Clinical Psychological Science 2013 Kisilevsky 2167702613509371

Clinical Psychological Science
http://cpx.sagepub.com/ Auditory Processing in Growth-Restricted Fetuses and Newborns and Later Language Development
Barbara S. Kisilevsky, Beverly Chambers, Kevin C. H. Parker and Gregory A. L. Davies Clinical Psychological Science published online 21 November 2013 DOI: 10.1177/2167702613509371 The online version of this article can be found at: http://cpx.sagepub.com/content/early/2013/11/18/2167702613509371
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CPXXXX10.1177/2167702613509371Kisilevsky et al.Auditory Processing and Language Development
Empirical Article
Auditory Processing in Growth-Restricted Fetuses and Newborns and Later Language Development
Barbara S. Kisilevsky1,2,3, Beverly Chambers1, Kevin C. H. Parker3, and Gregory A. L. Davies2,4
Clinical Psychological Science XX(X) 119 The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/2167702613509371 cpx.sagepub.com
1 School of Nursing, Queens University; 2Department of Obstetrics and Gynaecology, Kingston General Hospital, Kingston, Ontario, Canada; 3Department of Psychology, Queens University; and 4Department of Obstetrics and Gynaecology, Queens University
Abstract Growth-restricted fetuses and newborns are at increased risk for language deficits, and language impairments have been associated with increased risk for cognitive, social, emotional, and behavioral clinical disorders. Auditory-information processing was examined longitudinally in 167 fetuses in Study 1, 96 of whom were reexamined as newborns in Study 2. In Study 3, language was assessed at 15 months of age for 75 infants from Study 1. Compared with participants who were appropriately grown for gestational age, growth-restricted fetuses showed less sustained response to their mothers voice; growth-restricted newborns showed less recovery to a novel word after habituation and no preference for their mothers voice. At 15 months of age, those infants who had been born growth restricted showed expressivelanguage deficits on Mullen Scales of Early Learning and MacArthur-Bates Communicative Development Inventory subscales. Our results support the hypothesis that fetal growth restriction affects the development of auditory-system functioning and indicate that it may be possible to identify individual fetuses and newborns at risk for language deficits and to intervene early, when the foundation for language is being laid. Keywords fetus, newborn, infant, heart rate, auditory processing, language, development
Received 7/29/13; Revision accepted 9/23/13
Children born small for gestational age (SGA) are at increased risk for language deficits (e.g., Low et al., 1982; Low et al., 1992), and language impairments have been associated with increased risk for cognitive, social, emotional, and behavioral clinical disorders (e.g., Aram, Ekelman, & Nation, 1984). Although the etiology of language deficits in SGA populations is unknown, we previously have hypothesized that fetal growth restriction affects the development of auditory-system functioning, which results in differential auditory-information processing in SGA fetuses compared with healthy fetuses appropriately grown for gestational age (AGA; Kisilevsky & Davies, 2007). If our hypothesis is correct, voice/ speech perception, which lays the foundation for later language competence, should differ in SGA and AGA fetuses and newborns and be associated with language
abilities in 15-month-old infants. The present research was designed to test this hypothesis. For this study, we defined growth restriction as a newborn birth weight for gestational age less than or equal to the 10th percentile. The ultimate objective of this line of research is the identification of early behavioral markers of later language abilities in offspring in pregnancies associated with increased risk for language deficits. Such markers would facilitate the development of interventions to prevent or ameliorate language deficits very early in development,
Corresponding Author: Barbara S. Kisilevsky, School of Nursing, Queens University, 92 Barrie St., Kingston, Ontario K7L 3N6, Canada E-mail: kisilevb@queensu.ca
2 which is particularly important because the earlier the intervention, the better the outcome. Fetal growth restriction is a multicausal condition (e.g., LaBatide-Alanore, Tregouet, Jaquet, Bouyer, & Tiret, 2002; Low, 1994; Neerhof, 1995; Prada & Tsang, 1998) that most commonly results from nutritional/oxygen deprivation as a consequence of placental insufficiency (Giles, Trudinger, & Baird, 1985; Resnik, 2002; Trudinger et al., 1987). The condition complicates 7.8% of births in Canada (Health Canada, 2008), which manifests as fetuses (and infants) being SGA. SGA fetuses have an increased incidence of neurodevelopmental deficits (Low, 1994), including cerebral palsy (e.g., Blair & Stanley, 1992; Uvebrandt & Hagberg, 1992), cognitive deficits (e.g., Kok, den Ouden, Verloove-Vanhorick, & Brand, 1998), and learning disabilities (Low et al., 1992). An increased risk for language deficits in 2- to 5-yearold children born SGA has been well documented (Gutbrod, Wolke, Soehne, Ohrt, & Riegel, 2000; Low et al., 1982; Low et al., 1992; Vohr, Garcia Coll, & Oh, 1988). When term SGA and AGA infants were matched for age, sex, birth rank, and social class, both verbal comprehension and expressive language were found to be less developed in the SGA group (Walther & Ramaekers, 1982). In studies of 5- to 9-year-old children born very low birth weight SGA (Korkman, Liikanen, & Fellman, 1996) and born preterm SGA (Chaudhari, Bhalerao, Chitale, Pandit, & Nene, 1999), researchers reported an increased incidence of both neurodevelopmental deficits and language delay. At 9 to 11 years of age, infants born SGA, compared with infants born AGA, continued to show lower scores on neurodevelopmental assessments (Leitner et al., 2007), language difficulties, and learning disabilities (Geva, Eshel, Leitner, Fattal-Valevski, & Harel, 2006) on academic activities requiring language skills (e.g., reading, spelling; Low et al., 1992). Early identification and intervention of language impairment is important because language deficits are associated with numerous clinical disorders that manifest in emotional (e.g., anxiety disorder; Beitchman et al., 2001; Beitchman, Nair, Clegg, & Patel, 1986), cognitive (e.g., executive function; Henry, Messer, & Nash, 2012; working memory; Hutchinson, Bavin, Efron, & Sciberras, 2012), social (e.g., autism spectrum disorders; Joshi et al., 2013), and behavioral (e.g., attention-deficit/hyperactivity disorder; Helland, Biringer, Helland, & Heimann, 2012) dysfunction in everyday life. Results from the Ottawa Language Study, a 20-year prospective follow-up of children identified at 5 years of age with and without speech and language impairments, showed that children in the speech-and-language-impairment group had increased rates of concurrent attention-deficit/hyperactivity disorder and anxiety disorders at age 5 (Beitchman et al., 1986), increased rates of psychiatric disorder at age 12 (Beitchman, Wilson, Brownlie, Inglis, & Lancee, 1996),
Kisilevsky et al. increased rates of anxiety disorder at age 19 (Beitchman et al., 2001), and for those with a history of language impairments, poorer outcomes in communication, cognitive/academic achievement, educational attainment, and occupational status at age 25 ( Johnson, Beitchman, & Brownlie, 2010). Converging evidence has suggested a possible link between the development of the SGA fetal auditory system, fetal behavior, and later language competence. Researchers investigating animal models of placental insufficiency have demonstrated subtle deficits in neural conduction, which may have implications for auditory perception (Rees, Proske, & Harding, 1989; Rehn et al., 2002). In addition, differential fetal cardiac responses to auditory probes have been reported in comparisons of low-risk, uneventful, and high-risk pregnancies complicated by conditions associated with nutritional/oxygen deprivation, such as preeclampsia (Kisilevsky et al., 2011), hypertension (Lee, Brown, Hains, & Kisilevsky, 2007; Warner, Hains, & Kisilevsky, 2002), diabetes (Allen & Kisilevsky, 1999; Kisilevsky, Gilmour, Stutzman, Hains, & Brown, 2012), and smoking (Cowperthwaite, Hains, & Kisilevsky, 2007). Taken together, these findings indicate that fetal auditory-system development may influence subsequent language abilities. Moreover, a relation between late-gestation heart rate and language competence in 27 month olds has been shown (Bornstein et al., 2002), which indicates that fetal heart rate may serve as a reliable measure of auditory processing. Low-risk AGA fetuses respond to, discriminate between, and show evidence of learning voices, speech sounds, and language. An audio recording of their mothers voice elicits a heart rate increase beginning at a gestational age of approximately 32 weeks (Kisilevsky et al., 2003; Kisilevsky et al., 2009; Kisilevsky & Hains, 2011), with the pattern and number of participants who respond varying as a function of gestational age (Kisilevsky & Hains, 2011). Fetuses also discriminate a change in the gender of a speaker from male to female or female to male (Lecanuet, Granier-Deferre, & Busnel, 1989), their mothers tape-recorded voice played above the abdomen via a loudspeaker from her voice when she is speaking directly (Hepper & Shahidullah, 1994), and their native language from a foreign language (Kisilevsky et al., 2009). Moreover, differential heart rate responses to an audio recording of their mother reading a passage compared with an audio recording of a strange female reading a passage (Kisilevsky et al., 2003; Kisilevsky et al., 2009) provide evidence of fetal learning. Reliable response to sound, discrimination, and learning indicate that the fetus hears and attends to sound stimuli and that neural networks (present at birth; Perani et al., 2011) sensitive to the properties of the mothers voice, speech, and language are being formed before birth.
Auditory Processing and Language Development Systematic study of auditory function in SGA fetuses has not been reported. However, in a series of studies in which researchers used a vibroacoustic stimulus (mechanical touch plus sound; Gagnon, Hunse, Carmichael, & Patrick, 1989; Gagnon, Hunse, Fellows, Carmichael, & Patrick, 1988), a shorter duration heart rate acceleration response by SGA fetuses, compared with AGA fetuses, was found, which suggests that the stimulus was perceived as less intense or less salient. In another study (Leader, 1995), SGA fetuses took more trials to habituate, perhaps indicating a longer time to recognize the stimulus as familiar. These studies show differential perceptual processing between SGA and AGA fetuses and underscore a need to systematically examine auditory processing in SGA fetuses before and after birth. In the healthy newborn, auditory perception (i.e., discrimination, preference, and habituation) has been extensively studied using multiple measures, including, among others, head turning (e.g., Brody, Zelazo, & Chaika, 1984), nonnutritive sucking (e.g., DeCasper & Fifer, 1980), looking time (e.g., Morrongiello, Fenwick, & Chance, 1998), and heart rate (e.g., Ockleford, Vince, Layton, & Reader, 1988). Newborns exhibit differential heart rate responses to their mothers voice, compared with a female strangers voice (if younger than 24 hr old; Ockleford et al., 1988); recognize their mothers voice (Mehler, Bertoncini, Barriere, & Jassik-Gerschenfeld, 1978); prefer their mothers voice over a strangers voice (DeCasper & Fifer, 1980) or quiet (Moon & Fifer, 1990); and retain words in memory for at least 24 hr (Swain, Zelazo, & Clifton, 1993). Given a newborns limited auditory exposure, these findings suggest the influence of the sound environment and learning during the prenatal period that is supported by evidence of fetal learning of the mothers voice (Kisilevsky et al., 2003) and a passage (DeCasper, Lecanuet, Busnel, GranierDeferre, & Maugeais, 1994). In addition, newborns discriminate their native language from a foreign language but do not discriminate between two foreign languages (Mehler et al., 1988), which suggests that prenatal experience with language is necessary for discrimination. Auditory processing in infants born SGA has not been reported. However, using a habituation paradigm with stimulus words (e.g., tinder, beagle) matched on their length, phonetic content, and frequency of occurrence, researchers have shown differences in information-processing abilities among infants at high, moderate, and low risk for subsequent developmental delay (Zelazo, Weiss, Papageorgiou, & Laplante, 1989), and impaired processing has been reported in infants exposed to cocaine as fetuses (Potter, Zelazo, Stack, & Papageorgiou, 2000). Whether SGA and AGA newborns show differential auditory-information processing is unknown; we examine this possibility in the present study.
3 In summary, perceptual-cognitive processing of speech begins before birth, with evidence of an environmental influence by the last trimester of pregnancy. Moreover, differential voice processing has been reported in pregnancies complicated by placental insufficiency, and an increased risk of language deficits by 2 to 5 years of age has been reported in infants born growth restricted, the most common cause of which is placental insufficiency. Subsequently, language impairment is associated with clinical disorders that affect functioning in everyday life. Thus, the purpose of this prospective longitudinal study is to characterize auditory processing in a group of SGA fetuses (Study 1) and newborns (Study 2), compared with a group of AGA fetuses and newborns, and to examine language development in 15-month-old infants who were born SGA compared with infants born AGA (Study 3).
Study 1: Auditory-Information Processing in SGA Fetuses

