S t e ro i d s a n d In j u r y t o t h e

Developing Brain
Net Harm or Net Benefit?

a, b
Shadi N. Malaeb, MD *, Barbara S. Stonestreet, MD

KEYWORDS
 Brain injury  Cerebral palsy  Controversy  Development  Glucocorticoids
 Infant  Outcomes  Premature infant

KEY POINTS
 Steroid effects on the brain mimic an inverse-U–shaped curve, because deleterious ef-
fects result from both glucocorticoid insufficiency and/or excess glucocorticoid tissue
exposure.
 The effects of glucocorticoids on the developing central nervous system are a function of
both the stage of development and duration of exposure.
 The beneficial effects of glucocorticoids are optimal when given to sick premature infants
in a critical window before 32 weeks’ postmenstrual age.
 Glucocorticoids have net beneficial effects when given shortly after the first week of life to
premature infants at high risk for severe chronic lung disease.
 The challenge is to identify infants at high risk for bronchopulmonary dysplasia (BPD) early
in their course and to administer a dose that attenuates the progression of BPD.

INTRODUCTION

Glucocorticoids, commonly referred to as steroids, are widely used in neonatal-

perinatal medicine. They are prescribed to pregnant women at risk for premature birth,
and sometimes to infants with significant airway or lung disease, refractory hypoten-
sion, or septic shock. Preterm infants are at high risk for brain injury, morbidity, and
mortality. Steroids are thought to attenuate some of these risks.1,2 However, steroid
regimens used vary widely, from a single short course of antenatal steroids given to
the mother early in the third trimester, to repeated or prolonged courses of steroids

a
Department of Pediatrics, St. Christopher’s Hospital for Children, Drexel University College of
Medicine, 245 North 15th Street, New College Building, Room 7410, Mail Stop 1029, Philadelphia,
PA 19102, USA; b Department of Pediatrics, Women & Infants Hospital of Rhode Island, The
Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI 02905, USA
* Corresponding author.
E-mail address: [email protected]

Clin Perinatol 41 (2014) 191–208

http://dx.doi.org/10.1016/j.clp.2013.09.006 perinatology.theclinics.com
0095-5108/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
192 Malaeb & Stonestreet

given over weeks to the premature infant. As more data have accumulated regarding
the long-term outcomes of infants exposed to steroids, concern has been increasing
about neurodevelopmental impairment after exposure to steroids in certain settings.
This article summarizes some of the experimental and clinical findings, and explores
the complex nature of the relationship between steroids and brain injury, with a focus
on the premature brain.

OVERVIEW OF BRAIN DEVELOPMENT

Normal brain development requires a well-orchestrated ontogeny of cellular prolifer-

ation, migration, differentiation, angiogenesis, synaptogenesis, myelination, and
apoptosis.3 Neurogenesis remains active well into adulthood in the subventricular
zone and hippocampal dentate gyrus.4 Neuronal progenitor cells migrate from their
sites of origin and become mature integrated neurons. Early-stage neuronal progen-
itor cells maintain an active cell cycle and can either divide or die via apoptosis. As
progenitor cells mature, they exit the cell cycle and commit to differentiate.5 A large
number of migrating neurons populate a transient subcortical layer known as the
subplate zone. Other neurons enter the cortical plate and integrate into neuronal cir-
cuits. Synaptic connectivity is essential to maintain survival for cortical neurons.
Most subplate neurons involute through apoptosis toward late gestation and in in-
fancy. Oligodendrocyte progenitor cells follow neuronal tracts and mature to form
myelin. Cerebral vascular endothelial cells, pericytes, and astrocytes promote angio-
genesis to form neurovascular units that will support neurons and form the blood–
brain barrier.6,7 The ontogeny of the developing nervous system is under tight regu-
lation by intrinsic, paracrine, endocrine, and external modulators. Perturbations in
any of these factors could result in long-term consequences that affect the structure
and function of the developing central nervous system (CNS).3

