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Transthyretin levels are not related to Apgar score in low birth weight and very low birth weight infants
Early Human Development (2008) 84, 533–538
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v
Transthyretin levels are not related to Apgar score in low birth weight and very low birth weight infants Pen-Hua Su a , Shu-Li Wang b,c , Jia-Yuh Chen a,⁎, Jui-Ming Hu d , Hua-Pin Chang d , Suh-Jen Chen d a
Department of Pediatrics, Chung Shan Medical University, Taichung, Taiwan Department of Public Health, Chung Shan Medical University, Taichung, Taiwan c Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan d Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan b
Received 4 July 2007; received in revised form 28 December 2007; accepted 4 January 2008
KEYWORDS Thyroid hormone; Transthyretin; Very low birth weight; Low birth weight; Preterm infants
Abstract Background: Previous studies have reported an increased incidence of thyroid dysfunction in premature/low birth weight infants. The cord blood concentrations of transthyretin (TTR), a thyroid hormone binding protein, have also been found to be decreased in preterm infants. While thyroid hormone concentrations are decreased in sick infants, it is not known if physical condition influences TTR levels. Serial concentrations of TTR following birth have not previously been reported. Aims: To measure serial serum concentrations of TTR in premature infants following birth, and determine whether TTR levels are related to physical condition. Methods: A cohort of 65 premature very low birth weight (VLBW) and LBW infants were studied. Serum samples were obtained on the day of birth, and for 8 weeks following birth. Apgar scores at birth as well as the incidence of respiratory distress syndrome (RDS) were noted. Results: Baseline serum T4 concentrations and Apgar scores were significantly lower in VLBW infants, while the severity of RDS was significantly higher in the VLBW group. Multivariate analyses revealed that T4 levels were negatively associated with RDS, while TSH concentrations were positively related to gestational age. TTR concentrations were not related to gestational age at birth, Apgar score, or RDS, and did not change markedly over 8 weeks. Conclusions: These findings suggest that serum TTR concentrations are not related to birth weight/gestational age and are not associated with either clinical condition at birth (as assessed by Apgar score) or the occurrence of RDS. Reference values for TTR concentrations in VLBW and LBW infants are provided from birth to 8 weeks of age. © 2008 Elsevier Ireland Ltd. All rights reserved.
⁎ Corresponding author. Division of Pediatrics, Chung Shan Medical University Hospital, No. 110 Chien-Kuo N. Road, Sec. 1, Taichung, Taiwan, 402. Tel.: +886 4 24739595x34807; fax: +886 4 23248106. E-mail address: [email protected] (J.-Y. Chen). 0378-3782/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2008.01.001
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1. Introduction Thyroid dysfunction in infancy and childhood affects growth and development and can lead to metabolic abnormalities in adulthood [1]. Triiadothyronine (T3) and tetraiodothyronine (T4, also known as thyroxine) are released from the thyroid gland and transported to their target cells by specific carrier proteins within the circulation. There are three known thyroid hormone plasma binding proteins: transthyretin (TTR, often referred to as prealbumin), thyroxine binding globulin (TBG), and albumin. These proteins are synthesized in the liver and secreted into the blood stream [2]. TTR differs from TBG and albumin in that it is also synthesized in the brain, specifically by the epithelial cells of the choroid plexus [3,4]. TTR levels in infants are substantially lower than in adults [5,6], and concentrations of TTR in cord blood are lower in preterm as compared to term infants [7,8]. Indeed, several investigators have reported that cord blood TTR levels are dependent on gestational age and birth weight [8–11]. To date, however, there has been no report of serial serum TTR concentrations in infants from birth. Previous studies have demonstrated that TTR levels predict growth velocity and reflect nutrition status in preterm and infants [9,12–14]. In adults, previous studies have confirmed that clinically stressful conditions, such as inflammation and malnutrition, are accompanied by progressive increases in C-reactive protein concentrations and concomitant decreases in TTR concentrations [15,16]. In newborn infants, clinical condition is assessed by means of the Apgar score. This includes measures of heart rate, respiratory effort, muscle tone, and color. A higher Apgar score is indicative of better physical condition. It is not known whether serum TTR concentrations vary with physical condition/Apgar score at birth. In the present study, we measured and compared serial serum levels of TTR and thyroid hormones and their binding proteins in very low birth weight (VLBW) and low birth weight
Table 1 Correlation between basic characteristics at baseline and birth weight (n = 65) Variable
Table 2 Comparison of basic characteristics at baseline between very low birth weight and low birth weight infants (n = 65) Variable
Very low birth Low birth Pweight (n = 30) weight (n = 35) value
Maternal age (years) a Gestational age (weeks) a Gender (Male) c Presence of infection d RDS severity e Apgar score at 1 min e Apgar score at 5 min e Birth weight (g) a Hb (g/dL) a TTR (mg/dL) a T3 (ng/dL) a T4 (μg/dL) a TSH (μIU/mL) a TBG (μg/mL) a
31.67 ± 3.43
29.31 ± 3.46
b 0.01 b
30.46 ± 2.50
32.55 ± 1.93
b 0.01 b
15 (50.0%) 6 (20.0%)
20 (57.1%) 0 (0.0%)
0.57 b 0.01 b
3 (2–4) 5 (2.75–6)
1(1–2) 7 (5–8)
b 0.01 b b 0.01 b
7 (5–8)
8 (8–9)
b 0.01 b
1,185 ± 199 15.45 ± 1.81 8.95 ± 2.02 60.91 ± 33.01 6.80 ± 3.41 10.63 ± 14.43 18.01 ± 4.67
1,784 ± 203 16.20 ± 2.01 9.02 ± 1.30 78.02 ± 23.20 9.53 ± 2.72 11.60 ± 6.29 19.80 ± 4.38
b 0.01 b 0.12 0.87 0.02 b 0.01 b 0.72 0.12
Abbreviations: RDS = respiratory distress syndrome, Hb = hemoglobin, TTR = transthyretin, T3 = triiodothyronine, T4 = tetraiodothyronine, TSH = thyroid stimulating hormone, TBG = thyroxine binding globulin. Continuous variables are presented as the mean ± SD, categorical variables by number (%) and non-parametric variables as the median (inter-quartile range). a Independent samples t test for continuous variables. b Indicates a significant difference. c Chi-square test for categorical variables. d Fisher's exact test. e Mann–Whitney U test for non-parametric variables.
