Publications by authors named "Fusako Niwa"

19 Publications

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Longitudinal assessment of social attention in preterm and term infants: Its relation to social communication and language outcome.

Infancy 2021 Apr 15. Epub 2021 Apr 15.

Graduate School of Education, Kyoto University, Kyoto, Japan.

Preterm birth has been reported to be associated with an increased risk of social communication and language problems. Recently, we found that preterm infants showed atypical patterns of social attention compared with term infants. However, it is still unknown how social attention develops and whether the individual differences are associated with developmental outcomes for social communication and language in preterm infants. The social attention of preterm and term infants at 6, 12, and 18 months was investigated using two types of social attention tasks (human-geometric preference task and gaze-following task). The Modified Checklist for Autism in Toddlers (M-CHAT) and the MacArthur Communicative Development Inventory adapted for Japanese were measured at 18 months. We found that compared with term infants, preterm infants spent less time looking toward dynamic human images and followed another's gaze directions less frequently through 6, 12, and 18 months. Moreover, hierarchical multiple regression analysis revealed that less preference for dynamic human images and gaze-following abilities was associated with high M-CHAT and low language scores in preterm and term infants, respectively. These findings suggest that birth status affects development of social attention through 18 months and individual differences in social attention reflect differences in social communication and language outcomes.
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http://dx.doi.org/10.1111/infa.12402DOI Listing
April 2021

Effect of electrical activity of the diaphragm waveform patterns on SpO for extremely preterm infants ventilated with neurally adjusted ventilatory assist.

Pediatr Pulmonol 2021 Apr 6. Epub 2021 Apr 6.

Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objective: This study aimed to evaluate the association between electrical activity of the diaphragm (Edi) waveform patterns and peripheral oxygen saturation (SpO ) in extremely preterm infants who are ventilated with neurally adjusted ventilatory assist (NAVA).

Study Design: We conducted a retrospective cohort study at a level III neonatal intensive care unit. Extremely preterm infants born at our hospital between November 2019 and November 2020 and ventilated with NAVA were included. We collected Edi waveform data and classified them into four Edi waveform patterns, including the phasic pattern, central apnea pattern, irregular low-voltage pattern, and tonic burst pattern. We analyzed the Edi waveform pattern for the first 15 h of collectable data in each patient. To investigate the association between Edi waveform patterns and SpO , we analyzed the dataset every 5 min as one data unit. We compared the proportion of each waveform pattern between the desaturation (Desat [+]) and non-desaturation (Desat [-]) groups.

Results: We analyzed collected data for 105 h (1260 data units). The proportion of the phasic pattern in the Desat (+) group was significantly lower than that in the Desat (-) group (p < .001). However, the proportions of the central apnea, irregular low-voltage, and tonic burst patterns in the Desat (+) group were significantly higher than those in the Desat (-) group (all p < .05).

Conclusion: Our results indicate that proportions of Edi waveform patterns have an effect on desaturation of SpO in extremely preterm infants who are ventilated with NAVA.
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http://dx.doi.org/10.1002/ppul.25396DOI Listing
April 2021

Effects of passage through the digestive tract on incretin secretion: Before and after birth.

J Diabetes Investig 2021 Jun 28;12(6):970-977. Epub 2020 Nov 28.

Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Aims/introduction: It was reported that fetuses secrete endogenous incretin; however, the stimulants of fetal incretin secretion are not fully understood. To investigate the association between the passage of amniotic fluid through the intestinal tract and fetal secretion of incretin, we analyzed umbilical cord incretin levels of infants with duodenum atresia.

Materials And Methods: Infants born from July 2017 to July 2019 (infants with duodenum atresia and normal term or preterm infants) were enrolled. We measured and compared the concentrations of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide/glucose-dependent insulinotropic polypeptide (GIP) in the umbilical vein and preprandial blood samples after birth.

Results: A total of 98 infants (47 term, 46 preterm and 5 with duodenum atresia) were included. In patients with duodenum atresia, umbilical vein GLP-1 and GIP levels were the same as those in normal infants. In postnatal samples, there were positive correlations between the amount of enteral feeding and preprandial serum concentrations of GLP-1 (r = 0.47) or GIP (r = 0.49).