Study 1 was designed to test the hypothesis that fetal growth restriction affects the development of auditorysystem function, which results in differential auditoryinformation processing between SGA fetuses and healthy AGA fetuses (Kisilevsky & Davies, 2007). Fetal response to the mothers or a female strangers voice was examined. Differential fetal responding to sensory stimuli has been reported in previous studies of low risk, uneventful pregnancies compared to pregnancies complicated by conditions associated with nutritional/oxygen deprivationfor example, studies investigating mothers voice and preeclampsia (Kisilevsky et al., 2011), mothers voice and hypertension (Lee et al., 2007), vibroacoustic stimulus and hypertension (Warner et al., 2002), vibroacoustic stimulus and diabetes (Allen & Kisilevsky, 1999), mothers voice and diabetes (Kisilevsky et al., 2012), and mothers voice and smoking (Cowperthwaite et al., 2007)which is the most common cause of growth restriction (Giles et al., 1985; Resnik, 2002; Trudinger et al., 1987).
Method
Participants. A total of 167 mother-fetal pairs (43 SGA fetuses, 124 AGA fetuses; gestational age = 2841 weeks) who were recruited from antenatal clinics at a community teaching hospital in southern Canada provided the data for this study. Fetal growth restriction was identified by ultrasound-scan observation in the hospitals fetalassessment unit and confirmed at delivery using birth weight percentile. Gestational age was calculated from the 1st day of the last menstrual period if periods were reliable or from early ultrasound for dating. Data from an additional
4 19 AGA fetuses were not included10 infants were born prematurely (< 37 weeks of gestation completed), and 9 infants had evidence of compromise at delivery (5-min Apgar < 7, hypoxia, congenital heart anomaly, and infection). Inclusion criteria for all participants were a maternal age of at least 16 years, English speaking, and a singleton pregnancy. Inclusion criteria for the SGA group were a newborn birth weight for gestational age less than or equal to the 10th percentile. SGA exclusion criteria were chromosomal abnormalities and any condition incompatible with life. One woman had a diagnosis of hypertension, and 18 women reported smoking throughout pregnancy. Six SGA fetuses were born prematurely (gestational age = 3036 weeks). Their data were included in the fetal analyses. Inclusion criteria for the AGA group were an uneventful pregnancy with the delivery of a healthy, full-term newborn with birth weight for gestational age greater than the 10th percentile. AGA exclusion criteria were any medically treated comorbid conditions (e.g., diabetes, hypertension, thyroid disease, depression). Fifteen women reported smoking throughout pregnancy. Testing of fetuses and newborns was conducted in the Maternal-Fetal-Newborn Studies Laboratory located adjacent to the obstetrical outpatient and inpatient services of the hospital. Sex of the infants was determined at birth. Given that Canada possesses a universal health-care system, information on race and socioeconomic status are not routinely collected and were not collected for this study. In general, the total sample of women was well educated, with 78.4% reporting some postsecondary education. Approximately 98% of the women who volunteer for studies in this laboratory are White. According to the local economic development corporations June 2013 statistics, the top eight employers (number of employees) in the community are public sector (Kingston Economic Development Corporation, 2013). Statistics Canada 2011 data show the median total family income for all types of families in the community as C$79,140 (Statistics Canada, 2013). The study was carried out according to ethics approval from the University and Affiliated Teaching Hospitals Research Ethics Board. Women provided informed, voluntary, written consent prior to participation. Equipment/stimuli. Maternal blood pressure was obtained using a LifeSource One Step auto-inflation blood pressure monitor (Model UA-767); the user manual reports a standard deviation of 3-mm Hg. Continuous fetal heart rate was recorded using a Hewlett-Packard cardiotocograph (Model 1351A), which provides a digital recording of heart rate measured in beats per minute (bpm); auditory trial onset/offset was indicated on the strip recording and computer text file using an event marker. Custom software was used to capture and
Kisilevsky et al. average four readings per second; the average at each second was stored in a computer text file. A Siemens real-time two-dimensional ultrasound scanner with built in videocassette recorder (Sonoline SI-450) was used to observe and videotape body and breathing movements and to estimate amniotic fluid volume. Recording and playback of auditory stimuli were carried out using a computer running prerecorded auditory acoustic testing freeware (PRAAT version 4.4.27). For fetal testing, a 2-min voice stimulus was generated by having each mother read a passage from the story of Bambi (Salten & Chambers, 1928). The stimuli were augmented by a Yamaha Natural Sound stereo amplifier (Model AX-497) and delivered to the fetus through a loud speaker (Auratone 5C Super Sound Cube). Sound intensity was measured in air at a distance of 10 cm using the A scale of a Brel and Kjr sound pressure level meter (Model 2235). A Sony portable CD player and Panasonic noise-cancellation headphones were used to play masking music to the mother. Procedure. On arrival at the laboratory, each mother provided demographic information (e.g., age, education, weight, height), had her blood pressure taken three times in the right upper arm while seated, and read from the story of Bambi for 2 min while being audiotaped. Subsequently, with the mother at rest in a semirecumbant position, wedged left on a hospital bed, a standardized fetal observation of spontaneous behavior lasting approximately 40 min was carried out. First, the transducer of the cardiotocograph was positioned on the abdomen to obtain an optimal trace, and fetal heart rate was recorded continuously for 20 min. Second, the transducer was removed and the wand of the real-time ultrasound scanner was positioned on the abdomen to obtain a longitudinal or cross-sectional view of the fetal body, which may or may not have included limbs. For 20 min, the number of body movements observed and the cumulative amount of breathing were recorded simultaneously and independently by two researchers; in addition, the scan was videotaped. Any movement of the body, except hiccups, was counted as a movement, with a minimum interval of 2 s with no movement before a new movement would be counted. Reliability of the two research assistants independent judgments of the number of body movements (n = 144, r = .98, p < .001) and amount of breathing (n = 140, r = .94, p < .001) during scanning was high. A voice-processing procedure was carried out immediately after the observations of spontaneous behavior. The cardiotocograph transducer was replaced on the abdomen for continuous heart rate recording. The 6-min voice-processing procedure comprised a 2-min prevoice, no-sound baseline period; a 2-min voice (mother or female stranger) period; and a 2-min postvoice, no-sound
