(30.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e1(9.10)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e5(55.55)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026lt;0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 17.0pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eD and E \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e14(70.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e10(90.90)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e4(44.45)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003eNICU admission\u003csup\u003e9\u003c/sup\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; No\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e6(42.85)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e3(50.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e3(37.50)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026gt; 0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 1.0pt;\"\u003e\n\u003ctd style=\"width: 198.8pt; border-top: none; border-left: solid white 1.0pt; border-bottom: solid black 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"265\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u0026nbsp;\u0026nbsp; Yes\u003csup\u003e10\u003c/sup\u003e \u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 81.2pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"108\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e8(57.15)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 65.35pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"87\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e3(50.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.15pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center;\"\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e5(62.50)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 49.6pt; border-top: none; border-left: none; border-bottom: solid black 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 1.0pt;\" width=\"66\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 11.0pt; font-family: 'Meiryo',sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"text-indent: .5in;\"\u003e\u003csup\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Meiryo', sans-serif;\"\u003e1\u003c/span\u003e\u003c/sup\u003e\u003cspan style=\"font-size: 10.0pt; font-family: 'Meiryo',sans-serif;\"\u003e 11 missing values; \u003csup\u003e2\u003c/sup\u003e y.o.: years old; \u003csup\u003e3\u003c/sup\u003e 5 missing values; \u003csup\u003e4\u003c/sup\u003e 31.28 weeks; \u003csup\u003e5\u003c/sup\u003e 3 missing values; \u003csup\u003e6\u003c/sup\u003e 8 missing values; \u003csup\u003e7\u003c/sup\u003e 3 missing values; \u003csup\u003e8\u003c/sup\u003e \u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; font-family: 'Arial',sans-serif;\"\u003eBrazil Economic Classification Criteria (www.abep.org/criterio-brasil); \u003c/span\u003e\u003csup\u003e\u003cspan style=\"font-size: 10.0pt; font-family: 'Meiryo',sans-serif;\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003cspan style=\"font-size: 10.0pt; font-family: 'Meiryo',sans-serif;\"\u003e 9 missing values; \u003csup\u003e10\u003c/sup\u003e all infants stayed in NICU for 2 days\u003c/span\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-research-notes","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"resn","sideBox":"Learn more about [BMC Research Notes](http://bmcresnotes.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/resn/default.aspx","title":"BMC Research Notes","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"preterm, newborn, brain development, auditory, cortex","lastPublishedDoi":"10.21203/rs.2.22677/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.22677/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eObjective: Preterm infants are exposed earlier than their term counterparts to unattenuated sounds from the external environment during the sensitive period of the organization of the auditory cortical circuitry. In the current study, we investigate the effect of preterm birth on the course of development of auditory cortical areas by evaluating how gestational age (GA) correlates with the latency of the P1 component of the cortical auditory evoked potential (CAEP) of two experimental groups measured at one or three months of age. \u003c/p\u003e\u003cp\u003eResults: Our sample consisted of 23 infants delivered at GA ranging from 31.28-41.42 weeks and separated into two groups evaluated transversally at one or three months of corrected age (CA). In the group evaluated at one-month CA, the latency of the component P1 was similar in both terms and infants classified as late-preterm (GA\u0026gt;32 weeks). However, in the group evaluated at three months CA, P1 latency was significantly smaller in preterms. These preliminary results suggest an acceleration of the development of auditory cortical pathways in preterms, probably due to their early exposure to socially relevant auditory stimuli from the external environment.\u003c/p\u003e","manuscriptTitle":"Early exposure to environmental sounds and the development of cortical auditory evoked potentials of preterm infants during the first three months of life","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2020-06-05 01:09:40","doi":"10.21203/rs.2.22677/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2020-06-02T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-05-30T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-05-29T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-05-29T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-research-notes","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"resn","sideBox":"Learn more about [BMC Research Notes](http://bmcresnotes.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/resn/default.aspx","title":"BMC Research Notes","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-02-05 15:44:34","doi":"10.21203/rs.2.22677/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2020-04-20T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-04-17T12:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvited","content":"","date":"2020-02-04T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-02-04T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-02-04T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-02-03T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-02-02T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-02-01T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-research-notes","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"resn","sideBox":"Learn more about [BMC Research Notes](http://bmcresnotes.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/resn/default.aspx","title":"BMC Research Notes","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"83ee40e2-a50f-46b1-b655-f25e937ad37e","owner":[],"postedDate":"June 5th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":113994,"name":"Developmental Neuroscience"},{"id":113995,"name":"Pediatrics"}],"tags":[],"updatedAt":"2020-06-28T17:42:05+00:00","versionOfRecord":{"articleIdentity":"rs-13251","link":"https://doi.org/10.1186/s13104-020-05129-8","journal":{"identity":"bmc-research-notes","isVorOnly":false,"title":"BMC Research Notes"},"publishedOn":"2020-06-26 12:00:00","publishedOnDateReadable":"June 26th, 2020"},"versionCreatedAt":"2020-06-05 01:09:40","video":"","vorDoi":"10.1186/s13104-020-05129-8","vorDoiUrl":"https://doi.org/10.1186/s13104-020-05129-8","workflowStages":[]},"version":"v2","identity":"rs-13251","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-13251","version":["v2"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}