Conclusions: Our results show that enteral feeding is important for secretion of GLP-1 and GIP in postnatal infants, whereas the passage of amniotic fluid is not important for fetal secretion of GLP-1 and GIP. The effect of ingested material passing through the digestive tract on incretin secretion might change before and after birth. Other factors might stimulate secretion of GLP-1 and GIP during the fetal period.
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http://dx.doi.org/10.1111/jdi.13447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169361PMC
June 2021

Appropriate Phosphorus Intake by Parenteral Nutrition Prevents Metabolic Bone Disease of Prematurity in Extremely Low-Birth-Weight Infants.

JPEN J Parenter Enteral Nutr 2020 Aug 12. Epub 2020 Aug 12.

Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Metabolic bone disease (MBD) is a common disorder in extremely low-birth-weight (ELBW) infants. However, no studies have investigated whether high-dose calcium (Ca) and phosphorus (P) supplementation by parenteral nutrition (PN) prevents MBD in ELBW infants. This study aimed to identify the effect of PN on MBD in ELBW infants.

Methods: We retrospectively analyzed ELBW infants who were admitted between April 2011 and March 2017. ELBW infants were divided into the low-P group (n = 22) and the high-P group (n = 26) according to the dose of parenteral P supply. Biochemical and radiological markers of MBD and treatments were analyzed.

Results: Mean daily parenteral intake of Ca and P in the first week was significantly higher in the high-P group than in the low-P group (both P ≤ .001). Serum alkaline phosphatase (ALP) levels were significantly higher in the low-P group than in the high-P group in the first month. ELBW infants in the low-P group received alfacalcidol much more frequently than those in the high-P group. There was a trend of a higher rate of x-ray changes in the low-P group than in the high-P group. No infants developed bone fractures.

Conclusion: Appropriate P intake by PN is required to ensure high Ca intake, reduce ALP levels in the first month, and prevent MBD from hyperparathyroidism and does not worsen x-ray findings in ELBW infants.
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http://dx.doi.org/10.1002/jpen.1993DOI Listing
August 2020

Antenatal corticosteroids for threatened labour facilitate thyroid maturation among preterm neonates.

Clin Endocrinol (Oxf) 2020 11 14;93(5):613-619. Epub 2020 Jul 14.

Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objective: To examine the effect of antenatal corticosteroids (ANS) on the maturation of thyroid function in the preterm infants.

Context: ANS reduce mortality and morbidities in preterm neonates. Organ maturation by the glucocorticoids is the key, at least in part. However, the effect of ANS on thyroid is controversial.

Patients: A study group of 99 very low birthweight neonates (<34 weeks' gestational age) with the exception of those born more than 7 days after ANS administration were divided into a complete group (n = 49) whose mothers completed two doses of betamethasone and who were born more than 24 hours after the completion of ANS administration, and an incomplete group (n = 50) who were not exposed to any ANS or were born within 24 hours after the completion of ANS administration. Serum-free thyroxine and thyroid-stimulating hormone (TSH) levels were measured, and thyrotropin-releasing hormone (TRH) stimulation tests were performed at about 2 weeks of age.

Results: The incidence of hyperthyrotropinaemia (TSH > 15 mIU/L) in the complete group was significantly lower than in the incomplete group (6% vs 22%, P = .023). Exaggerated responses to TRH tests were more frequent in the incomplete group (17% vs 44%; P = .053). TSH was significantly lower in the complete group, (P = .046). Multivariate logistic regression analysis showed that the incidence of hyperthyrotropinaemia was associated with complete ANS administration (adjusted odds ratios 0.39).

Conclusions: ANS administration might facilitate thyroid maturation in preterm neonates.
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http://dx.doi.org/10.1111/cen.14272DOI Listing
November 2020

Response of preterm infants with transient hypothyroxinaemia of prematurity to the thyrotropin-releasing hormone stimulation test is characterized by a delayed decrease in thyroid-stimulating hormone after the peak.

Clin Endocrinol (Oxf) 2020 11 21;93(5):605-612. Epub 2020 Jun 21.

Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objectives: We evaluated the response to the thyrotropin-releasing hormone (TRH) stimulation test in very low-birth weight (VLBW) infants to elucidate the aetiology of transient hypothyroxinaemia of prematurity (THOP).