Auditory Processing and Language Development period. The female strangers voice used was that of the previous mother in the study. The voice recordings were delivered at an average of 95 dB A (estimated uterine attention = 3540 dB) through a loudspeaker placed 10 cm above the maternal abdomen. The ambient noise level with all equipment running averaged 48 dB A. After completion of the voice-processing procedure, an estimate of amniotic fluid volume was obtained by measuring the largest visible pocket of fluid in two dimensions in each of the four maternal abdominal quadrants. An amniotic fluid index was calculated by summing the vertical dimension of each pocket. During the auditory procedure, mothers wore headphones and listened to soft jazz or classical guitar music to mask the sounds being played to the fetus. Data-analysis strategy. Data analyses were conducted using IBM SPSS Statistics 21 (significance level set at p .05). For repeated measures analyses, Greenhouse-Geisser p values are reported. Because onset and offset of sounds were indicated manually, the voice and voice offset periods varied by 1 to 2 s, and a 118-s period of fetal heart rate was used in analyses to include all participants. Data analyses focused on group (SGA vs. AGA), voice (mothers vs. strangers), period (prevoice, voice, and postvoice phases of the auditory procedure), and time (the seconds of fetal heart rate recorded118 s per period).
5 auditory stimulusinduced responding, we used t tests for independent groups (SGA vs. AGA) to examine fetal spontaneous behavior observed during the two consecutive 20-min periods while the mother was at rest. Heart rate records were available for all 167 participants, and movement ultrasound-scan scores were available for 158 participants. Analyses of the SGA and AGA fetuses, including the average number of spontaneous fetal heart rate accelerations greater than 10 bpm (SGA: 6.9; AGA: 6.9; p = .94, d = 0.01) and 15 bpm (SGA: 4.2; AGA: 4.3; p = .93, d = 0.02) and decelerations greater than 10 bpm (SGA: 0.5; AGA: 0.7; p = .35, d = 0.17) and 15 bpm (SGA: 0.1; AGA: 0.2; p = .87, d = 0.02), the average number of body movements (SGA: 13.2; AGA: 16.0; p = .08, d = 0.33), and the average amount of fetal breathing (SGA: 456 s; AGA: 508 s; p = .37, d = 0.15), showed no significant differences between groups, which indicated no differences in spontaneous behavior prior to presentation of the voices. Repeated analyses for those participants tested as newborns and as 15-month-old infants also showed no differences between these subsamples for any of the measures. Heart rate changes to mothers voice compared with strangers voice. The following series of analyses was used to test the hypothesis that fetal growth restriction affects the development of auditory-system functioning, which results in differential auditory-information processing in SGA fetuses. Preliminary analyses revealed effects of gestational age, and in subsequent analyses, completed weeks of gestation was used as a covariate to control for maturation. Maternal smoking status showed no effects and it was not considered further. A mixedmodel analysis of variance, with two between-subjects (group and voice) and two within-subjects (period and time) factors and with completed weeks of gestation as a covariate, used to examine fetal heart rate responding to the mothers voice or the strangers voice revealed a main effect of voice, F(1, 161) = 8.05, p = .01, 2 = .05, and quadratic contrastsPeriod Voice Group: F(1, 161) = 4.38, p = .04, 2 = .03; Period Time Group: F(1, 161) = 4.51, p = .04, 2 = .03. Given the effects found for period, the baseline period prior to voice onset was examined separately. The analysis revealed a main effect of voice, F(1, 161) = 4.52, p = .04, 2 = .03. Average fetal heart rate was higher prior to the presentation of the strangers voice (M = 144.8 bpm, SEM = 2.4) than to the presentation of the mothers voice (M = 139.4 bpm, SEM = 0.9). Thus, the average heart rate in the prevoice period and weeks of completed gestation were used as covariates and the analysis was repeated to examine fetal response to voices during the voice and voice offset periods. Results demonstrated a Period Voice Group interaction, F(1, 160) = 4.71, p = .03, 2 = .03. A simple effects
Results
Demographic and obstetrical data for the 167 motherfetal pairs analyzed in all three studies are displayed in Tables 1 and 2. At fetal testing, mothers in the SGA group, compared with mothers in the AGA group, had on average a lower level of education and a lower body mass index1 prior to pregnancy and at the time of the fetal observation. As expected by definition, SGA infants had an average lower birth weight. These infants also had a smaller head circumference, were born earlier, and had a lower 5-min Apgar score; both the average gestation at delivery and the Apgar score were within normal limits. Primiparas made up 46.5% of the SGA group and 44.4% of the AGA group. Public-health records were available for routine hearing screening (i.e., otoacoustic emission testing with audiology follow-up for failure) for 155 of the participants. In the SGA group, 38 infants passed a hearing-screening test and 5 infants had no record. In the AGA group, 115 infants passed a hearing-screening test, 2 infants did not pass and had no available follow-up information, and 7 infants had no record. Spontaneous heart rate changes and movements. To determine whether there were differences in spontaneous heart rate changes or movements prior to
6
Fetus AGA M (SD) .04 .02 .01 29.2 35.2 25.3 30.6 121 75 141 < .001 (4.5) (2.5) (5.3) (5.0) (10) (8) (33) 124 124 120 118 123 123 124 26.9 35.6 22.8 27.3 118 73 117 (6.4) (2.3) (6.2) (5.8) (11) (10) (29) 43 43 40 37 39 39 43 29.1 35.4 25.5 30.9 123 75 141 (4.4) (2.8) (5.4) (5.1) (11) (8) (28) 78 78 77 77 78 78 78 25.9 35.5 20.6 25.0 118 72 126 (7.1) (2.4) (5.8) (5.3) (8) (10) (32) 18 18 18 .01 17 < .001 18 18 18 .05 30.3 35.5 25.8 31.1 122 75 143 (4.7) (2.5) (5.8) (5.1) (10) (8.0) (30) n M (SD) n t-test p value M (SD) n M (SD) n M (SD) t-test p value n 57 57 56 55 56 56 57 SGA AGA SGA AGA Newborn 15-month-old infant SGA M (SD) 27.2 35.2 21.7 25.9 121 71 127 (7.1) (2.3) (6.4) (6.4) (10) (11) (33) n 18 18 17 15 17 17 18 t-test p value 39.4 3,573 50.1 51.5 35.0 34.1 2.6 8.9 2.3 (1.1) (432) (25.3) (2.1) (1.3) (1.9) (0.3) (0.5) (0.9) 124 38.2 (2.1) 124 2,493 (470) 124 5.6 (3.1) 120 46.9 (3.9) 120 32.4 (2.0) 56 30.2 (1.1) 120 2.4 (0.2) 124 8.3 (1.5) 121 3.3 (3.0) 43 43 41a 41 41 10 41 41 39 < < < < < < < .001 .001 .001 .001 .001 .001 .001 .01 39.5 3,578 49.3 51.8 35.1 34.1 2.6 8.9 2.4 (1.2) (431) (26.0) (2.0) (1.3) (1.9) (0.3) (0.5) (0.9) 78 38.4 (1.4) 78 2,526 (296) 78 5.0 (2.7) 77 47.7 (2.8) 77 32.9 (1.1) 56 30.1 (1.0) 77 2.4 (0.2) 78 8.6 (1.3) 78 2.6 (2.3) 18 18 18 18 18 9 18 18 18 < < < < < .01 .001 .001 .001 .001 .001 .01 39.5 3,591 50.3 51.5 35.0 34.1 2.6 8.9 2.4 (1.2) (455) (27.0) (2.0) (1.3) (2.0) (0.3) (0.5) (0.9) 57 57 57 55 55 33 55 57 56 38.7 2,584 5.1 48.2 33.1 30.2 2.3 8.3 3.1 (1.7) (315) (2.6) (2.8) (1.2) (1.1) (0.2) (1.4) (2.2) 18 18 18 18 18 7 18 18 18 .02 .01 .05 .03 < .001 < .001 < .001 < .001 < .001 < .001
Table 1. Maternal and Newborn Demographic and Obstetrical Variables for AGA and SGA Fetuses Tested as Fetuses, Newborns, and 15-Month-Old Infants
Variable
Mother Age (years) GA at testing (weeks) BMI prepregnancy BMI at testing Systolic BP Diastolic BP Amniotic fluid index Newborn GA at birth (weeks) Birth weight (g) Birth weight (percentile) Length (cm) Head circumference (cm) Chest circumference (cm) Ponderal index Apgar 5 min Hospital stay (days)
Note: Only significant p vales are displayed. AGA = appropriately grown for gestational age; SGA = small for gestational age; GA = gestational age; BMI = body mass index; BP = blood pressure (average of three successive readings taken while seated immediately prior to testing). a Two infants had birth weight percentiles below 0 and are not included.
Table 2. Maternal and Newborn Demographic and Obstetrical Variables for the AGA and SGA Fetuses Tested as Fetuses, Newborns, and 15-Month-Old Infants Fetus AGA % (n) 12.1 (15) 29.8 (37) < .001 11.5 (9) 88.5 (69) 43 41.9 (18) 58.1 (25) 48.7 (38) 51.3 (40) 78 33.3 (6) 66.7 (12) 12.9 (16) 87.1 (108) 124 50.8 (63) 49.2 (61) 46.5 (20) 53.5 (23) 44.4 (8) 55.6 (10) 18 57.9 (33) 42.1 (24) 124 124 124 41.9 (18) 20.9 (9) 43 43 43 < .001 9.0 (7) 32.1 (25) 78 78 78 44.4 (8) 5.6 (1) 18 18 18 n % (n) n 2 test p value % (n) n % (n) n SGA AGA SGA Newborn AGA % (n) < .001 .05 < .001 8.8 (5) 29.8 (17) 8.8 (5) 91.2 (52) 57 33.3 (6) 66.7 (12) n 57 57 57 15-month-old infant SGA % (n) 27.8 (5) 16.7 (3) 27.8 (5) 72.2 (13) 18 n 18 18 18