NEUROTROPHIC EFFECTS OF STEROIDS

Steroids are essential for maturation and survival of several cell types in the CNS.
Adrenalectomy in adult rats results in massive cell death in the dentate gyrus and
decreases the number of dendritic branch points.8,9 Corticosterone replacement
after adrenalectomy reverses these processes.9 Corticosterone administration ac-
celerates neuronal migration of cerebellar granule cells and enhances cerebellar
Purkinje cell growth in the offspring. This treatment also accelerates the emergence
of perinucleolar rosettes forming accessory nucleolar bodies of Cajal.10 The emer-
gence of this structure signifies increases in transcriptional activity present during
the late stages of neuronal maturation.11 Corticosterone application early in devel-
opment also accelerates the differentiation of membrane electrical properties in
embryonic chick neurons.12 In addition, glucocorticoids activate brain-derived neu-
rotrophic factor receptor (Trk) tyrosine kinases and induce the expression of thyroid
hormone–dependent transcription factor Kruppel-like factor 9 gene.13–15 These
events are implicated in the plasticity of hippocampal neurons and postnatal de-
velopment.13–15 Short-term corticosterone exposure increases synaptogenesis in
the developing cortex. Reducing endogenous glucocorticoid activity decreases
spine process turnover, and corticosterone reverses this process.16,17 Therefore,
corticosterone seems to accelerate neuronal maturation. Glucocorticoids also
induce oligodendrocyte precursor differentiation18 and increase oligodendroglial
marker expression during myelinogenesis.19–21 In summary, steroids exert impor-
tant trophic effects on cell survival, differentiation, maturation, and synaptogenesis
(Box 1).
 Steroids and Brain Injury 193

Box 1
Neurotrophic effects of glucocorticoids

 Enhance survival of early-stage neuroblasts

 Accelerate neuronal cell migration and maturation
 Facilitate synaptogenesis, pruning, and plasticity
 Induce oligodendrocyte precursor differentiation

NEUROPROTECTION BY STEROIDS

Steroids protect the brain acutely from neuroinflammatory damage.22 Glucocorticoids

also attenuate excitotoxic white matter injury by protecting oligodendrocytes from
alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)–induced excito-
toxicity through upregulating erythropoietin signaling.23 Prenatal glucocorticoid
administration enhances pericyte coverage, inhibits angiogenesis, and results in trim-
ming of the germinal matrix neovasculature, thereby reducing the propensity for
germinal matrix hemorrhage.24

ANTENATAL STEROIDS ACCELERATE ONTOGENIC CHANGES IN THE DEVELOPING CNS

Ontogenic decreases in blood–brain barrier permeability have been reported in ovine

fetuses from 60% of gestation up to maturity in the adult.25 Treatment of pregnant
ewes with a glucocorticoid regimen similar to those used in the clinical setting
was associated with decreases in blood–brain barrier permeability in fetal sheep at
60% and 80% of gestation.26,27 Ontogenic decreases in brain water content have
also been reported in fetal sheep between 60% and 90% of gestation.28 Maternal
treatment with dexamethasone resulted in decreases in regional brain water content
in fetal sheep at 60% of gestation.28 At the molecular level, Na1/K1-ATPase pump
a1-subunit expression is lower at 60% than at 90% of gestation, and dexamethasone
treatment of pregnant ewes at 60% of gestation increased the expression of this pro-
tein.29 Therefore, antenatal steroid treatment of pregnant ewes using regimens similar
to those used in the clinical setting accelerates some aspects of brain development in
the immature sheep fetus.

DEVELOPMENTAL STAGE AT TIME OF EXPOSURE AND DURATION OF EXPOSURE

MODULATE STEROID EFFECTS ON THE CNS

The effects of glucocorticoids on the developing CNS are a function of both the stage
of development at the time of exposure and the duration of exposure. The develop-
mental stage reflects the systemic physiology and the nature of different cellular pop-
ulations within the brain, both of which are affected by postmenstrual and chronologic
ages. For example, cerebral water content in the fetal brain decreased after treatment
of pregnant ewes with dexamethasone at 60% of gestation, but not at 80% or 90%.28
Similarly, aquaporin protein expression was decreased in lambs and adult sheep
brains after dexamethasone treatment, but not in the fetal brain after exposure of
the ewes to dexamethasone.30 Maternal treatment with glucocorticoids was also
associated with decreases in blood–brain barrier permeability in fetal sheep at 60%
and 80% of gestation, but not at 90%, and not in lambs after postnatal glucocorti-
coids.27,31 Dexamethasone also reduced the affinity of the N-methyl-D-aspartate
(NMDA) receptor to its ligand in lambs, but not in the fetal or adult sheep brain.32
194 Malaeb & Stonestreet