(LBW) infants. We also assessed the relationship between physical condition at birth (specifically as indicated by Apgar score), the occurrence of respiratory distress syndrome (RDS) and serum thyroid hormones and thyroid hormone binding proteins including TTR.
Correlation coefficients P- value
−0.33 Maternal age (years) Gestational age (weeks) a 0.57 RDS severity c −0.55 Apgar score at 1 min c 0.47 Apgar score at 5 min c 0.46 Hb (g/dL) a 0.24 0.18 TTR (mg/dL) a 0.30 T3 (ng/dL) a 0.36 T4 (μg/dL) a TSH (μIU/mL) a 0.09 0.14 TBG (μg/mL) a a
b0.01 b b0.01 b b0.01 b b0.01 b b0.01 b 0.06 0.15 0.02 b0.01 b 0.49 0.28
Abbreviations: RDS = respiratory distress syndrome, Hb = hemoglobin, TTR = transthyretin, T3 = triiodothyronine, T4 = tetraiodothyronine, TSH = thyroid stimulating hormone, TBG = thyroxine binding globulin. a Pearson's correlation coefficient. b Indicates a significant difference. c Kendall's correlation coefficient.
2. Subjects and methods 2.1. Subjects This was a prospective study of premature infants who were consecutively admitted to the neonatal intensive care unit of our university hospital between August 2006 and February 2007. Infants were eligible for inclusion if they were born at 36 weeks gestational age or less and weighed less than 2500 g. Premature infants were further categorized as LBW (weight between 1500 and 2500 g) or VLBW (weight b 1500 g). Infants with evidence of severe congenital abnormalities or lethal chromosomal anomalies, conditions known to lower thyroid stimulating hormone (TSH) or T4 levels (such as maternal thyroid history) or who were receiving amiodarone medications were excluded. The study was approved by the ethics review committee of our university hospital and written parental consent was obtained.
TTR levels are not related to Apgar score in low birth weight and very low birth weight infants
535
2.2. Blood sampling and Apgar score and RDS assessment
this assay was 1.17mg/dL and the intra- and interassay coefficients of variation 1.8% and 2.0%, respectively.
Venous blood samples were obtained from all infants at 1day, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks and 8 weeks after birth. Apgar scores were assessed and recorded at 1 and 5 min after birth. Infants were observed for obvious clinical signs of RDS (tachypnea, grunting, retractions, and cyanosis) over the entire 8-week study period; the diagnosis of RDS was confirmed and the severity graded by CXR. [17].
2.4. Statistical analysis
2.3. Sample analysis Blood samples were immediately centrifuged and the serum frozen at −70 C until analysis. Serum T3, T4, TSH and TBG levels were measured using an automated chemiluminescent immunometric assay (IMMULITE 2000: Diagnostic Products Corp, Los Angeles, CA). Sensitivities were 19 ng/dL, 0.3 μg/dL, 0.002 μIu/mL and 1.6 μg/mL for T3, T4, TSH and TBG, respectively. All assays have linear precision profiles. Intraand interassay coefficients of variation were 4.4% and 5.3% for T3, 4.6% and 5.6% for T4, 5.1% and 6.4% for TSH and 6.1% and 9.6% for TBG. Serum TTR levels were measured using a kinetic nephelometric method by automated nephelometer (Beckman Coulter, Inc. Array® System, Carlsbad, CA). The sensitivity of
Relationships between baseline characteristics and birth weight were assessed using Pearson's (for continuous variables) and Kendall's (for ordinal variables) correlation coefficients. Continuous data was compared by independent samples T test and categorical variables were compared by Chi-square test. Median values for Apgar score and RDS were non-parametric and compared by Mann–Whitney U test. Linear regression analysis was performed to assess the factors influencing thyroid and thyroid hormone binding protein levels. Changes in thyroid hormones and binding proteins over time for the two groups (LBW and VLBW) were compared using repeated measures ANOVA. All statistical assessments were two-sided and considered significant when P b 0.01. Statistical analyses were performed using SPSS 15.0 statistical software (SPSS Inc, Chicago, IL).
3. Results Sixty-five preterm infants were enrolled in this study. These infants ranged in weight from 780 to 2466 g, and gestational
Table 3 Results from linear regression analyses assessing the influence of various factors on serum TTR, T3, T4, TSH, and TBG, levels in infants Factors
TTR β value (95% C.I.)