Variable
2 test p value
2 test p value .04 .04
Mother Smoker Cesarean section Education Secondary or less Postsecondary Newborn Sex Male Female
Note: Only significant p values are displayed. AGA = appropriately grown for gestational age; SGA = small for gestational age.
8
AGA SGA 144
Kisilevsky et al.
Fetal Heart Rate Response to Mothers Voice
142
Mean Fetal Heart Rate (bpm)
140
138
136
134 1 14 27 40 53 66 79 92 105 118 131 144 157 170 183 196 209 222 235 248 261 274 287 300 313 326 339 352
Time (Seconds)
Fig. 1. Mean fetal heart rate response to the mothers voice during the prevoice baseline, voice, and voice offset periods for the SGA and AGA groups. The x-axis reference lines indicate the onset and offset of the mothers voice, respectively. bpm = beats per minute; SGA = small for gestational age; AGA = appropriately grown for gestational age.
analysis for the mothers voice showed a Period Group interaction, F(1, 147) = 4.13, p =.04, 2 = .03. There were no effects for the strangers voice. Figure 1 illustrates fetal heart rate response to the mothers voice during the prevoice baseline, voice, and voice offset periods for the SGA and AGA groups. The average fetal heart rate increased in both groups during the 1st min of the mothers voice and then returned to baseline in the SGA group but remained elevated in the AGA group.
Discussion
Differential responding to the mothers voice was observed: SGA fetuses showed a heart rate increase limited to approximately the 1st min, whereas AGA fetuses sustained a response during the 4 min of the voice and voice offset periods. The shorter duration of heart rate response in the SGA fetuses is consistent with results reported by researchers using a vibroacoustic stimulus
(Gagnon et al., 1988; Gagnon et al., 1989). The increased and sustained response in the AGA group is similar to results reported previously in low-risk fetuses (Kisilevsky et al., 2003; Kisilevsky et al., 2011). The mechanisms responsible for an effect of growth restriction on fetal and newborn auditory-system functioning are unknown and a matter of speculation. Dissimilar auditory-system development, which has been observed in studies of animal models of placental insufficiency (Rees et al., 1989; Rehn et al., 2002) as well as in studies of human fetuses in which magnetoencephalographic recordings were used (Kiefer et al., 2008), is one possible explanation. Moreover, animal studies showing that delays return to control levels postnatally (Tolcos et al., 2011) have suggested that the effects may be ameliorated after birth once nutrition/oxygenation are no longer compromised. The differential SGA and AGA responses also could be due to increased sensorineural threshold elevation in the SGA group, given that the
Auditory Processing and Language Development magnitude of the endocochlear potential depends on oxygen supply (Sohmer & Freeman, 1995) and placental insufficiency results in less oxygen being transported to the fetus. If so, SGA fetuses may have perceived their mothers voice as less intense or the voice may not have been loud enough to be perceived consistently. Because the SGA fetuses showed an initial heart rate increase to the mothers voice and the 88.4% who were tested passed a newborn hearing-screening test, it is unlikely that hearing per se is an issue. Structural and functional deficits in auditory processing also have been reported in the presence of lower levels of iron stores, which can occur with maternal smoking (42% of the SGA sample here; see review by Georgieff, 2008). Iron deficiency can have negative effects on myelination (Connor & Menzies, 1996), structural development of dendrites ( Jorgenson, Wobken, & Georgieff, 2003), synaptic function ( Jorgenson, Sun, OConnor, & Georgieff, 2005), and brain energy metabolism (deUngria et al., 2000), which result in abnormalities in hippocampally dependent rodent behaviors (Georgieff, 2008). Furthermore, the level of thyroid hormone could play a role in differential auditory responses, given that cochlear structures are sensitive to the morphogenetic effect of thyroid hormone throughout the whole duration of maturation (Uziel, 1986). Reduced circulating levels of free thyroxine (T4) and triiodothyronine (T3) and reduced expression of alpha and beta isoforms of thyroid protein have been reported in growth-restricted fetuses (Kilby et al., 1998; Kilby, Gittoes, McCabe, Verhaeg, & Franklyn, 2000). Both newborn ferritin and newborn thyroid levels could be measured in future studies to examine their effect on auditory processing. The issues discussed in this section can be redressed after birth when increased nutrient and oxygen supplies become adequate for normal growth, environmental sounds are no longer attenuated by the maternal abdomen and tissues, and oxygenation improves with lung diffusion. Thus, whether differential auditory processing would persist into the newborn period was unknown and the focus of Study 2.
Method
Participants. In total, 96 of the fetuses from Study 1 (18 SGA and 78 AGA) participated in Study 2 as newborns. The SGA newborn group included only 1 of the 6 prematurely born (gestational age = 35 weeks) infants who was tested at corrected age and whose data were included in analyses. A comparison of fetus and newborn demographic and obstetrical variables showed that maternal age and 5-min Apgar score no longer differed in this subsample (see Table 1). There was a difference in the number of cesarean section births, 2(1, N = 96) = 3.82, p = .05, = 0.20, with fewer cesarean sections in the SGA group (see Table 2). Equipment/stimuli. Newborn auditory stimuli included the audiotaped stimulus words tinder and beagle (Zelazo et al., 1989), each spoken by a female stranger at 1-s intervals for 20 s, and the previously recorded mothers readings shortened to a 20-s duration beginning at the start of the story. Auditory stimuli were augmented by a Klipsch Luscasfilm THX amplifier and delivered through Klipsch Luscasfilm THX speakers. A cardboard protractor for reading degree of head turns was mounted on a tripod that stood behind the table that held the speakers. A foot pedal connected to two lightemitting diodes located on the rim of the protractor was used to signal to the newborn handler the offset of a trial. Procedure. Within 5 days of birth, newborns were brought to the laboratory on one occasion for approximately 20 min (immediately after a feeding, when the newborns were alert). Two auditory-processing procedures using a head-turning response were carried out: (a) a habituation-novelty paradigm and (b) response to the mothers voice versus a strangers voice. We followed the head-turning procedure developed by Muir and Field (1979). Infants were bundled in a blanket and held by a researcher (seated) so that the newborns body was supine and the head was positioned at the midline of a protractor, between two speakers approximately 30 cm from the newborns ears. The handler wore headphones with music playing to mask the speaker sounds. In the habituation-novelty procedure, the stimulus words tinderbeagle or beagletinder (counterbalanced across infants) were presented through speakers on the newborns left (L) and right (R) side in either an LRR/RLL or an RLL/LRR order. Sounds were delivered at an average of 80 dB sound pressure level. Each word was delivered for either 20 s or until a head turn of at least 45 was achieved and maintained for 4 s. Trials continued until the infant either habituated (defined as any combination of three successive head turns away from the word or no head turns) or completed 16 trials. The novel word was then presented using the same criteria. Subsequently, the mothers and a female strangers (previous mother in the
Study 2: Auditory-Information Processing in SGA Newborns