Maternal exposure to dexamethasone at 70% of gestation, but not at 90%, resulted in

significant decreases in total and nonneuronal apoptosis in the fetal cerebral cortex.33
The effect of the duration of exposure to glucocorticoids was examined by
comparing fetuses of ewes exposed to a single course of dexamethasone or placebo
injections every 12 hours for 48 hours between 104 and 107 days of gestation versus
fetuses of ewes receiving the same treatment once a week for 5 weeks between
76 and 107 days of gestation. Full-term gestation in sheep is 147 days. Maternal dexa-
methasone treatment at 70% of gestation was associated with decreases in water
content in the fetal brain after multiple, but not after a single course of steroids.34 Like-
wise, multiple courses of steroids, but not single courses, also increased myosin iso-
form expression in the fetal carotid arteries.35 In contrast, apoptosis in the fetal
cerebral cortex was decreased at 70% of gestation after exposure to single, but not
after multiple courses of dexamethasone.33 Even more concerning is the finding
that Na1/K1-ATPase enzyme activity, as an index of neuronal membrane integrity in
the fetal brain, was reduced after multiple courses of dexamethasone, but not after
single courses.36 Perhaps the most intriguing aspect of modulation of the steroid
effects on the brain with reference to the duration of exposure stems from observa-
tions suggesting that chronic glucocorticoid exposure facilitates paradoxic proinflam-
matory responses to injury in the brain,22,37 which is in direct contrast to classical
anti-inflammatory responses expected after acute glucocorticoid exposure.38
Taken together, these findings suggest that the developmental stage at the time of
exposure and the duration of exposure each have important contributions to the ulti-
mate glucocorticoid effects on the developing CNS. Comprehension of the pharmaco-
dynamics of steroids in the developing CNS is also necessary to understand the
multifaceted effects of glucocorticoids on the brain, and these are addressed in the
following sections (Box 2).

Box 2
Determinants of the effect of glucocorticoids on the developing CNS

 Stage of brain development at the time of exposure

 Duration of exposure
 Pharmacodynamic properties of the steroid
 Dosage used

PHARMACODYNAMICS OF NATURAL VERSUS SYNTHETIC GLUCOCORTICOIDS IN THE

BRAIN

Glucocorticoids are synthesized by the fetal adrenal cortex, mostly by maternal pro-
gesterone that crosses the placenta.39 The natural glucocorticoid in humans is
cortisol and in rodents is corticosterone. Human fetal serum cortisol levels decrease
from 8 ng/mL at 15 weeks to 4 ng/mL by 20 weeks. In the absence of labor and under
the regulation of placental corticotropin-releasing hormone and fetal adrenocortico-
trophin, a steep increase occurs in cortisol levels: to 20 ng/mL by 36 weeks of gesta-
tion and 45 ng/mL near term.40 Glucocorticoids are approximately 75% bound to
corticosteroid-binding globulins in the circulation. Both natural and synthetic steroids
readily penetrate the blood–brain barrier to reach the parenchyma. However, syn-
thetic steroids such as dexamethasone are actively pumped out of the brain by the
multidrug resistance protein 1A (mrd1A) P-glycoprotein, which is highly expressed
 Steroids and Brain Injury 195

at the blood–brain barrier.41 Hence, dexamethasone is retained less efficiently than

natural glucocorticoids in brain regions possessing a functional blood–brain barrier,
and more efficiently when the blood–brain barrier is injured. Dexamethasone is also
effectively retained in regions devoid of a blood–brain barrier, such as the circumven-
tricular organs, where glucocorticoids suppress the hypothalamic-pituitary-adrenal
(HPA) axis. Once in the parenchyma, steroids diffuse readily across cell membranes.
Natural and related steroids such as hydrocortisone are inactivated by an intracel-
lular glucocorticoid-metabolizing enzyme, 11b-hydroxysteroid dehydrogenase type
2 (HSD2),42 which converts them into inactive 11-keto derivatives.42 HSD2 significantly
attenuates the actions of natural glucocorticoids on the brain.43,44 HSD2 expression
decreases with advancing gestation from fetal to newborn, and up to adulthood,
concomitantly as endogenous glucocorticoid production increases. Consequently, a
larger portion of endogenous cortisol or exogenous hydrocortisone that enters the
brain at more mature postmenstrual ages will remain active to bind more receptors
and augment their biologic actions.45,46 On the other hand, synthetic glucocorticoids
are resistant to inactivation by HSD2. The same property, which prevents their
placental deactivation, exaggerates their biologic actions in the brain, even though
very little is retained because of elimination by the multiple drug resistance mrd1A pro-
tein expressed at the blood–brain barrier.

