Indian Pediatr 2012;49:
Neurodevelopmental Evaluation of Very Low
Birth Weight Infants With Transient Hypothyroxinemia at
Corrected Age of 18-24 Months
#Zeynep Eras, *Nesibe
Andiran, Ugur Dilmen and #Evrim
From the Department of Neonatology, and #Department of
Developmental Pediatrics, Zekai Tahir Burak Maternity Teaching Hospital;
and *Department of Pediatric Endocrinology, Keçiören Training and
Correspondence to: Dilek Dilli, Department of
Neonatology, Zekai Tahir Burak Kadýn Saglýgi Egitim ve Arastirma
Hastanesi Yenidogan Klinigi, Talatpasa bulvari, Hamamönü/Ankara/Turkey.
Received: August 24, 2011;
Initial review: October 03, 2011;
Accepted: December 14, 2011.
Published online: 2012, March 30.
P II : S097475591100706-1
Objective: To perform neurodevelopmental evaluation at 18 to 24
months’ corrected age in very low birth infants (VLBW) with transient
Design: Cohort study.
Setting: Maternity teaching hospital.
Patients: Premature infants who were previously
evaluated for thyroid hormone values in the first weeks of life were
Intervention: Data of these infants who weighed
g and £32
weeks of gestation were retrieved for the current study. Available
subjects (n=56) were evaluated for neurodevelopmental status at
18 to 24 months of corrected age. Bayley Scales of Infant Development
–Second Edition (BSID-II) was performed to define Mental developmental
index (MDI) and Psychomotor developmental index (PDI).
Results: The mean MDI and PDI scores were similar
between the infants with and without transient hypothyroxinemia of
prematurity (THOP) [79.9 ± 14.9 vs 70 ± 20.7, respectively (P=0.54);
and 92.2 ± 16.4 vs 85.6 ± 18.9, respectively (P=0.68)].
After adjustment for gestational age and multiple prenatal, perinatal,
and early and late neonatal variables, THOP was not associated with an
increased risk of disabling cerebral palsy, or a reduction of MDI and
Conclusions: THOP may not be an important cause
of problems in neurologic and mental development detected at the age of
18 to 24 months’ corrected age.
Key words: Neurodevelopment, Newborn, Outcome, Transient
hypothyroxinemia of prematurity, Turkey.
Transient hypothyroxinemia of
prematurity (THOP) is frequent among very low birth infants (VLBW) and
is considered as a benign developmental phenomenon, an expression of
temporary hypothalamic-pituitary immaturity. There is a controversy
whether THOP is associated with long term sequelae and requires thyroid
hormone replacement [1,2]. A previous double-blind trial of thyroid
supplementation did not improve the developmental outcome at 24 months
. However, thyroid supplementation was found to be beneficial for
children <29 weeks’ gestation, especially those of 25/26 weeks’
gestation, at early school age .
In this study, we studied the relation between THOP
experienced in the first weeks of life, and neurodevelopmental
disabilities when the children were 18 to 24 months’ corrected age.
This prospective cohort study was conducted in the
Ministry of Health Zekai Tahir Burak Maternity Teaching Hospital. In a
previous study , infants with a gestational age of less than 33 week
were enrolled between March 2008 and February 2009, and 200 infants were
available at 1st week of
life. The data were available for 196, 182, and 172 infants at postnatal
week of life, respectively (Fig. 1). Perinatal data of the
mother and the baby was also collected from the records. In the current
study, we restricted our analysis to 116 newborns weighing
≤1500 g and born
≤32 weeks of
gestation. A comprehensive neurodevelopmental assessment was performed
on the surviving and available 56 infants at 18 to 24 months’ corrected
Fig. 1 Study flow diagram
Neurodevelopmental evaluation: During the study
period, the Bayley Scales of Infant Development–Second Edition (BSID-II)
was administered by experienced testers . The BSID-II gives two main
scales: the mental developmental index (MDI) and the psychomotor
developmental index (PDI). MDI and PDI scores of 100±15 represent the
mean±1SD. Cerebral palsy was defined as a nonprogressive central nervous
system disorder characterized by abnormal muscle tone in at least one
extremity and abnormal control of movement and posture that interfered
with or prevented age-appropriate motor activity. Children with
moderate-to-severe cerebral palsy were nonambulatory or required an
assistive device for ambulation. Bilateral severe hearing loss was
defined as permanent hearing loss that required amplification in both
ears. Bilateral blindness was defined as the absence of functional
vision in either eye. Neurodevelopmental impairment was defined as any
of the following: moderate-to-severe cerebral palsy, an MDI or PDI of
less than 70, bilateral deafness, or bilateral blindness. Profound
impairment was defined as an MDI of less than 50 or a Gross Motor
Function Classification System level of 4 or 5. Minimal impairment was
defined as a MDI or PDI scores between 70-84 and not having
moderate-to-severe cerebral palsy, bilateral severe hearing loss, or
We had defined THOP as T4 <25th
percentile, with a normal TSH value at 1st
week of life. However, we evaluated the effects of both low T4 and fT4
values on neurodevelopmental outcome at 18-24 months’ corrected age .