Given a lack of studies on auditory processing in growthrestricted newborns, two different head-turning procedures were used to explore the issue. A habituation-novelty paradigm using speech (words) was employed because the paradigm has been reported (Zelazo et al., 1989) to differentiate between high-, moderate-, and low-risk newborn groups. In addition, newborn preference for the mothers voice or a female strangers voice was examined because preference for the mothers voice has been demonstrated (DeCasper & Fifer, 1980).
10 study) voices, order counterbalanced across newborns, were each presented three successive times for a maximum of 20 s or until a head turn of at least 45 was achieved and maintained for 4 s. The handler signaled the onset of a trial by placing the infant supine with the infants head in position between the two speakers. The handler judged the direction and degree of head turn, which were recorded by a second researcher operating the computer. In the event of no head turn, the second researcher signaled the offset of a trial via light-emitting diodes on the protractor. Between trials, the infant was held upright.
Kisilevsky et al. words. Figure 2 shows the mean number of head-turning responses toward the stimulus word across the habituation and novelty trial blocks. When the analysis was repeated with the last habituation trial block and the first novelty trial block to determine a novelty response, we again found an effect of trial block, F(1, 94) = 8.01, p =.01, 2 = .08; responding increased to the presentation of a novel word, which indicated a novelty response. Analysis of head turning across the four novelty trial blocks showed habituation to the novel words; responding declined across trial blocks, F(3, 282) = 14.38, p < .001, 2 = .13, with differences between the SGA and AGA groups accounted for by a lower magnitude of response on the second novelty trial block in the SGA groupTrial Block Group interaction: F(3, 282) = 3.15, p = .03, 2 = .03 (see Fig. 2). Both SGA and AGA newborns showed a novelty response, with an increase in responding on the first novelty trial block. On the second novelty trial block, the SGA newborns decreased responding, whereas the AGA newborns continued to increase responding. Both groups habituated over repeated trials to the novel stimulus. Preference for mothers voice versus strangers voice. For each newborn, two preference scores were calculated (one for each voice). To calculate a preference score for the mothers voice, we subtracted the number of head turns away from her voice from the number of
Results
Habituation and novelty response to words. Because newborns took varying numbers of trials to meet habituation criteria, habituation and novelty trials were divided into four nearly equal blocks, following Brody et al. (1984). Preliminary analyses showed no differences in head-turning responses to the two stimulus words during either the habituation or the novelty phases and they were combined for further analyses. A 2 (Group) 4 (Trial Block) analysis of variance across the habituation trial blocks showed a decrease in head-turning responses toward the stimulus words, F(3, 282) = 34.39, p < .001, 2 = .27, with no differences between the SGA and AGA groups; newborns habituated to the repeatedly presented
a
2
AGA
SGA
b
Novelty Response: Head turns toward word
2
Newborn Habituation: Head turns toward word
Mean Number of Head Turns
1.5
Mean Number of Head Turns
1.5
0.5
0.5
Habituation Trial Blocks
Novelty Trial Blocks
Fig. 2. Mean number of head-turning responses toward a stimulus word across the habituation trial blocks and the novelty trial blocks for the AGA and SGA newborn groups. AGA = appropriately grown for gestational age; SGA = small for gestational age.
Auditory Processing and Language Development head turns toward her voice, with possible scores ranging from 3 (e.g., 3 toward 0 away) to 3 (e.g., 0 toward 3 away). A preference score for the female strangers voice was calculated in the same way. Preliminary analyses showed no effect of order of presentation of the voices, and order was not considered further. In the SGA group, t tests showed no significant preference for the mothers voice (M = 1.06, SEM = 0.4) compared with the strangers voice (M = 0.11, SEM = 0.3), t(17) = 1.77, p = .09, d = 0.72. In the AGA group, we found a clear preference for the mothers voice (M = 1.38, SEM = 0.2) compared with the strangers voice (M = 0.42, SEM = 0.2), t(75) = 6.19, p < .001, d = 1.16. Given the smaller sample size of the SGA group (n = 18), the number of individual newborns showing a preference for the mothers voice, a preference for the strangers voice, or no preference was examined. Nine newborns showed a preference for the mothers voice, 6 newborns showed a preference for the strangers voice, and 3 newborns showed no preference, 2(2, N = 18) = 1.6, p = .45, = 0.30. Both the average scores and the number of newborns showing a preference yielded the same results.
11 could be either less responsive or less able to mount a sustained response over time or trials. Reducing the number of habituation trials and counterbalancing the habituation and voice presentations could address the time/ trials issue. Measuring ferritin and thyroid levels in cord blood and examining newborn auditory event related potentials to the mothers voice compared with the strangers voice also could be used to address in utero conditions. The results of Studies 1 and 2 showed differential auditory responding between SGA and AGA fetuses and newborns. In Study 3, we examined language abilities in this same cohort at 15 months of age and explored the relationship between the participants auditory responses and language abilities.
Study 3: Language Abilities and Neurodevelopment at 15 Months of Age