Design And Methods: We performed TRH stimulation tests on 43 VLBW infants. Subjects were divided into two groups; a THOP group (N = 11; basal TSH < 15 mU/L and basal FT4 ≤ 0.8 ng/dL) and a non-THOP group (N = 32; basal TSH < 15 mU/L and basal FT4 > 0.8 ng/dL). Basal FT4 and FT3 were measured before, and TSH (0, 30, 60, 90, 120 and 180 minutes) was measured after, the administration of TRH (7 µg/kg). We calculated the ratio of TSH 180 minutes to THS 0 minute as the primary outcome. We also collected data on T3 and rT3 in this study.

Results: In both groups, TSH 30 minutes values were the highest. However, the ratios of TSH 180 minutes to THS 0 minutes in the non-THOP group and the THOP group were (median [IQR]) 1.3 [1.0-1.7] and 3.0 [1.5-5.3] (P < .01). No significant differences were observed in T3 (1.0 [0.8-1.3] and 0.7 [0.4-0.7] ng/mL, P = .06). However, in the THOP group, rT3 was significantly lower than that of the non-THOP group (168.0 [148.1-197.0] and 92.9 [74.7-101.6] pg/mL, P < .01).

Conclusions: The delayed decrease in the TSH concentration after the peak for the TRH tests and decreased levels of rT3 suggest that the main aetiology for THOP is suppression at the level of the hypothalamus, but not inactivation of peripheral thyroid hormone metabolism.
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http://dx.doi.org/10.1111/cen.14260DOI Listing
November 2020

Antenatal Glucocorticoids Reduce the Incidence of Refractory Hypotension in Low Birthweight Infants during the Early Neonatal Period, but Do Not Affect It beyond This Time.

Am J Perinatol 2020 Feb 18. Epub 2020 Feb 18.

Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Objective:  This study aimed to clarify the effect of antenatal glucocorticoids (AGs) on the incidence of refractory hypotension (RH) in very low birthweight (VLBW) infants after the first week of life.

Study Design:  We included VLBW infants born at a gestational age of <30 weeks and divided them into three groups: the complete group (born within 7 days of completing a single course [two doses] of AGs), the incomplete group (born without complete course), and the late delivery group (born at ≥8 days after a single course). We compared the incidence and period of onset of RH among the three groups.

Results:  A total of 115 infants were enrolled. The incidence of RH in the first week of life was significantly lower in the complete group than in the other groups. However, there was no significant difference in the incidence of RH after the first week of life among the groups.

Conclusion:  AGs contribute to circulatory stabilization during the first week of life, but this effect does not last after 1 or 2 weeks of administration. In infants who receive AGs, physicians should consider that the risk of RH after the first week of life is not low.
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http://dx.doi.org/10.1055/s-0040-1701608DOI Listing
February 2020

Audiovisual speech perception and language acquisition in preterm infants: A longitudinal study.

Early Hum Dev 2019 01 9;128:93-100. Epub 2018 Dec 9.

Graduate School of Education, Kyoto University, Kyoto, Japan.

Background: Preterm infants have a higher risk of language delay throughout childhood. The ability to integrate audiovisual speech information is associated with language acquisition in term infants; however, the relation is still unclear in preterm infant.

Aim And Methods: This study longitudinally investigated visual preference for audiovisual congruent and incongruent speech during a preferential looking task using eye-tracking in preterm and term infants at 6, 12, and 18 months of corrected age. The infants' receptive and expressive vocabulary at 12 and 18 months were obtained by parent report, using the Japanese MacArthur Communicative Development Inventory.

Results: We found that preterm infants did not clearly show visual preference for the congruent audiovisual display at any age, whereas term infants looked at the congruent audiovisual display longer than the incongruent audiovisual display at 6 and 18 months. Preterm infants' receptive and expressive vocabulary scores were lower than those of term infants at 12 and 18 months. Furthermore, the proportion of looking time toward the congruent audiovisual display at 6 months was positively correlated with receptive vocabulary scores at 12 and 18 months for both groups.