Birth weight (g) Gender Female Male
0.00 (0.00, 0.00)
T3 P
β value (95% C.I.)
0.15 0.02 (0.01, 0.04)
T4 P
β value (95% C.I.) 0.02 0.00 (0.00, 0.01)
TSH P
β value (95% C.I.)
b 0.01 0.00 (−0.01, 0.01)
TBG P
β value
P
(95% C.I.) 0.49 0.00 (−0.00, 0.01)
1 0.98 1 0.48 1 0.99 1 0.53 1 −0.01 −5.23 0.01 −4.97 −0.92 (−0.84, 0.82) (− 19.81, 9.34) (−1.66, 1.67) (−10.21, 0.27) (−3.20, 1.36) Gestational −0.01 0.89 3.00 0.05 0.35 0.04 1.76 b 0.01 0.24 age (−0.18, 0.16) (0.07, 5.92) (0.01, 0.68) (0.74, 2.78) (−0.23, 0.71) (weeks) 0.78 −0.09 0.82 −0.01 Maternal −0.03 0.56 −0.64 0.53 −0.03 (−0.83, 0.66) (−0.33, 0.31) age (−0.15, 0.08) (− 2.66, 1.39) (−0.26, 0.20) (years) Infection No 1 0.57 1 0.06 1 0.10 1 0.56 1 Yes −0.41 23.39 2.36 −2.69 2.84 (−1.84, 1.02) (− 1.14, 47.90) (−0.45, 5.17) (−11.95, 6.58) (−1.04, 6.72) RDS −0.02 0.91 −8.66 b 0.01 −1.30 b 0.01 −1.95 0.10 −1.05 (−0.39, 0.35) (− 14.79, −2.53) (−1.96, − 0.63) (−4.30, 0.40) (−2.03, −0.07) Apgar 0.15 0.14 4.74 b 0.01 0.47 0.02 0.94 0.15 0.18 score at (−0.05, 0.35) (1.39, 8.09) (0.08, 0.86) (−0.35, 2.23) (−0.38, 0.73) 1 min 0.19 0.14 4.93 0.03 0.55 0.03 1.34 0.20 0.36 Apgar score at (−0.07, 0.44) (0.54, 9.33) (0.05, 1.05) (−0.31, 2.98) (−0.34, 1.07) 5 min
0.28
0. 42
0.31
0.94
0.15
0.04 0.53
0.31
Abbreviations: RDS = respiratory distress syndrome, TTR = transthyretin, T3 = triiodothyronine, T4 = tetraiodothyronine, TSH = thyroid stimulating hormone, TBG = thyroxine binding globulin. P-value in bold indicates a statistically significant difference, P b 0.01.
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Table 4 Results from multivariate analyses assessing the influence of various factors on serum TTR, T3, T4, TSH, and TBG, levels in infants Factors
TTR β value (95% C.I.)
Birth weight (g) Gender Female Male Gestational age (weeks) RDS Apgar score at 1 min
T3 P
β value
T4 P
(95% C.I.)
TSH
β value
P
(95% C.I.)
0.00 (0.00, 0.00)
0.11 0.00 (− 0.03, 0.03)
0.88 0.00 (−0.00, 0.00)
1 −0.22 (−1.08, 0.65) −0.13 (−035, 0.90) 0.29 (−0.22, 0.81) 0.14 (−0.11, 0.40)
0.62 1 −4.48 (− 19.16, 10.21) 0.24 0.29 (− 3.48, 4.06) 0.26 −5.00 (− 13.71, 3.71) 0.27 2.96 (− 1.39, 7.30)
0.54 1 0.11 (−1.52, 0.88 0.01 (−0.41, 0.26 − 1.05 (−2.01, 0.18 0.10 (−0.38,
β value (95% C.I.)
TBG P
β value
P
(95% C.I.)
0.70 − 0.01 0.09 −0.00 0.84 (−0.02, 0.00) (−0.01, 0.00)
0.89 1 − 2.45 1.74) (−7.65, 2.75) 0.95 1.89 0.43) (0.55, 3.23) 0.03 − 1.34 −0.08) (−4.43, 1.75) 0.67 0.59 0.58) (−0.95, 2.13)
0.35 1 0.81 (−3.21, 0.01 −0.02 (−0.63, 0.39 −1.27 (−2.69, 0.45 0.11 (−0.82,
0.50 1.59) 0.96 0.60) 0.08 0.15) 0.75 0.60)
Abbreviations: RDS = respiratory distress syndrome, TTR = transthyretin, T3 = triiodothyronine, T4 = tetraiodothyronine, TSH = thyroid stimulating hormone, TBG = thyroxine binding globulin. P-value in bold indicates a statistically significant differences, P b 0.01.