The purpose of Study 3 was to test the hypothesis that differential fetal and newborn auditory processing would be associated with 15-month-old infants language abilities (Kisilevsky & Davies, 2007); thus, both language and neurodevelopment were assessed. We expected that the SGA group would show decreased language ability (Gutbrod et al., 2000; Low et al., 1982; Low et al., 1992; Vohr et al., 1988) and neurodevelopmental deficits (Blair & Stanley, 1992; Kok et al., 1998; Low, 1994; Low et al., 1992; Uvebrandt & Hagberg, 1992) as had been reported previously. It is unknown whether fetal and newborn involuntary auditory-elicited responses and later infant intentional behaviors (e.g., receptive and expressive language), which indicate cognitive control, are directly comparable across development. Because such behaviors may represent similar or different processes or levels of processes in the brain (e.g., Chein & Schneider, 2012), we used them in this study as a first attempt to link early auditory processing with later language development.
Discussion
After birth, SGA newborns, compared with AGA newborns, continued to show the differential auditory-information processing found in our earlier testing of fetuses. In the habituation-novelty paradigm, the SGA newborns showed similar habituation but less recovery to a novel word. These results are in keeping with the results found by Zelazo et al. (1989), who showed no differences in habituation but less recovery when they compared low-, moderate-, and high-risk infant head turning. In addition, whether average preference score or number of newborns showing a preference was examined, SGA newborns showed no preference for their mothers voice compared with the voice of a female stranger. As expected from previous reports, AGA newborns showed a clear preference. The reason for the differential responding observed in both procedures is unknown and a matter of speculation. In the habituation procedure, it could be that SGA newborns are not as attentive to novel auditory stimuli because such stimuli are not as salient in holding the infants attention. With regard to the mothers voice, it could be that conditions in utero, such as those discussed earlier (e.g., auditory-system development, sensorineural threshold, decreased iron or thyroid levels), may influence the amount of exposure or attention to the mothers voice with the outcome that SGA newborns, as a group, have not yet developed a clear preference. Alternatively, it is possible that responding by the SGA newborns was affected by the duration of the testing procedure; they
Method
Participants. A total of 75 infants (18 SGA and 57 AGA) participated in neurodevelopmental or language follow-up at 15 months of age. The Mullen Scales of Early Learning: Infant and Preschool (MSEL; Mullen, 1995) and the fourth edition of the Preschool Language Scale (PLS-4; Zimmerman, Steiner, & Pond, 2002) were completed for 12 SGA and 55 AGA infants; the second edition of the MacArthur-Bates Communicative Development Inventory: Words and Gestures (MBCDI-2; Fenson et al., 2007) was completed for 16 SGA and 54 AGA infants. The 1 prematurely born infant who was tested as
12 a newborn had data only for the MBCDI-2, which were included in analyses. Follow-up testing at age 15 months was carried out in the universitys psychology clinic under the supervision of a registered psychologist naive to both the participants SGA/AGA status and the study hypothesis. Demographic and obstetrical variables for those infants participating in Study 3 are displayed in Tables 1 and 2. Instruments. The MSEL (Mullen, 1995) is an individually administered measure of gross motor, fine motor, visual reception, receptive-language skills, and expressive-language skills in children from birth through 5.8 years of age. Results are summarized into five scale scores using either t scores (M = 50, SD = 10), percentile ranks, or age equivalents and into a composite score using a standard score (M = 100, SD = 15), percentile, or category (e.g., average, below average). Internal consistency in the 15-month range is between .72 and .91, and interscorer reliability ranges from .93 to .98. The MSEL correlates appropriately with the Bayley Scales of Infant Development, showing higher correlations of like scales and lower correlations of unlike scalesMSEL Gross Motor with Bayley Psychomotor Development: r = .76; MSEL Gross Motor with Bayley Mental Development: r = .30; MSEL Early Language Composite with Bayley Psychomotor Development: r = .43; MSEL Early Language Composite with Bayley Mental Development: r = .70. At initiation of follow-up, the MSEL had the advantage over the Bayley Scales of Infant Development of providing a subscale score for receptive and expressive language. The MSEL takes approximately 35 min to administer to 15 month olds. The PLS-4 (Zimmerman et al., 2002) is an individually administered test of language skills for children from birth to almost 7 years of age. It produces norm-referenced scores for expressive, receptive, and combined language skills. Internal consistency in the 15-month range is between .72 and .88. Interscorer reliability ranges are .99 for the Expressive Communication subscale. The PLS-4 has sensitivities from .77 to .80 and specificities from .84 to .92 in identifying children with language disorders in the 3- to 6-year age range. The primary validity data are based on content analysis, and the scale takes 20 to 30 min to administer to 15-month-old infants. The MBCDI-2 (Fenson et al., 2007) is a parent-report form that allows month-by-month norm-based assessment of words produced, words understood, and total gestures. Internal consistency in the 15-month range is between .95 and .96. Correlations with similar tests range from approximately .51 to approximately .72. Procedure. When the infants were approximately 6 months of age, mothers were contacted by phone to remind them about follow-up testing and to obtain new
Kisilevsky et al. contact information as necessary. When the infants were 13 months of age, mothers were again contacted by phone to arrange an appointment at the psychology clinic for neurodevelopment and language follow-up testing. Appointments were scheduled days, evenings, and weekends to accommodate work schedules. Once the appointment was scheduled, mothers were mailed a copy of the MBCDI-2 to complete and bring with them to the appointment. The MSEL and PLS-4 were administered and scored by trained personnel naive to both the study hypothesis and the infants SGA/AGA status. Data analysis. There is no established method of converting fetal heart rate change over seconds in response to the mothers voice or newborn head turning over repeating habituation/novelty trials to a single, representative value for use in correlation and regression techniques. Thus, as a first pass, the average fetal heart rate over seconds during the voice and voice offset periods were calculated. These two values (voice and voice offset periods) and the number of trials during the second novelty trial block, which showed differential responding between the SGA and AGA groups, were used in correlation and regression analyses.
Results
Language abilities and neurodevelopmental outcome at 15 months of age. To determine differences in language development and neurodevelopmental outcome between the SGA and AGA groups, we used t tests to compare the percentile ranks on the five subscales and the composite score of the MSEL. Results showed that those infants born SGA had, on average, a significantly lower percentile for expressive language (M = 28.8, SEM = 4.8) compared with infants born AGA (M = 46.8, SEM = 4.1), t(65) = 2.86, p = .01, d = 0.65. To determine whether aggregate data accounted for the results given the smaller SGA group sample size, we compared individual SGA scores with the mean of the AGA sample. Of the SGA infants, 83% (10 of 12) had a mean Expressive Language subscale score below the mean of the AGA group, which indicated that aggregating the data did not account for the difference between groups. Using t tests to compare the percentile ranks of the subscales of the MBCDI-2, we found that the SGA infants early word vocabulary production (M = 35.8, SEM = 5.7) was below that of the AGA infants (M = 50.3, SEM = 3.7), t(68) = 1.92, p = .05, d = 0.56. Again, as a check on whether aggregate data accounted for the results given the smaller SGA sample size, individual SGA scores were compared with the mean of the AGA sample. Of the SGA infants, 81% (13 of 16) had a mean Early Word Vocabulary Produced subscale score below the mean of the AGA group;
Auditory Processing and Language Development aggregating the data did not account for the difference between groups. Correlation between the MSEL Expressive Language subscale and the MBCDI-2 Early Word Vocabulary Produced subscale scores was .72 (p < .001). There were no differences between the groups on percentile rank for the two subscales or total score for the PLS-4. To further examine neurodevelopment, we used paired t tests to compare age at testing (months) and age equivalent (months) for the five subscales of the MSEL separately for the SGA (test age: M = 15.5 months, SEM = 0.5) and AGA (test age: M = 15.1 months, SEM = 0.3) groups. The SGA infants scored above their chronological age on the Fine Motor subscale (M = 17.1 months, SEM = 0.7), t(11) = 2.33, p = .04, d = 0.77, and below their chronological age on the Expressive Language subscale (M = 14.2 months, SEM = 0.6), t(11) = 2.33, p = .04, d = 0.65. Average scores were at chronological age for the Gross Motor subscale (M = 16.2 months, SEM = 0.9), p = .36, d = 0.27, Visual Receptive subscale (M = 16.3 months, SEM = 0.8), p = .24, d = 0.35, and Receptive Language subscale (M = 16.5 months, SEM = 1.0), p = .39, d = 0.36. The AGA infants scored above their chronological age on the Gross Motor subscale (M = 16.9 months, SEM = 0.4), t(54) = 5.11, p < .001, d = 0.72, Fine Motor subscale (M = 17.2 months, SEM = 0.4), t(54) = 5.18, p < .001, d = 0.83, and Visual Receptive subscale (M = 16.8 months, SEM = 0.5), t(54) = 4.43, p < .001, d = 0.59, and scored at chronological age on both the Receptive Language (M = 15.4 months, SEM = 0.6), p = .66, d = 0.06, and the Expressive Language (M = 14.8 months, SEM = 0.6), p = .59, d = 0.09, subscales. Exploration of attrition effects. To explore the effects of attrition over testing times, we examined response to auditory probes in the SGA subgroups of fetuses, newborns, and 15-month-old infants (a) tested one time as fetuses, (b) tested two times (fetus plus newborn or fetus plus 15-month-old infant), or (c) tested three times (fetus plus newborn plus 15-month-old infant, having MBCDI-2 or MSEL results). Fetal heart rate response to the mothers voice, newborn head turning to the last habituation trial block and the first two novelty trial blocks, and preference scores for the mothers and strangers voices did not differ among the subgroups. Associations among auditory-processing, demographic/obstetrical, and anthropometric variables. Correlational analyses were used to begin to explore the relation among (a) measures of early auditory processing that showed differential responding by the SGA and AGA groups (mean fetal heart rate during mothers voice and voice offset periods, number of head turns toward the novel word on the second novelty trial block, preference scores for mothers and strangers voices, MSEL Expressive Language subscale percentile rank, and