Statistical analysis: SPSS 17.0 (SPSS, Chicago
ILL, USA) was used for statistical analysis. Differences for continuous
variables between two groups were analyzed by Student t or
Mann-Whitney U tests according to spread of data. Chi-square test
analyses were used to evaluate group differences in the binary
(present/absent) medical morbidities. Pearson or Spearman correlation
tests were used to analyze relation between thyroid hormone values and
BSID-II scores. Logistic regression model was developed to evaluate the
independent risk for unimpairment or minimally impairment, and
neurodevelopment impairment. Test variables included the following
perinatal variables: gestational age, gender, intracranial hemorrhage
II, respiratory distress syndrome (RDS), patent ductus arteriosus (PDA),
sepsis, necrotizing enterocolitis (NEC), bronchopulmonary dysplasia
(BPD), retinopathy of prematurity (ROP) and also included T4 <25th
percentile (<68 nmol/L) at 1st
and 3rd -4th
week of life, and fT4<25th
percentile (<13.4 pmol/L) at 1st
and 3-4th week of life. A
two-tailed significance level of 0.05 was applied to all analyses.
The study was approved by the Local Ethics Committee
on Medical Research Ethics of The Ministry of Health Zekai Tahir Burak
Maternity Teaching Hospital, Turkey. Parents of all subjects provided
signed informed consent.
56 infants (53.6% male) were evaluated at 18 to 24
months’ corrected age. The mean birthweight was 1198±194 g and
gestational age 29.4±1.7 week. The mean age at follow up was 21.0±1.9
months. Perinatal data were similar in children who could not be
evaluated at 18 to 24 months’ corrected age. Demographic and clinical
characteristics of the study subjects according to thyroid hormone
percentiles at 1st week of
life are summarized in Table I.
TABLE I Relation of Neurodevelopmental Status at 18-24 Months Corrected Age With Thyroid Hormone
Percentiles at 1st Week of Life
|| P value
||≥ 25th percentile
||< 25th percentile
||≥ 25th percentile
|MDI, point, mean ± SD
||79.9 ± 4.9
||70 ± 20.7
||76.6 ± 19.2
|PDI, point, mean ± SD
||92.2 ± 6.4
||85.6 ± 18.9
||87.2 ± 19.2
|Minimal impairment, n (%)
|Neurodevelopmental Impairment, n (%)
|Neurodevelopmental evaluation done by Bayley
Scales of Infant Development – Second Edition (BSID II); MDI:
Mental Developmental Index; PDI: Psychromotor Developmental
Index; T4:Thyroxine levels; fT4: free T4.
The mean MDI scores were similar between the infants
with and without THOP at 1st
week of life (79.9±14.9 vs 70±20.7, respectively) (P=0.36).
There was also no difference between these groups according to PDI
scores (92.2±16.4 vs 85.6±18.9, respectively) (P=0.17).
MDI scores were <70 in 22 (39.2%) and PDI scores were <70 in 10 (17.8%)
of the study infants. There was disabling cerebral palsy in 7 (12.5%)
infants. Neurodevelopmental impairment was present in 28 (50.0%)
infants. There was no infant with bilateral hearing loss or blindness;
profound impairment was also not observed. Minimal impairment was
present in 10 (17.9%) of the subjects. Neurodevelopmental evaluation at
18 to 24 months’ corrected age and its relation with thyroid hormone
percentiles at 1st week of
life are summarized in Table II.