Conclusions: These findings suggest that better audiovisual speech perception abilities are one factor that results in better language acquisition in preterm as well as term infants. Early identification of behaviors associated with later language in preterm infants may contribute to planning intervention for developmental problems.
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http://dx.doi.org/10.1016/j.earlhumdev.2018.11.001DOI Listing
January 2019

Fundamental Frequency Variation of Neonatal Spontaneous Crying Predicts Language Acquisition in Preterm and Term Infants.

Front Psychol 2017 22;8:2195. Epub 2017 Dec 22.

Graduate School of Education, Kyoto University, Kyoto, Japan.

Spontaneous cries of infants exhibit rich melodic features (i.e., time variation of fundamental frequency [ ]) even during the neonatal period, and the development of these characteristics might provide an essential base for later expressive prosody in language. However, little is known about the melodic features of spontaneous cries in preterm infants, who have a higher risk of later language-related problems. Thus, the present study investigated how preterm birth influenced melodic features of spontaneous crying at term-equivalent age as well as how these melodic features related to language outcomes at 18 months of corrected age in preterm and term infants. At term, moderate-to-late preterm (MLP) infants showed spontaneous cries with significantly higher variation and melody complexity than term infants, while there were no significant differences between very preterm (VP) and term infants. Furthermore, larger variation within cry series at term was significantly related to better language and cognitive outcomes, particularly expressive language skills, at 18 months. On the other hand, no other melodic features at term predicted any developmental outcomes at 18 months. The present results suggest that the additional postnatal vocal experience of MLP preterm infants increased variation and the complexity of spontaneous cries at term. Additionally, the increases in variation may partly reflect the development of voluntary vocal control, which, in turn, contributes to expressive language in infancy.
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http://dx.doi.org/10.3389/fpsyg.2017.02195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744644PMC
December 2017

Corticotrophin-releasing hormone stimulation tests for the infants with relative adrenal insufficiency.

Clin Endocrinol (Oxf) 2017 Dec 4;87(6):660-664. Epub 2017 Sep 4.

Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Very low birthweight (VLBW) infants are considered to be vulnerable to relative adrenal insufficiency (RAI); however, diagnosis is difficult in some clinical settings. Considering this background, it is necessary to establish a diagnosis of RAI in preterm infants.

Objective: In this study, we attempted to clarify the difference in response to CRH stimulation tests for preterm infants with or without RAI.

Methods: Between June 2009 and December 2015, we performed CRH stimulation tests for preterm infants born at a gestational age of <30 weeks at around 2 weeks of age. Retrospectively, subjects were classified into two groups: infants with RAI (n = 9) or without RAI (n = 17) based on the clinical symptoms and responsiveness to hydrocortisone.

Results: We found no difference in base or peak serum cortisol levels related to CRH stimulation tests between the two groups; however, delta cortisol levels and responsive ratio (peak-to-base ratio) were significantly reduced in infants with RAI. 140 nmol/L for delta cortisol or 1.5 times for peak-to-base ratio may be cut-off levels in preterm infants.

Conclusion: This study provides evidence that base cortisol levels of preterm infants with RAI were not different from those without RAI; however, CRH stimulation tests may be a useful tool for the diagnosis of RAI in preterm infants.
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http://dx.doi.org/10.1111/cen.13446DOI Listing
December 2017

Preference for Dynamic Human Images and Gaze-Following Abilities in Preterm Infants at 6 and 12 Months of Age: An Eye-Tracking Study.

Infancy 2017 Mar 31;22(2):223-239. Epub 2016 Mar 31.

Graduate School of Education, Kyoto University.

Preterm children are reported to be at higher risk of social communication problems such as autism spectrum disorder compared with full-term infants. Although previous studies have suggested that preference for social stimuli in infancy is a possible indicator of later social communication development, little is known about this relation in preterm infants. We examined the gaze behavior of low-risk preterm and full-term infants at 6 and 12 months' corrected ages using two types of eye-tracking tasks, which measured 1) preference for social stimuli by biological motion and human geometric preference and 2) ability to follow another's gaze direction. We found that preterm (compared with full-term) infants at both 6 and 12 months of age spent less time looking toward dynamic human images, followed another's gaze less frequently, and looked for a shorter time at an object cued by another. Moreover, we found a positive correlation between looking time toward dynamic human images and frequency of gaze following at 12 months of age in full-term, but not preterm, infants. We discuss the relation between the atypical patterns of gaze behavior in preterm infants and their higher risk of later social communication problems.
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http://dx.doi.org/10.1111/infa.12144DOI Listing
March 2017

Associations between respiratory arrhythmia and fundamental frequency of spontaneous crying in preterm and term infants at term-equivalent age.