13 MBCDI-2 Early Word Vocabulary Produced subscale percentile rank), (b) spontaneous fetal behaviors (number of heart rate accelerations greater than 10 and 15 bpm, number of body movements, and amount of breathing), (c) demographic/obstetrical characteristics (maternal: age, body mass index prepregnancy and at testing, systolic and diastolic blood pressure, amniotic fluid index, education level, and smoking status; fetus: gestational age at testing and delivery, birth weight in grams and percentile, 5-min Apgar score, sex, and delivery outcome group), and (d) newborn anthropometric measures (length, head circumference, and ponderal index2). There were significant intercorrelations (r = .73 to r = .92, p < .001 to p < .05) among the 29 variables, and all were used in subsequent exploratory regression analyses. Predictors of the MSEL Expressive Language subscale. To identify predictors of language development at 15 months of age for participants with data at all three time points (fetus, newborn, and 15-month-old infant), we performed an exploratory backward regression using the MSEL Expressive Language subscale percentile rank as the dependent variable and the 27 other variables listed in the previous paragraph (MBCDI-2 subscale scores were excluded) as independent variables. A combination of 4 of the 27 independent variables predicted the MSEL Expressive Language subscale scores (r = .58, p = .01), which accounted for 26.5% (adjusted R2) of the variability. Table 3 presents the beta weights and p values for the significant predictors. Predictors included fetal responses to the mothers voice (average heart rate during and after the mothers voice), spontaneous fetal heart rate accelerations greater than or equal to 15 bpm, and infant head circumference. Note that the multicollinearity of the variables is high enough to require caution in interpreting these beta weights, especially if a variable is not included in the final array. Any particular variable that made the cut in the backward regression analysis may be a placeholder for a group of other highly correlated variables. Although an included variable does indeed account for significant variance, any excluded variable may account for nearly as much. Predictors of the MBCDI-2 Early Word Vocabulary Produced subscale. The backward regression was repeated with the MBCDI-2 Early Word Vocabulary Produced percentile score as the dependent variable and the same 27 other variables listed earlier (with the MSEL Expressive Language subscale percentile rank score excluded) as independent variables. Of the independent variables, 9 of 27 best predicted the MBCDI-2 Early Word Vocabulary Produced subscale percentile score (r = .74, p < .001), which accounted for 43.1% (adjusted R2) of the variability. Table 3 presents the beta weights and p values for the significant predictors. Predictors included fetal
14
Table 3. Exploratory Backward Regression Beta Weights and p Values for the Significant Predictors of the MSEL Expressive Language Subscale Percentile Rank and the MBCDI-2 Early Word Vocabulary Produced Subscale Percentile Rank MSEL Variable Mean FHR during mothers voice Mean FHR after mothers voice Spontaneous FHR increases 15 bpm Body mass index prepregnancy Body mass index at testing Mean systolic blood pressure Sex Infant birth weight (g) Infant head circumference (cm) Ponderal index 0.69 0.64 0.31 p .02 .02 .05 0.60 0.58 0.28 1.06 0.86 0.29 0.26 0.36 0.26 MBCDI-2 p .03 .03 .04 .01 .02 .05 .04 .03 .07
Kisilevsky et al.
0.42
.01
Note: MSEL = Mullen Scales of Early Learning; MBCDI-2 = second edition of the MacArthur-Bates Communicative Development Inventory: Words and Gestures; FHR = fetal heart rate; bpm = beats per minute.
responses to the mothers voice (average heart rate during and after the mothers voice), spontaneous fetal heart rate accelerations greater than or equal to 15 bpm, birth weight (in grams), ponderal index, sex, mean systolic blood pressure, and body mass index prepregnancy and at time of testing.
Discussion
At 15 months of age, SGA infants showed expressive-language deficits, scoring more than 2 standard deviations below the AGA mean on both the MSEL Expressive Language subscale percentile rank (SGA: M = 28.8; AGA: M = 46.8) and the MBCDI-2 Early Word Vocabulary Produced subscale percentile rank (SGA: M = 35.8; AGA: M = 50.4). Exploratory regression analyses revealed that MSEL and MBCDI-2 subscale scores were predicted, in part, by fetal heart rate response during and after the playing of the mothers voice. The results of this study provide support for the hypothesis that fetal growth restriction affects the development of auditory-system functioning, which results in differential auditory-information processing in SGA fetuses and newborns at increased risk for subsequent language impairment (Kisilevsky & Davies, 2007). Analyses of individual SGA expressive-language scores showed that the 2 SGA infants who had MSEL scores at or above the AGA means and the 3 SGA infants who had MBCDI-2 scores at or above the AGA means were all children whose mothers had postsecondary education. These results are in keeping with findings from several recent general population studiesfrom, for example, Taiwan (Lung, Shu, Chiang, & Lin, 2009), Melbourne (Reilly et al., 2010), and Norway (Schjlberg, Eadie,
Zachrisson, Oyen, & Prior, 2011)as well as a U.S. study that included subsamples of low-income families (Mistry, Biesanz, Chien, Howes, & Brenner, 2008), which showed that lower levels of language competence in toddlers and preschoolers were associated with lower maternal education. Conversely, higher education was positively associated with 18-month-olds receptive and expressive language in a study from Crete (Koutra et al., 2012). Analysis of neurodevelopment in general using the MSEL showed that, as expected, the normal comparison AGA group means were at or above the chronological age on all five MSEL subscales. Moreover, except for the Expressive Language subscale, the SGA group showed average or above-average scores on the MSEL subscales. For the SGA group, the difference in language scores was expected from the existing literature. However, the ageappropriate-or-higher neurodevelopmental scores in other areas were unexpected. Substantive existing literature demonstrates neurodevelopmental deficits in infants born growth restricted with and without abnormal umbilical artery blood flow (Figueras, Eixarch, Gratacos, & Gardosi, 2008; Figueras, Eixarch, Meler, et al., 2008), born with and without brain sparing ( Jelliffe-Pawlowski & Hansen, 2004; Scherjon, Oosting, Smolders-DeHaas, Zondervan, & Kok, 1998), and born preterm and at term (Bassan et al., 2011). Explaining the overall good outcome in the SGA group is a matter of speculation because the study was not designed to untangle the issue. The outcome could be attributed, in part, to the fact that of the 6 SGA infants in the study who were born prematurely, only 1 returned for follow-up, given that premature infants, compared with term infants, are at a higher risk for developmental delays.
Auditory Processing and Language Development The outcome also might be partially due to the level of maternal education72% of the SGA group mothers and 91% of the AGA group mothers who brought their infant back for 15-month follow-up had postsecondary education. The possibility exists that the expressive-language deficits observed in this study represent a communication disorder known as specific language impairment (Bishop, 2006). The condition indicates difficulty with understanding and producing oral language that cannot be accounted for by sensorimotor or intellectual deficits or by brain lesions. Our study was not designed to identify specific communication disorders and, thus, no firm conclusions can be drawn. Attrition was high in both groups, with only 43% of the SGA group and only 46% of the AGA group providing data at 15 months. Nevertheless, when we examined the SGA subgroups having one, two, or three tests, we found no evidence that attrition accounted for the differential response to the auditory probes by either the fetuses (response to the mothers voice) or the newborns (head turning during habituation/novelty trials and voice-preference scores). Much of the attrition was likely due to the unanticipated increase in government maternity benefits from 6 months to 1 year that occurred after initiation of the study. When contacted at 13 months for follow-up, mothers were in the process of returning to work, and adaptation to work and family responsibilities precluded attendance at that time. To our knowledge, this is the first prospective study to link differential auditory-information processing immediately before birth to later language impairment. The timing is important because, at least in some instances, such early identification could allow for early intervention to prevent or ameliorate language deficits, thereby resulting in better long-term linguistic, cognitive, emotional, social, and behavioral outcome. Of course, given our samples small size and very early age at language assessment, these findings need to be replicated. The results of this study raise a number of critical issues for future research, including the generalizability of our results to high-risk pregnancy conditions associated with nutritional/oxygen deprivation and to other sensory domains. It is unknown whether the differential auditory processing observed here is specific to growth restriction or occurs across multiple pregnancy conditions associated with placental insufficiency in which the fetus/newborn is most often AGA. Previous research reports of differential fetal cardiac responses to acoustic and vibroacoustic probes in low-risk pregnancies compared with high-risk pregnancies (such as those involving preeclampsia, hypertension, diabetes, and maternal smoking, as discussed earlier) suggest that the effects could be more general. Replication of the present study with a larger sample size and the addition of fetuses and