age ranged from 26 to 36 weeks. The relationships between basic characteristics and birth weight are shown in Table 1. Maternal age and RDS severity showed significant negative correlations with birth weight. In contrast, there were positive correlations between birth weight and gestational age, both Apgar scores at 1 and 5 min, and T3 and T4 levels (P b 0.01). For clinical insight, premature infants were further categorized as LBW (n = 35) or VLBW (n = 30). Ten of the VLBW and 8 of the LBW infants were exposed to prenatal steroids. The basic characteristics for each group are presented in Table 2. There were significant differences in maternal age, gestational age and presence of infection between the two groups (P b 0.01). Mean maternal age was higher in VLBW infants, while gestational age was lower in these infants. Six VLBW infants (20.0%) suffered infection. There were signifi-
cant differences in both Apgar scores at 1 and 5 min and the severity of RDS between the groups (P b 0.01). Apgar scores were lower in VLBW infants, while RDS severity was greater in these infants. Baseline T4 and concentrations were significantly higher in LBW compared to VLBW infants (P b 0.01). Results from the univariate analysis examining the influence of birth variables on thyroid hormones and thyroid hormone binding protein levels are presented in Table 3. Serum TSH concentrations were positively related to gestational age (P b 0.01), while serum T4 were related to birth weight (P b 0.01). T3 concentrations were positively associated with Apgar scores at 1 min (P b 0.01), while T3 and T4 levels were negatively associated with RDS (P b 0.01). TTR and TBG concentrations were unrelated to any of these variables. Multivariate analysis (Table 4) revealed that TSH concentrations were positively related to gestational age (P b 0.01).
Figure 1 Serum TTR concentrations in VLWB and LBW infants from birth until 8 weeks of age.
Figure 2 Serum T3 concentrations in VLWB and LBW infants from birth until 8 weeks of age.
TTR levels are not related to Apgar score in low birth weight and very low birth weight infants
537
Figure 3 Serum T4 concentrations in VLWB and LBW infants from birth until 8 weeks of age.
Figure 5 Serum TBG concentrations in VLWB and LBW infants from birth until 8 weeks of age.
TTR, T3 and TBG concentrations were unrelated to any of the variables. Serum levels of T3, T4, TSH, TBG and TTR in VLBW and LBW infants over the 8-week sampling period are presented in Figs. 1–5 respectively. Between group differences were only apparent for T4 (Fig. 4), where concentrations in LBW infants were significantly higher than in VLBW infants at day 1 and week 1 (both P b 0.01).
respectively. TTR concentrations were not associated with either of these variables, and did not change over the 8-week period. In keeping with previous studies, we found that T4 concentrations were significantly decreased in more premature neonates [19,20]. Also in line with prior findings, we found that prematurity/gestational age was inversely proportional to concentrations of these variables [21,22]. Mercado and colleagues noted that the incidence of hypothyroxinemia increased over the first week after birth before decreasing [21]. Indeed such decreases are commonly observed in preterm infants [23]. In our study there appeared to be trends for both T3 and T4 levels to decrease after birth, however these changes were not significant. This may be a reflection of the lower sample size in this study. A number of previous studies have examined the relationship between cord blood concentrations of TTR and gestational age at birth. Sasanow and colleagues found that cord TTR levels increased with gestational in a sample of 68 infants born between 25 and 42 weeks [11]. Georgieff et al. examined samples of appropriate for gestation age, small for gestational age and large for gestational age infants and reported that cord TTR concentrations were significantly correlated with both gestational age and birth weight [12]. Bhatia and Ziegler have published similar findings [8]. In contrast to these reports, we found no such relationships between infant serum TTR concentrations and gestational age and birth weight. There are several explanations for the disparity between and the older reports. Firstly, in our study, blood samples were obtained on the day of birth as opposed to the previous studies where cord blood was sampled at birth. It may be that TTR concentrations in preterm infants are altered at delivery but rapidly recover to normal. It would be interesting to compare serial changes in TTR concentrations from systemic blood obtained immediately after birth onwards to determine if this is the case. Methodological differences in the measurement of TTR may also explain the disparity between the aforementioned studies and ours. In accordance with previous studies, we found that lower thyroid hormone concentrations were significantly associated with poorer overall condition at birth (as indicated
4. Discussion In this prospective study, we examined serum thyroid hormone and thyroid hormone binding protein concentrations in VLBW and LBW infants, and assessed the relationship between these variables and fetal health as indicated by both Apgar scores at birth and the occurrence of RDS. We found that while T4 levels were significantly lower in VLBW infants, there were no differences in T3, TSH, TBG or TTR concentrations between the groups. Apgar scores were lower and RDS incidence higher in VLBW infants. TSH and T4 levels were significantly related to gestational age and RDS
Figure 4 Serum TSH concentrations in VLWB and LBW infants from birth until 8 weeks of age. ⁎ Indicates a statistically significant between group differences (P b 0.01).
538 by Agar score) and the occurrence of RDS [18,24–26]. It has also been reported that low T3 and T4 levels are associated with increased mortality [18]. To our knowledge, there has only been one report published concerning the relationship between TTR levels and RDS. Georgieff and colleagues found that cord blood TTR concentrations were significantly decreased in RDS infants [10]. We observed no such relationship in the present study. Again, differences in sample timing and analysis may underlie the disparate findings. This is the first reported study examining the relationship between Apgar score at birth and serum TTR concentrations. We found that there was no relationship between these variables. Regarding infant well being, a previous report demonstrated that low serum TTR concentrations in extremely low birth weight infants at 28 days of age were associated with increased morbidity and mortality [27]. However, the infants were followed for far longer (36 weeks) than in our study, making any direct comparison inappropriate. Given that serum TTR concentrations were not altered in preterm infants, our findings suggest that the function of TTR in transporting T4 to the CNS is not compromised in such infants. In this study we have reported for the first time serial serum TTR concentrations from birth to 8 weeks of age in VLBW and LBW infants. These values may be useful for future reference. Serum TTR concentrations were not related to birth weight and were not associated with condition at birth (as assessed by Apgar score) or the occurrence of RDS.
