Rapid advances in neonatal care have led to a
dramatic surge in survival of the very- and extremely-premature infants.
This is, however,tempered by a concomitant increase in the incidence of
severe neuromorbidity in the survivors, including cognitive delay,
cerebral palsy, hearing loss, blindness, mental retardation, and
epilepsy. Thus, an emerging challenge in newborn care is to translate
the gains in survival achieved into gains in healthy survival, without
the current high frequency of neurodevelopmental impairments.
Transient hypothyroxinemia of prematurity (THOP),
though a self-limiting condition seen in newborns <34 weeks of
gestation, assumes significance since its occurrence coincides with the
period critical for brain development. In newborns with congenital
hypothyroidism, a delay of even two weeks in instituting thyroxine (T4)
replacement has an adverse impact on the intelligence quotient (IQ).
Motor and cognitive deficits are seen in these children despite early
thyroxine replacement. Thus, even transiently low thyroxine levels are
considered to be a potent risk factor for adverse neurodevelopmental
outcome in preterm infants and have been the subject of many elegant
long-term studies [1-5]. All cohorts have documented a measure of
abnormal mental development in children with THOP. Concern about the
possible consequences of hypothyroidism has also led to several trials
of treatment with thyroxine.
In the article published in this issue of the
journal, Dilli, et al.  have reported the neurodevelopmental
status of preterm infants born at ≤32 weeks gestation with a birth weight of
≤1500 g, at 18-24
months corrected age. They have reported similar mean mental and
psychomotor developmental index scores in infants with and without THOP.
After adjustment for gestational age and multiple perinatal and neonatal
variables, they found that THOP is not associated with an increased risk
of disabling cerebral palsy or reduction in MDI or PDI scores. Based on
these observations, the authors have concluded that THOP may not be an
important cause of neurological problems or delayed mental development
in these infants. The results of this study; however, need to be
interpreted with caution. Firstly, the very cut-off value of T4
used by the authors to define THOP is much higher that the usually
accepted definitions. Though there is no consensus on the level of
thyroxine for defining hypothyroxinemia in the preterm, definitions used
by other authors have been 2 , 2.6 , or 3 [3,4] SDS below the mean
thyroxine level seen on newborn screening of the reference population.
Other authors have used an absolute cut-off level like 40 nmol/L  or
6 mcg/dL for T4 . All
these are significantly lower that the 25th
centile used by the authors of the present study, which corresponds to
more than -1 SDS (-1 SDS = 15.9 percentile). Thus many infants
classified as hypothyroxinemic in this study do not meet the criterion
used by others. In fact, for preterm infants more appropriate levels for
comparison of thyroxine values are T4/free
T4 levels in cord blood
corrected for an equivalent gestational age had the infant remained in
utero . Using a cut-off of 10th
centile of cord T4 corrected
for gestational age, Delahunty, et al.,  found that 20% of all
infants born at <34 weeks gestation were hypothyroxinemic, with only 10%
being between 31-34 weeks, and rest more premature. Reuss, et al.
 found a 15% incidence of
THOP in infants born at <33 weeks gestation using a cut-off of -2.6 SD.
Dilli, et al. , on the other hand, have classified nearly 29%
of their subjects to have THOP using a higher cut-off value. It is
therefore not surprising that results reported in this study are better
than those reported by other authors. Another important factor that
could have a bearing on the results of this study is the small number of
subjects, despite using a higher cut-off criterion. This is evident by
the wide range of 95% CIs reported for the odds ratios. Absence of a
significant association of adverse neurodevelopmental outcome with not
only THOP, but also with other important medical morbidities is also a
likely reflection of the small sample size.
Thus, concerns about long-term effects of THOP
remain, and establishing the role of thyroxine supplementation,
especially to extremely premature infants or those with documented
hypothyroxinemia remains a research priority.
Competing interests: None; Funding:
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