TABLE II Relation of Clinical and Laboratory Variables With Neurodevelopmental Impairment
|| Minimal impairment
||OR (CI 95%)
||OR (CI 95%)
|Gestational age, wk
|Intracranial hemorrhage ³grade II
|Respiratory distress syndrome
|Patent ductus arteriosus
|Retinopathy of prematurity
|T4<25th percentile at 3rd-4th
|FT4<25th percentile at 3rd-4th
There were no correlations between T4
values at 1st week and MDI
and PDI scores at 18 to 24 months’ corrected age (P=0.17 and P=0.17).
MDI and PDI scores were not correlated with gestational age, (P=0.28,
and P=0.78), but positively correlated with each other (P=0.001).
In logistic regression model, after adjustment for selected clinical
variables, low T4 or low fT4
values at 3rd-4th
week of life were not associated with an increased risk of minimal or
neurodevelopmental impairment (Table III).
Although we did not assess attention deficit, there
were no association between BSID-II scores and thyroid hormone levels or
This cohort study sought to investigate whether THOP
experienced in the first weeks of life in VLBW infants would result in
neurodevelopmental deficits at 18 to 24 months’ corrected age. As it was
proposed that developing brain depended on circulating fT4
for local intracellular T3
generation and fT4 levels
should be addressed when considering the effects of thyroid hormone on
brain development (8). Therefore we also presented data on fT4 levels in
addition to T4.
Although the importance of thyroid hormones to
perinatal neural development is well defined, their relation to the
developmental sequelae of preterm birth remains unclear [9,10]. It was
suggested that low plasma thyroxine concentrations could well be a
preventable factor contributing to the developmental delay in VLBW
infants . In this study, at 18 to 24 months’ corrected age, we did
not find any association between THOP and neurodevelopmental disability.
Our findings are not consistent with some studies [2,12] in which
preterm infants with very low thyroid hormone concentrations had
significantly poorer motor and cognitive outcomes than other infants.
Previous studies have shown that infants born <30
weeks gestation are at a high risk of neurocognitive impairment [13,14].
Simic, et al.  showed that it was not gestational age alone,
but gestational age plus low thyroid hormone, and presence of certain
medical morbidities that contributed to a significant proportion of
variance in these measures. They compared infants born 24 to 35 weeks
gestation with healthy full-term infants at 3 months corrected age, and
found that preterm infants scored significantly below full-term on
BSID-II MDI and PDI, selective, sustained and total attention scales.
Williams, et al.  also demonstrated an association between
reduced thyroid hormone levels and the presence of PDA and infection in
preterm infants. In this study, MDI and PDI scores were not correlated
with gestational age in VLBW preterms. Among evaluated infants,
according to 1st week
thyroid hormone percentile groups, gestational age was lower in infants
In a recent follow-up study of a cohort of infants
born at ≤34
week gestation in Scotland from 1999 to 2001,
the authors measured scores obtained from the
McCarthy scale adjusted for
26 influences of neurodevelopment including parental
intellect, home environment, breast or formula
fed, growth retardation, and
use of postnatal drugs .
Infants with hypothyroxinemia defined as T4
levels 10th percentile on
days 7, 14, or 28 corrected for gestational age scored significantly
lower than euthyroid infants. After adjustment
for confounders of neurodevelopment,
scored significantly lower than euthyroid infants on the general
cognitive and verbal scales.
The strength of our study includes combining
assessment of thyroid hormone levels at two time points with a detailed
neurodevelopmental evaluation. Nevertheless, there are several
limitations of this study. Firstly, the overall sample size was
relatively small, involving only 56 VLBW infants. Many parents could not
come to the hospital because of family reasons and soicoeconomical
problems. Secondly, T4
supplemen-tation was not given to the study infants in the 1st
weeks of life. Therefore, we could not evaluate the effect of thyroid
hormone supplementation on neuro-developmental outcome.
Reduced levels of thyroid hormone with a normal TSH
values in the first weeks of life in VLBW infants are not associated
with neurodevelopmental impairment at 18 to 24 months’ corrected age.
Further studies are needed to define other factors affecting
Acknowledgement: We thank Developmental
Pediatrics Unit of Zekai Tahir Burak Maternity Teaching Hospital for
carrying out the Bayley assessments.