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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
w w w. e l s e v i e r. c o m / l o c a t e / e a r l h u m d e v
Transthyretin levels are not related to Apgar score in low birth weight and very low birth weight infants Pen-Hua Su a , Shu-Li Wang b,c , Jia-Yuh Chen a,⁎, Jui-Ming Hu d , Hua-Pin Chang d , Suh-Jen Chen d a
Department of Pediatrics, Chung Shan Medical University, Taichung, Taiwan Department of Public Health, Chung Shan Medical University, Taichung, Taiwan c Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan d Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan b
Received 4 July 2007; received in revised form 28 December 2007; accepted 4 January 2008
KEYWORDS Thyroid hormone; Transthyretin; Very low birth weight; Low birth weight; Preterm infants
Abstract Background: Previous studies have reported an increased incidence of thyroid dysfunction in premature/low birth weight infants. The cord blood concentrations of transthyretin (TTR), a thyroid hormone binding protein, have also been found to be decreased in preterm infants. While thyroid hormone concentrations are decreased in sick infants, it is not known if physical condition influences TTR levels. Serial concentrations of TTR following birth have not previously been reported. Aims: To measure serial serum concentrations of TTR in premature infants following birth, and determine whether TTR levels are related to physical condition. Methods: A cohort of 65 premature very low birth weight (VLBW) and LBW infants were studied. Serum samples were obtained on the day of birth, and for 8 weeks following birth. Apgar scores at birth as well as the incidence of respiratory distress syndrome (RDS) were noted. Results: Baseline serum T4 concentrations and Apgar scores were significantly lower in VLBW infants, while the severity of RDS was significantly higher in the VLBW group. Multivariate analyses revealed that T4 levels were negatively associated with RDS, while TSH concentrations were positively related to gestational age. TTR concentrations were not related to gestational age at birth, Apgar score, or RDS, and did not change markedly over 8 weeks. Conclusions: These findings suggest that serum TTR concentrations are not related to birth weight/gestational age and are not associated with either clinical condition at birth (as assessed by Apgar score) or the occurrence of RDS. Reference values for TTR concentrations in VLBW and LBW infants are provided from birth to 8 weeks of age. © 2008 Elsevier Ireland Ltd. All rights reserved.
⁎ Corresponding author. Division of Pediatrics, Chung Shan Medical University Hospital, No. 110 Chien-Kuo N. Road, Sec. 1, Taichung, Taiwan, 402. Tel.: +886 4 24739595x34807; fax: +886 4 23248106. E-mail address: [email protected] (J.-Y. Chen). 0378-3782/$ - see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2008.01.001
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1. Introduction Thyroid dysfunction in infancy and childhood affects growth and development and can lead to metabolic abnormalities in adulthood [1]. Triiadothyronine (T3) and tetraiodothyronine (T4, also known as thyroxine) are released from the thyroid gland and transported to their target cells by specific carrier proteins within the circulation. There are three known thyroid hormone plasma binding proteins: transthyretin (TTR, often referred to as prealbumin), thyroxine binding globulin (TBG), and albumin. These proteins are synthesized in the liver and secreted into the blood stream [2]. TTR differs from TBG and albumin in that it is also synthesized in the brain, specifically by the epithelial cells of the choroid plexus [3,4]. TTR levels in infants are substantially lower than in adults [5,6], and concentrations of TTR in cord blood are lower in preterm as compared to term infants [7,8]. Indeed, several investigators have reported that cord blood TTR levels are dependent on gestational age and birth weight [8–11]. To date, however, there has been no report of serial serum TTR concentrations in infants from birth. Previous studies have demonstrated that TTR levels predict growth velocity and reflect nutrition status in preterm and infants [9,12–14]. In adults, previous studies have confirmed that clinically stressful conditions, such as inflammation and malnutrition, are accompanied by progressive increases in C-reactive protein concentrations and concomitant decreases in TTR concentrations [15,16]. In newborn infants, clinical condition is assessed by means of the Apgar score. This includes measures of heart rate, respiratory effort, muscle tone, and color. A higher Apgar score is indicative of better physical condition. It is not known whether serum TTR concentrations vary with physical condition/Apgar score at birth. In the present study, we measured and compared serial serum levels of TTR and thyroid hormones and their binding proteins in very low birth weight (VLBW) and low birth weight
Table 1 Correlation between basic characteristics at baseline and birth weight (n = 65) Variable
Table 2 Comparison of basic characteristics at baseline between very low birth weight and low birth weight infants (n = 65) Variable
Very low birth Low birth Pweight (n = 30) weight (n = 35) value
Maternal age (years) a Gestational age (weeks) a Gender (Male) c Presence of infection d RDS severity e Apgar score at 1 min e Apgar score at 5 min e Birth weight (g) a Hb (g/dL) a TTR (mg/dL) a T3 (ng/dL) a T4 (μg/dL) a TSH (μIU/mL) a TBG (μg/mL) a
31.67 ± 3.43
29.31 ± 3.46
b 0.01 b
30.46 ± 2.50
32.55 ± 1.93
b 0.01 b
15 (50.0%) 6 (20.0%)
20 (57.1%) 0 (0.0%)
0.57 b 0.01 b
3 (2–4) 5 (2.75–6)
1(1–2) 7 (5–8)
b 0.01 b b 0.01 b
7 (5–8)
8 (8–9)
b 0.01 b
1,185 ± 199 15.45 ± 1.81 8.95 ± 2.02 60.91 ± 33.01 6.80 ± 3.41 10.63 ± 14.43 18.01 ± 4.67
1,784 ± 203 16.20 ± 2.01 9.02 ± 1.30 78.02 ± 23.20 9.53 ± 2.72 11.60 ± 6.29 19.80 ± 4.38
b 0.01 b 0.12 0.87 0.02 b 0.01 b 0.72 0.12
Abbreviations: RDS = respiratory distress syndrome, Hb = hemoglobin, TTR = transthyretin, T3 = triiodothyronine, T4 = tetraiodothyronine, TSH = thyroid stimulating hormone, TBG = thyroxine binding globulin. Continuous variables are presented as the mean ± SD, categorical variables by number (%) and non-parametric variables as the median (inter-quartile range). a Independent samples t test for continuous variables. b Indicates a significant difference. c Chi-square test for categorical variables. d Fisher's exact test. e Mann–Whitney U test for non-parametric variables.