15 newborns from these high-risk pregnancy groups who are born AGA would allow for an examination of the specificity issue. In addition, questions remain concerning development of other sensory systems in the presence of growth restriction or placental insufficiency. As noted earlier, differential fetal response to touch plus audition has been observed. Other senses, such as vision, are difficult to study in the fetus because of a lack of direct access. Nevertheless, evidence that face processing, especially decoding of facial emotions, is associated with expressive specific language impairment at 7 to 11 years of age (e.g., placing these children at risk for problems in social interaction; Merkenschlager, Amorosa, Kiefl, & Martinius, 2012) and adolescent schizotypal personality disorder (e.g., Wickline, Nowicki, Bollini, & Walker, 2012) indicates that examining visual processing, face and emotion perception in particular, in newborns and infants would aid in determining the extent of multisensory system involvement. In the present study, we examined a narrow window in time, that is, language abilities very early in development (at 15 months of age). It is unknown whether the deficits in expressive language identified here will persist or be associated with other clinical disorders. Longerterm language and neurodevelopmental follow-up of a much larger sample clearly is necessary to gain a more thorough understanding of the implications of these findings. To extend these findings, researchers could more broadly conceive longitudinal follow-up to establish criteria for the identification of typical versus atypical fetal/ newborn auditory processing at the individual level. Establishing criteria for a typical fetal response to the mothers voice at term and a newborn preference for her voice compared with that of a female stranger might be a reasonable place to start to identify those individuals who could be at highest risk given the results presented here and the literature noted earlier. Routinely collected perinatal risk factors, such as average Apgar score, have been associated with specific language impairment (SGA 5-min Apgar: M = 9.3; Diepeveen, Kroon, Dusseldorp, & Snik, 2013) and differed here in the SGA (5-min Apgar: M = 8.3) and AGA (5-min Apgar: M = 8.9) fetal groups. However, the group averages fell within the normal range and were not identified as predictors on either expressive-language subscale. Such measures may not be discriminatory at the individual level. Simultaneously, given the results of the present study, the long history of language impairment observed in growth restriction, and the association of language impairment with increased risk for cognitive, social, emotional, and behavioral clinical disorders, it also would be advantageous to design and test interventions to prevent or ameliorate later language deficits. Providing systematic experience with the mothers voice, either naturally
16 occurring or audiotaped, might prove to be a safe and effective intervention for at-risk fetuses, newborns, and premature infants. Finally, employing imaging techniques (e.g., functional MRI; de Guibert et al., 2011) to examine differential brain function and changes in brain function with intervention also might be useful in identifying those individuals at greatest risk for language deficits and long-term sequelae. Long-term follow-up could be particularly important in determining when brain differences indicate language deficits. Author Contributions
B. S. Kisilevsky and G. A. L. Davies generated the hypothesis and designed the study. B. S. Kisilevsky supervised the fetal and newborn data collection, analyzed the data, and drafted the manuscript. B. Chambers carried out a preliminary fetal study for a masters of science thesis. K. C. H. Parker provided the expertise for the neurodevelopmental testing. All authors critically revised the manuscript and approved the final version of the manuscript for submission.
Kisilevsky et al.
Bassan, H., Stolar, O., Geva, R., Eshel, R., Fattal-Valevski, A., Leitner, Y., . . . Harel, S. (2011). Intrauterine growthrestricted neonates born at term or preterm: How different? Pediatric Neurology, 44, 122130. doi:10.1016/j.pediatr neuro1.2010.09.012 Beitchman, J. H., Nair, R., Clegg, M., & Patel, P. G. (1986). Prevalence of speech and language disorders in 5-yearold kindergarten children in the OttawaCarleton region. Journal of Speech and Hearing Disorders, 51, 98110. Beitchman, J. H., Wilson, B., Brownlie, E. B., Inglis, A., & Lancee, W. (1996). Long-term consistency in speech and language profiles: II. Behavioral, emotional, and social outcomes. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 804814. Beitchman, J. H., Wilson, B., Johnson, C. J., Atkinson, L., Young, A., Adlaf, E., & Douglas, L. (2001). Fourteen-year followup of speech/language impaired and control children: Psychiatric outcome. Journal of the American Academy of Child and Adolescent Psychiatry, 40, 7582. Bishop, D. V. M. (2006). What causes specific language impairment in children? Current Directions in Psychological Science, 15, 217221. Blair, E., & Stanley, F. (1992). Intrauterine growth and spastic cerebral palsy: II. The association with morphology at birth. Early Human Development, 28, 91103. Bornstein, M. H., DiPietro, J. A., Hahn, C.-S., Painter, K., Haynes, O. M., & Costigan, K. A. (2002). Prenatal cardiac function and postnatal cognitive development: An exploratory study. Infancy, 3, 475494. Brody, L. R., Zelazo, P. R., & Chaika, H. (1984). Habituationdishabituation to speech in neonates. Developmental Psychology, 20, 114119. Chaudhari, S., Bhalerao, M. R., Chitale, A., Pandit, A. N., & Nene, U. (1999). Pune low birth weight study: A six year follow up. Indian Pediatrics, 36, 669676. Chein, J. M., & Schneider, W. (2012). The brains learning and control architecture. Current Directions in Psychological Science, 21, 7884. doi:10.1177/0963721411434977 Connor, J. R., & Menzies, S. L. (1996). Relationship of iron to oligodendrocytes and myelination. Glia, 17, 8393. Cowperthwaite, B. C., Hains, S. M. J., & Kisilevsky, B. S. (2007). Fetal auditory processing in smoking compared to non-smoking pregnant women. Infant Behavior and Development, 30, 422430. DeCasper, A. J., & Fifer, W. P. (1980). Of human bonding: Newborns prefer their mothers voices. Science, 208, 11741176. DeCasper, A. J., Lecanuet, J.-P., Busnel, M.-C., Granier-Deferre, C., & Maugeais, R. (1994). Fetal reactions to recurrent maternal speech. Infant Behavior and Development, 17, 159164. de Guibert, C., Maumet, C., Jannin, P., Ferre, J.-C., Treguier, C., Barillot, C., . . . Biraben, A. (2011). Abnormal functional lateralization and activity of language brain areas in typical specific language impairment (developmental dysphasia). Brain, 134, 30443058. deUngria, M., Rao, R., Luciana, M., Wobken, J., Nelson, C. A., & Georgieff, M. (2000). Perinatal iron deficiency decreases cytochromec oxidase (CytOx) activity in selective regions of neonatal rat brain. Pediatric Research, 48, 243255.
Acknowledgments
We thank Joanne Rovet and Linda Polka for their valuable contributions to the selection of the standardized instruments used in the neurodevelopmental and language testing of the 15-month-old participants. Portions of this article were presented at the European Conference on Developmental Psychology, Bergen, Norway, August 2011; the Society for Research in Child Development, Montreal, Canada, March 2011; and the European Congress of Perinatal Medicine, Istanbul, Turkey, September 2008.
Declaration of Conflicting Interests

The authors declared that they had no conflicts of interest with respect to their authorship or the publication of this article.
Funding
This research was supported by March of Dimes Foundation Grant 12-FY06-237 to B. S. Kisilevsky and G. A. L. Davies. A preliminary study (a masters of science thesis) was supported by funding from the Queens University School of Nursing Research Development Fund to B. S. Kisilevsky.
Note
1. Body mass index is calculated as follows: weight (kg) / [height (m)]2. 2. Ponderal index is calculated as follows: birth weight (kg) / [length (m)]3.
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CPXXXX10.1177/2167702613509371Kisilevsky et al.Auditory Processing and Language Development

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Study 1: Auditory-Information Processing in SGA Fetuses

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2 test p value .04 .04

Fetal Heart Rate Response to Mothers Voice

Mean Fetal Heart Rate (bpm)

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Study 2: Auditory-Information Processing in SGA Newborns

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Newborn Habituation: Head turns toward word

Mean Number of Head Turns

Mean Number of Head Turns

Habituation Trial Blocks

Novelty Trial Blocks

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Study 3: Language Abilities and Neurodevelopment at 15 Months of Age

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Declaration of Conflicting Interests

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Auditory Processing and Language Development

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Auditory Processing and Language Development

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