Dev Psychobiol 2016 09 31;58(6):724-33. Epub 2016 Mar 31.

Graduate School of Education, Kyoto University, Kyoto, Japan.

This study investigated whether lower vagal function in preterm infants is associated with increased fundamental frequency (F0 ; frequency of vocal fold vibration) of their spontaneous cries. We assessed respiratory sinus arrhythmia (RSA) during quiet sleep as a measure of vagal function, and its relationship with the F0 of spontaneous cries in healthy preterm and term infants at term-equivalent age. The results showed that preterm infants have significantly lower RSA, and higher overall F0 than term infants. Moreover, lower RSA was associated with higher overall F0 in preterm infants, whereas higher RSA was positively associated with mean and maximum F0 , and a larger F0 range in term infants. These results suggest that individual differences in vagal function may be associated with the F0 of spontaneous cries via modulation of vocal fold tension in infants at an early developmental stage. © 2016 The Authors. Developmental Psychobiology Published by Wiley Periodicals, Inc. Dev Psychobiol 58:724-733, 2016.
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http://dx.doi.org/10.1002/dev.21412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071706PMC
September 2016

Fetal growth restriction but not preterm birth is a risk factor for severe hypospadias.

Pediatr Int 2016 Jul 4;58(7):573-7. Epub 2016 Feb 4.

Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: Hypospadias has multifactorial causes and occurs at a high frequency among very low-birthweight infants. Placental insufficiency is hypothesized to be one cause of hypospadias; that is, decreased human chorionic gonadotropin (hCG) secretion caused by placental insufficiency is suspected to result in abnormal male external genitalia, but there is little direct evidence to support this. The aim of this study was therefore to identify the features of hypospadias and to clarify the male genital abnormalities caused by fetal growth restriction (FGR).

Methods: We reviewed the clinical data of boys who underwent hypospadias repair between 2005 and 2011 at Kyoto University Hospital.

Results: Twenty boys were included in this study. Fifteen (75%) of the subjects were preterm or low-birthweight infants. Thirteen (65%) had FGR, 60% of whom had severe hypospadias regardless of gestational age. In addition, 92% of the FGR infants also had other genital anomalies, such as cryptorchidism, bifid scrotum, or micropenis. In contrast, only 14% and 43% of the non-FGR infants had severe hypospadias or genital anomalies other than hypospadias, respectively. Placental histopathology was available in eight FGR infants, in seven of whom it was suggestive of blood flow deficiency such as infarction and single umbilical artery.

Conclusions: Infants with FGR have a high incidence of hypospadias. FGR caused by placental dysfunction, but not low birthweight, is a risk factor for severe hypospadias associated with multiple genital anomalies.
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http://dx.doi.org/10.1111/ped.12864DOI Listing
July 2016

Preterm birth is associated with an increased fundamental frequency of spontaneous crying in human infants at term-equivalent age.

Biol Lett 2014 Aug;10(8)

Graduate School of Education, Kyoto University, Kyoto, Japan

Human infant crying has been researched as a non-invasive tool for assessing neurophysiological states at an early developmental stage. Little is known about the acoustic features of spontaneous cries in preterm infants, although their pain-induced cries are at a higher fundamental frequency (F0) before term-equivalent age. In this study, we investigated the effects of gestational age, body size at recording and intrauterine growth retardation (IUGR) on the F0 of spontaneous cries in healthy preterm and full-term infants at term-equivalent age. We found that shorter gestational age was significantly associated with higher F0, although neither smaller body size at recording nor IUGR was related to increased F0 in preterm infants. These findings suggest that the increased F0 of spontaneous cries is not caused by their smaller body size, but instead might be caused by more complicated neurophysiological states owing to their different intrauterine and extrauterine experiences.
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http://dx.doi.org/10.1098/rsbl.2014.0350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155907PMC
August 2014

Effects of preterm birth on intrinsic fluctuations in neonatal cerebral activity examined using optical imaging.

PLoS One 2013 28;8(6):e67432. Epub 2013 Jun 28.