(LBW) infants. We also assessed the relationship between physical condition at birth (specifically as indicated by Apgar score), the occurrence of respiratory distress syndrome (RDS) and serum thyroid hormones and thyroid hormone binding proteins including TTR.
Correlation coefficients P- value
−0.33 Maternal age (years) Gestational age (weeks) a 0.57 RDS severity c −0.55 Apgar score at 1 min c 0.47 Apgar score at 5 min c 0.46 Hb (g/dL) a 0.24 0.18 TTR (mg/dL) a 0.30 T3 (ng/dL) a 0.36 T4 (μg/dL) a TSH (μIU/mL) a 0.09 0.14 TBG (μg/mL) a a
b0.01 b b0.01 b b0.01 b b0.01 b b0.01 b 0.06 0.15 0.02 b0.01 b 0.49 0.28
Abbreviations: RDS = respiratory distress syndrome, Hb = hemoglobin, TTR = transthyretin, T3 = triiodothyronine, T4 = tetraiodothyronine, TSH = thyroid stimulating hormone, TBG = thyroxine binding globulin. a Pearson's correlation coefficient. b Indicates a significant difference. c Kendall's correlation coefficient.
2. Subjects and methods 2.1. Subjects This was a prospective study of premature infants who were consecutively admitted to the neonatal intensive care unit of our university hospital between August 2006 and February 2007. Infants were eligible for inclusion if they were born at 36 weeks gestational age or less and weighed less than 2500 g. Premature infants were further categorized as LBW (weight between 1500 and 2500 g) or VLBW (weight b 1500 g). Infants with evidence of severe congenital abnormalities or lethal chromosomal anomalies, conditions known to lower thyroid stimulating hormone (TSH) or T4 levels (such as maternal thyroid history) or who were receiving amiodarone medications were excluded. The study was approved by the ethics review committee of our university hospital and written parental consent was obtained.
TTR levels are not related to Apgar score in low birth weight and very low birth weight infants
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2.2. Blood sampling and Apgar score and RDS assessment
this assay was 1.17mg/dL and the intra- and interassay coefficients of variation 1.8% and 2.0%, respectively.
Venous blood samples were obtained from all infants at 1day, 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks and 8 weeks after birth. Apgar scores were assessed and recorded at 1 and 5 min after birth. Infants were observed for obvious clinical signs of RDS (tachypnea, grunting, retractions, and cyanosis) over the entire 8-week study period; the diagnosis of RDS was confirmed and the severity graded by CXR. [17].
2.4. Statistical analysis
2.3. Sample analysis Blood samples were immediately centrifuged and the serum frozen at −70 C until analysis. Serum T3, T4, TSH and TBG levels were measured using an automated chemiluminescent immunometric assay (IMMULITE 2000: Diagnostic Products Corp, Los Angeles, CA). Sensitivities were 19 ng/dL, 0.3 μg/dL, 0.002 μIu/mL and 1.6 μg/mL for T3, T4, TSH and TBG, respectively. All assays have linear precision profiles. Intraand interassay coefficients of variation were 4.4% and 5.3% for T3, 4.6% and 5.6% for T4, 5.1% and 6.4% for TSH and 6.1% and 9.6% for TBG. Serum TTR levels were measured using a kinetic nephelometric method by automated nephelometer (Beckman Coulter, Inc. Array® System, Carlsbad, CA). The sensitivity of
Relationships between baseline characteristics and birth weight were assessed using Pearson's (for continuous variables) and Kendall's (for ordinal variables) correlation coefficients. Continuous data was compared by independent samples T test and categorical variables were compared by Chi-square test. Median values for Apgar score and RDS were non-parametric and compared by Mann–Whitney U test. Linear regression analysis was performed to assess the factors influencing thyroid and thyroid hormone binding protein levels. Changes in thyroid hormones and binding proteins over time for the two groups (LBW and VLBW) were compared using repeated measures ANOVA. All statistical assessments were two-sided and considered significant when P b 0.01. Statistical analyses were performed using SPSS 15.0 statistical software (SPSS Inc, Chicago, IL).
3. Results Sixty-five preterm infants were enrolled in this study. These infants ranged in weight from 780 to 2466 g, and gestational
Table 3 Results from linear regression analyses assessing the influence of various factors on serum TTR, T3, T4, TSH, and TBG, levels in infants Factors
TTR β value (95% C.I.)