Contributors: All authors designed, supervised
and analyzed the study, and prepared the manuscript.
Funding: None; Competing interests: None
What is Already Known?
• Thyroid hormones affect brain growth and
are essential to normal behavioral and intellectual development.
What This Study Adds?
• Transient hypothyroxinemia without TSH
elevation may not be an important cause of problems in
neurologic and mental development detected at 18 to 24 months’
1. Karna P. Developmental follow-up of very low
birthweight premature infants with low free thyroxine. Am J Perinatol.
2. Bayley N. Bayley Scales of Infant Development II.
San Antonio, TX: Psychological Corp;1993.
3. Reuss ML, Paneth N, Pinto-Martin JA, Lorenz JM,
Susser M. The relation of transient hypothyroxinemia in preterm infants
to neurologic development at two years of age. N Engl J Med.
4. van Wassenaer AG, Kok JH, de Vijlder JJ, Briët JM,
Smit BJ, Tamminga P, et al. Effects of thyroxine supplementation
on neurologic development in infants born at less than 30 weeks’
gestation. N Engl J Med. 1997;336:21-6.
5. Briët JM, van Wassenaer AG, Dekker FW, de Vijlder
JJ, van Baar A, Kok JH. Neonatal thyroxine supplementation in very
preterm children: developmental outcome evaluated at early school age.
6. Dilli D, Oguz SS, Andiran N, Dilmen U,
Büyükkagnici U. Serum thyroid hormone levels in preterm infants born
before 33 weeks of gestation and association of transient
hypothyroxinemia with postnatal characteristics. J Pediatr Endocrinol
Metab. 2010; 23:899-912.
7. Hintz SR, Kendrick DE, Wilson-Costello DE, Das A,
Bell EF, Vohr BR, et al. NICHD Neonatal Research Network.
Early-childhood neurodevelopmental outcomes are not improving for
infants born at <25 weeks’ gestational age. Pediatrics.
8. Morreale de Escobar G, Obregón MJ, Escobar del Rey
F. Is neuropsychological development related to maternal hypothyroidism
or to maternal hypothyroxinemia? J Clin Endocrinol Metab.
9. Uhrmann S, Marks KH, Maisels MJ, Kulin HE, Kaplan
M, Utiger R. Frequency of transient hypothyroxinaemia in low birthweight
infants: potential pitfall for neonatal screening programmes. Arch Dis
10. Porterfield SP, Hendrich CE. The role of thyroid
hormones in prenatal and neonatal neurological development – current
perspectives. Endocr Rev. 1993;14:94-106.
11. Veen S, Ens-Dokkum MH, Schreuder AM,
Verloove-Vanhorick SP, Brand R, Ruys JH. Impairments, disabilities, and
handicaps of very preterm and very-low-birthweight infants at five years
of age. Lancet. 1991;338:33-6.
12. Meijer WJ, Verloove-Vanhorick SP, Brand R, van
den Brande JL. Transient hypothyroxinaemia associated with developmental
delay in very preterm infants. Arch Dis Child. 1992;67:944-7.
13. van Wassenaer AG, Briët JM, van Baar A, Smit BJ,
Tamminga P, de Vijlder JJ, et al. Free thyroxine levels during
the first weeks of life and neurodevelopmental outcome until the age of
5 years in very preterm infants. Pediatrics. 2002;110:534-9.
14. Anderson PJ, Doyle LW. Cognitive and educational
deficits in children born extremely preterm. Semin Perinatol.
15. Simic N, Asztalos EV, Rovet J. Impact of neonatal
thyroid hormone insufficiency and medical morbidity on infant
neurodevelopment and attention following preterm birth. Thyroid.
16. Williams FL, Ogston SA, van Toor H, Visser TJ,
Hume R. Serum thyroid hormones in preterm infants: associations with
postnatal illnesses and drug usage. J Clin Endocrinol Metab.
17. Delahunty C, Falconer S, Hume R, Jackson L,
Midgley P, Mirfield M, et al. Scottish Preterm Thyroid Group.
Levels of neonatal thyroid hormone in preterm infants and
neurodevelopmental outcome at 5 1/2 years: millennium cohort study. Clin
Endocrinol Metab. 2010;95:4898-908.