Japan Science Technology Agency, Exploratory Research for Advanced Technology (ERATO), Okanoya Emotional Information Project, Honcho, Kawaguchi, Saitama, Japan.

Medical advancements in neonatology have significantly increased the number of high-risk preterm survivors. However, recent long-term follow-up studies have suggested that preterm infants are at risk for behavioral, educational, and emotional problems. Although clear relationships have been demonstrated between preterm infants and developmental problems during childhood and adolescence, less is known about the early indications of these problems. Recently, numerous studies on resting-state functional connectivity (RSFC) have demonstrated temporal correlations of activity between spatially remote cortical regions not only in healthy adults but also in neuropathological disorders and early childhood development. In order to compare RSFC of the cerebral cortex between preterm infants at term-equivalent ages and full-term neonates without any anatomical abnormality risk during natural sleep, we used an optical topography system, which is a recently developed extension of near-infrared spectroscopy. We clarified the presence of RSFC in both preterm infants and full-term neonates and showed differences between these groups. The principal differences were that on comparison of RSFC between the bilateral temporal regions, and bilateral parietal regions, RSFC was enhanced in preterm infants compared with full-term neonates; whereas on comparison of RSFC between the left temporal and left parietal regions, RSFC was enhanced in full-term neonates compared with preterm infants. We also demonstrated a difference between the groups in developmental changes of RSFC related to postmenstrual age. Most importantly, these findings suggested that preterm infants and full-term neonates follow different developmental trajectories during the perinatal period because of differences in perinatal experiences and physiological and structural development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067432PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696115PMC
January 2014

Decreased right temporal activation and increased interhemispheric connectivity in response to speech in preterm infants at term-equivalent age.

Front Psychol 2013 1;4:94. Epub 2013 Mar 1.

Okanoya Emotional Information Project, The Exploratory Research for Advanced Technology, Japan Agency of Science and Technology Saitama, Japan ; Graduate School of Education, Kyoto University Kyoto, Japan.

Preterm infants are at increased risk of language-related problems later in life; however, few studies have examined the effects of preterm birth on cerebral responses to speech at very early developmental stages. This study examined cerebral activation and functional connectivity in response to infant-directed speech (IDS) and adult-directed speech (ADS) in full-term neonates and preterm infants at term-equivalent age using 94-channel near-infrared spectroscopy. The results showed that compared with ADS, IDS increased activity in larger brain areas such as the bilateral frontotemporal, temporal, and temporoparietal regions, both in full-term and preterm infants. Preterm infants exhibited decreased activity in response to speech stimuli in the right temporal region compared with full-term infants, although the significance was low. Moreover, preterm infants exhibited increased interhemispheric connectivity compared with full-term controls, especially in the temporal and temporoparietal regions. These differences suggest that preterm infants may follow different developmental trajectories from those born at term owing to differences in intrauterine and extrauterine development.
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http://dx.doi.org/10.3389/fpsyg.2013.00094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585712PMC
March 2013

Limited response to CRH stimulation tests at 2 weeks of age in preterm infants born at less than 30 weeks of gestational age.

Clin Endocrinol (Oxf) 2013 May;78(5):724-9

Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: The high incidence of glucocorticoid-responsive complications in extremely preterm infants suggests the immaturity of their adrenal function; however, knowledge of the hypothalamus-pituitary-adrenal (HPA) axis in extremely preterm infants is limited.

Methods: To clarify the characteristics of the HPA axis in preterm very low birthweight (VLBW) infants, we performed CRH tests repeatedly: at about 2 weeks of age and at term (37-41 weeks of postmenstrual age) for 21 VLBW infants with a gestational age (GA) <30 weeks at birth.

Results: Basal cortisol values at 2 weeks of age were significantly higher than those at term in VLBW infants < 30 weeks of gestation at birth (304·1 ± 146·3 nmol/l vs 184·7 ± 108·2 nmol/l). Response to corticotropin-releasing hormone (CRH) stimulation tests at 2 weeks of age was significantly lower than at term (delta cortisol 148·3 ± 90·7 nmol/l vs 271·8 ± 167·0 nmol/l, delta ACTH 3·9 ± 3·2 pmol/l vs 12·3 ± 9·2 pmol/l, respectively). We found that earlier GA contributed to the higher basal cortisol values, and antenatal glucocorticoid (AG) contributed to the lower response of cortisol to CRH tests at 2 weeks of age.