Birth weight (g) Gender Female Male
0.00 (0.00, 0.00)
T3 P
β value (95% C.I.)
0.15 0.02 (0.01, 0.04)
T4 P
β value (95% C.I.) 0.02 0.00 (0.00, 0.01)
TSH P
β value (95% C.I.)
b 0.01 0.00 (−0.01, 0.01)
TBG P
β value
P
(95% C.I.) 0.49 0.00 (−0.00, 0.01)
1 0.98 1 0.48 1 0.99 1 0.53 1 −0.01 −5.23 0.01 −4.97 −0.92 (−0.84, 0.82) (− 19.81, 9.34) (−1.66, 1.67) (−10.21, 0.27) (−3.20, 1.36) Gestational −0.01 0.89 3.00 0.05 0.35 0.04 1.76 b 0.01 0.24 age (−0.18, 0.16) (0.07, 5.92) (0.01, 0.68) (0.74, 2.78) (−0.23, 0.71) (weeks) 0.78 −0.09 0.82 −0.01 Maternal −0.03 0.56 −0.64 0.53 −0.03 (−0.83, 0.66) (−0.33, 0.31) age (−0.15, 0.08) (− 2.66, 1.39) (−0.26, 0.20) (years) Infection No 1 0.57 1 0.06 1 0.10 1 0.56 1 Yes −0.41 23.39 2.36 −2.69 2.84 (−1.84, 1.02) (− 1.14, 47.90) (−0.45, 5.17) (−11.95, 6.58) (−1.04, 6.72) RDS −0.02 0.91 −8.66 b 0.01 −1.30 b 0.01 −1.95 0.10 −1.05 (−0.39, 0.35) (− 14.79, −2.53) (−1.96, − 0.63) (−4.30, 0.40) (−2.03, −0.07) Apgar 0.15 0.14 4.74 b 0.01 0.47 0.02 0.94 0.15 0.18 score at (−0.05, 0.35) (1.39, 8.09) (0.08, 0.86) (−0.35, 2.23) (−0.38, 0.73) 1 min 0.19 0.14 4.93 0.03 0.55 0.03 1.34 0.20 0.36 Apgar score at (−0.07, 0.44) (0.54, 9.33) (0.05, 1.05) (−0.31, 2.98) (−0.34, 1.07) 5 min
0.28
0. 42
0.31
0.94
0.15
0.04 0.53
0.31
Abbreviations: RDS = respiratory distress syndrome, TTR = transthyretin, T3 = triiodothyronine, T4 = tetraiodothyronine, TSH = thyroid stimulating hormone, TBG = thyroxine binding globulin. P-value in bold indicates a statistically significant difference, P b 0.01.
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Table 4 Results from multivariate analyses assessing the influence of various factors on serum TTR, T3, T4, TSH, and TBG, levels in infants Factors
TTR β value (95% C.I.)
Birth weight (g) Gender Female Male Gestational age (weeks) RDS Apgar score at 1 min
T3 P
β value
T4 P
(95% C.I.)
TSH
β value
P
(95% C.I.)
0.00 (0.00, 0.00)
0.11 0.00 (− 0.03, 0.03)
0.88 0.00 (−0.00, 0.00)
1 −0.22 (−1.08, 0.65) −0.13 (−035, 0.90) 0.29 (−0.22, 0.81) 0.14 (−0.11, 0.40)
0.62 1 −4.48 (− 19.16, 10.21) 0.24 0.29 (− 3.48, 4.06) 0.26 −5.00 (− 13.71, 3.71) 0.27 2.96 (− 1.39, 7.30)
0.54 1 0.11 (−1.52, 0.88 0.01 (−0.41, 0.26 − 1.05 (−2.01, 0.18 0.10 (−0.38,
β value (95% C.I.)
TBG P
β value
P
(95% C.I.)
0.70 − 0.01 0.09 −0.00 0.84 (−0.02, 0.00) (−0.01, 0.00)
0.89 1 − 2.45 1.74) (−7.65, 2.75) 0.95 1.89 0.43) (0.55, 3.23) 0.03 − 1.34 −0.08) (−4.43, 1.75) 0.67 0.59 0.58) (−0.95, 2.13)
0.35 1 0.81 (−3.21, 0.01 −0.02 (−0.63, 0.39 −1.27 (−2.69, 0.45 0.11 (−0.82,
0.50 1.59) 0.96 0.60) 0.08 0.15) 0.75 0.60)
Abbreviations: RDS = respiratory distress syndrome, TTR = transthyretin, T3 = triiodothyronine, T4 = tetraiodothyronine, TSH = thyroid stimulating hormone, TBG = thyroxine binding globulin. P-value in bold indicates a statistically significant differences, P b 0.01.
age ranged from 26 to 36 weeks. The relationships between basic characteristics and birth weight are shown in Table 1. Maternal age and RDS severity showed significant negative correlations with birth weight. In contrast, there were positive correlations between birth weight and gestational age, both Apgar scores at 1 and 5 min, and T3 and T4 levels (P b 0.01). For clinical insight, premature infants were further categorized as LBW (n = 35) or VLBW (n = 30). Ten of the VLBW and 8 of the LBW infants were exposed to prenatal steroids. The basic characteristics for each group are presented in Table 2. There were significant differences in maternal age, gestational age and presence of infection between the two groups (P b 0.01). Mean maternal age was higher in VLBW infants, while gestational age was lower in these infants. Six VLBW infants (20.0%) suffered infection. There were signifi-
cant differences in both Apgar scores at 1 and 5 min and the severity of RDS between the groups (P b 0.01). Apgar scores were lower in VLBW infants, while RDS severity was greater in these infants. Baseline T4 and concentrations were significantly higher in LBW compared to VLBW infants (P b 0.01). Results from the univariate analysis examining the influence of birth variables on thyroid hormones and thyroid hormone binding protein levels are presented in Table 3. Serum TSH concentrations were positively related to gestational age (P b 0.01), while serum T4 were related to birth weight (P b 0.01). T3 concentrations were positively associated with Apgar scores at 1 min (P b 0.01), while T3 and T4 levels were negatively associated with RDS (P b 0.01). TTR and TBG concentrations were unrelated to any of these variables. Multivariate analysis (Table 4) revealed that TSH concentrations were positively related to gestational age (P b 0.01).
Figure 1 Serum TTR concentrations in VLWB and LBW infants from birth until 8 weeks of age.
Figure 2 Serum T3 concentrations in VLWB and LBW infants from birth until 8 weeks of age.
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Figure 3 Serum T4 concentrations in VLWB and LBW infants from birth until 8 weeks of age.
Figure 5 Serum TBG concentrations in VLWB and LBW infants from birth until 8 weeks of age.
TTR, T3 and TBG concentrations were unrelated to any of the variables. Serum levels of T3, T4, TSH, TBG and TTR in VLBW and LBW infants over the 8-week sampling period are presented in Figs. 1–5 respectively. Between group differences were only apparent for T4 (Fig. 4), where concentrations in LBW infants were significantly higher than in VLBW infants at day 1 and week 1 (both P b 0.01).
respectively. TTR concentrations were not associated with either of these variables, and did not change over the 8-week period. In keeping with previous studies, we found that T4 concentrations were significantly decreased in more premature neonates [19,20]. Also in line with prior findings, we found that prematurity/gestational age was inversely proportional to concentrations of these variables [21,22]. Mercado and colleagues noted that the incidence of hypothyroxinemia increased over the first week after birth before decreasing [21]. Indeed such decreases are commonly observed in preterm infants [23]. In our study there appeared to be trends for both T3 and T4 levels to decrease after birth, however these changes were not significant. This may be a reflection of the lower sample size in this study. A number of previous studies have examined the relationship between cord blood concentrations of TTR and gestational age at birth. Sasanow and colleagues found that cord TTR levels increased with gestational in a sample of 68 infants born between 25 and 42 weeks [11]. Georgieff et al. examined samples of appropriate for gestation age, small for gestational age and large for gestational age infants and reported that cord TTR concentrations were significantly correlated with both gestational age and birth weight [12]. Bhatia and Ziegler have published similar findings [8]. In contrast to these reports, we found no such relationships between infant serum TTR concentrations and gestational age and birth weight. There are several explanations for the disparity between and the older reports. Firstly, in our study, blood samples were obtained on the day of birth as opposed to the previous studies where cord blood was sampled at birth. It may be that TTR concentrations in preterm infants are altered at delivery but rapidly recover to normal. It would be interesting to compare serial changes in TTR concentrations from systemic blood obtained immediately after birth onwards to determine if this is the case. Methodological differences in the measurement of TTR may also explain the disparity between the aforementioned studies and ours. In accordance with previous studies, we found that lower thyroid hormone concentrations were significantly associated with poorer overall condition at birth (as indicated
4. Discussion In this prospective study, we examined serum thyroid hormone and thyroid hormone binding protein concentrations in VLBW and LBW infants, and assessed the relationship between these variables and fetal health as indicated by both Apgar scores at birth and the occurrence of RDS. We found that while T4 levels were significantly lower in VLBW infants, there were no differences in T3, TSH, TBG or TTR concentrations between the groups. Apgar scores were lower and RDS incidence higher in VLBW infants. TSH and T4 levels were significantly related to gestational age and RDS
Figure 4 Serum TSH concentrations in VLWB and LBW infants from birth until 8 weeks of age. ⁎ Indicates a statistically significant between group differences (P b 0.01).
538 by Agar score) and the occurrence of RDS [18,24–26]. It has also been reported that low T3 and T4 levels are associated with increased mortality [18]. To our knowledge, there has only been one report published concerning the relationship between TTR levels and RDS. Georgieff and colleagues found that cord blood TTR concentrations were significantly decreased in RDS infants [10]. We observed no such relationship in the present study. Again, differences in sample timing and analysis may underlie the disparate findings. This is the first reported study examining the relationship between Apgar score at birth and serum TTR concentrations. We found that there was no relationship between these variables. Regarding infant well being, a previous report demonstrated that low serum TTR concentrations in extremely low birth weight infants at 28 days of age were associated with increased morbidity and mortality [27]. However, the infants were followed for far longer (36 weeks) than in our study, making any direct comparison inappropriate. Given that serum TTR concentrations were not altered in preterm infants, our findings suggest that the function of TTR in transporting T4 to the CNS is not compromised in such infants. In this study we have reported for the first time serial serum TTR concentrations from birth to 8 weeks of age in VLBW and LBW infants. These values may be useful for future reference. Serum TTR concentrations were not related to birth weight and were not associated with condition at birth (as assessed by Apgar score) or the occurrence of RDS.
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