Conclusions: VLBW infants showed a characteristic pattern in the HPA axis at 2 weeks of age: higher basal cortisol values and lower response to CRH tests. This study suggested that AG was related to the lower response to CRH tests, at least partly.
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http://dx.doi.org/10.1111/cen.12049DOI Listing
May 2013

Diagnostic value of salivary cortisol in the CRH stimulation test in premature infants.

J Clin Endocrinol Metab 2012 Mar 18;97(3):890-6. Epub 2012 Jan 18.

Department of Pediatrics, Graduate School of Medicine, Kyoto University, 54 Shogoin-kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan.

Context: According to a recent nationwide survey in Japan, a significant proportion of very low birth weight infants (VLBWI) develop late-onset circulatory collapse after the first week of life. Small doses of glucocorticoid are very effective in these patients, and relative adrenal insufficiency is suspected to be the main cause of the condition. Although the CRH test is required to evaluate the hypothalamic-pituitary-adrenal axis, obtaining multiple blood samples is invasive.

Objectives: The present study was carried out to validate the consistency of the cortisol profiles of matched serum and saliva samples collected as part of the CRH test from VLBWI.

Subjects/methods: In 23 VLBWI with a gestational age of less than 29 wk, we performed CRH tests at 2 wk after birth and at term. Their cortisol values were measured at the baseline and 30 min after the administration of a single dose of human CRH (1 μg/kg) using matched serum and saliva samples.

Results: In 26 CRH tests in 19 infants, we were able to measure both serum and salivary cortisol. Significant correlations were detected between the infants' serum and salivary cortisol values (r=0.78; P<0.0001), the increases in these values induced in response to the CRH test (r=0.81; P<0.0001), and their peak serum and salivary cortisol values (r=0.68; P=0.0001).

Conclusion: This study indicated that using salivary cortisol measurements for the CRH test could be a reliable method for evaluating the hypothalamic-pituitary-adrenal axis in VLBWI with gestational age of less than 29 wk.
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http://dx.doi.org/10.1210/jc.2011-1814DOI Listing
March 2012

Hyperthyrotropinemia at 2 weeks of age indicates thyroid dysfunction and predicts the occurrence of delayed elevation of thyrotropin in very low birth weight infants.

Clin Endocrinol (Oxf) 2012 Aug;77(2):255-61

Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Background: For preterm infants, transient hypothyroxinemia of prematurity and transient primary hypothyroidism, especially with delayed elevation of serum thyrotropin (TSH), are important.

Methods: To address the above two issues, we performed thyrotropin-releasing hormone (TRH) stimulation tests at about 2 weeks of age for 31 preterm infants with a gestational age of 30 weeks or less.

Results: For basal TSH levels, 68% of infants (21 of 31) showed normal values (TSH < 10 mU/l) and 32% of infants (10 of 31) showed higher values (four infants: TSH 10-15 mU/l, six infants: TSH > 15 mU/l). Peak TSH values in response to TRH stimulation tests ranged from 9·76 to 114·8 mU/l. All infants showed a significant response to TRH stimulation tests. Only 9·5% of infants (two of 21) with normal basal TSH values showed a hyperresponse (peak TSH > 45 mU/l), whereas 80% of infants (eight of 10) who had higher basal TSH values showed a hyperresponse. All infants who showed mildly elevated basal TSH values (TSH 10-15 mU/l) and a hyperresponse to TRH stimulation tests showed delayed elevation of basal TSH values (TSH > 15 mU/l) later.

Conclusions: Thyrotropin-releasing hormone stimulation tests at about 2 weeks of age suggested that the hypothalamic-pituitary-thyroid axis might be established even in extremely premature infants. Basal increased TSH levels (TSH > 10 mU/l) and a hyperresponse to TRH stimulation tests (peak TSH > 45 mU/l) suggested subclinical thyroid dysfunction. Serum TSH values at about 2 weeks of age could be useful for the prediction of delayed TSH elevation.
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http://dx.doi.org/10.1111/j.1365-2265.2011.04323.xDOI Listing
August 2012