GLUCOCORTICOID RECEPTORS IN THE BRAIN

Two types of glucocorticoid receptors are present in the CNS.47,48 The type 1 receptor
is a mineralocorticoid receptor (MR), which has high affinity for cortisol and corticoste-
rone, with aldosterone and hydrocortisone as agonists, and spironolactone as an
antagonist. It binds poorly to dexamethasone and betamethasone. The type 2 recep-
tor is a glucocorticoid receptor (GR), which has a high affinity for dexamethasone but
10 times lower affinity for corticosterone, with methylprednisolone and betametha-
sone as agonists, and mifepristone (RU 38486) as an antagonist. MRs are unique in
that they are highly expressed exclusively in the hippocampus and limbic brain re-
gions, whereas GRs are expressed ubiquitously across all brain regions. The main re-
ceptor activated at physiologic cortisol levels is the MR in the hippocampus, with little
to no GR activation. The MR nuclear response elements are thought to mediate neuro-
trophism.47,49 At higher cortisol levels, GRs throughout the brain become activated
along with the activated MRs in the limbic brain. In contrast, when pure GR agonists
such as dexamethasone or betamethasone are administered, GR activation primarily
occurs throughout the CNS with little or no MR activation. Prolonged dexamethasone
administration suppresses the HPA axis and depletes systemic and local cortisol
levels within brain tissue. Hence, prolonged administration of pure GR agonists, as
opposed to mixed MR/GR agonists, paradoxically attenuates MR activation in the hip-
pocampus and other brain structures responsible for learning and memory.22,37,47
Local cortisol depletion, along with limited the ability of dexamethasone to be retained
because of MDR1A P-glycoprotein elimination, leads to a paradoxically enhanced
microglial reactivity and sustained neuroinflammation after brain injury with prolonged
exposure to the supposedly “anti-inflammatory” synthetic glucocorticoid. This pro-
cess results in neurodegeneration, demyelination, synaptic dysfunction, and a loss
of cortisol-mediated positive trophism. Administration of a GR antagonist, such as
RU 38486 or corticosterone replacement, counteracts the cortisol-depleting effects
of prolonged dexamethasone exposure on the hippocampus.50,51 Hence, the balance
between MR/GR stimulation is a major determinant of the effects of glucocorticoids on
the brain.
196 Malaeb & Stonestreet

HAZARDS OF GR OCCUPANCY

Accentuated and prolonged GR occupancy underlies an array of injurious effects of

glucocorticoids on the brain. Stimulation of cultured embryonic rat neural stem cells
with dexamethasone or with high concentrations of corticosterone, but not low con-
centrations, reduces cell proliferation.52 These effects were inhibited by specific GR,
but not MR blockade. Chronic corticosterone administration reduces neurogenesis
in the adult rat dental gyrus.50 This inhibitory effect can be reversed by treatment
with the GR antagonist mifepristone.50,53,54 Proliferation of cells in the dentate gyrus
also was reduced in fetuses of pregnant monkeys receiving dexamethasone both
early and late in gestation.55 Premature human neonates whose mothers were treated
with synthetic glucocorticoids and died shortly after delivery exhibited lower hippo-
campal neuronal densities than neonates who were not exposed to glucocorticoids.56
These findings suggest that accentuated GR stimulation mediates glucocorticoid-
related cell cycle inhibition in the developing brain.52 Excess maternal glucocorticoid
administration also retarded migration of postmitotic neurons in the fetal cerebral cor-
tex in rats.57 Offspring of pregnant rats exposed to high-dose maternal corticosterone
showed long-lasting neurobehavioral impairment.58 Betamethasone administration to
pregnant sheep reduced the number of oligodendrocytes and axons in the corpus cal-
losum, and delayed myelination in the fetal brain.59–61 The inhibitory effects of syn-
thetic steroids on myelination in the sheep were dependent on the stage of
development, and decreased with advancing gestational age.60,62 Repeated adminis-
tration of dexamethasone during the first week of life to rat pups resulted in prominent
apoptosis, particularly in proliferating cells, and depleted the hippocampal neural pre-
cursor cell pool, resulting in sustained reductions in the volume of the dentate gyrus.63
Therefore, accentuated GR occupancy could have adverse effect on neurons and glia
in the developing brain (Box 3).

Box 3
Effects of MR and GR occupancy on the developing brain

 MR occupancy mediates neurotrophism by steroids.

 Accentuated or prolonged GR occupancy underlies an array of injurious effects of
glucocorticoids on the brain.

GLUCOCORTICOIDS AND RECOVERY AFTER BRAIN INJURY

Cerebral hypoxia-ischemia and reperfusion induces waves of free-radical injury, exci-

totoxicity, neuroinflammation, and delayed cell death.64 Induction of neural stem cell
proliferation often occurs after brain injury and during the subsequent recovery and
remodeling phases.4,65 Survival of early progenitor cells requires trophism by MR oc-
cupancy, whereas their proliferation is hindered by heightened GR occupancy. In fact,
maternal pretreatment with antenatal dexamethasone did not attenuate ischemic
brain injury in the ovine fetus.66 The effects of glucocorticoids on hypoxic-ischemic
brain injury were elegantly summarized in a recent review by Bennet and colleagues.67

UNIFYING HYPOTHESIS

The emerging picture of glucocorticoid effects on the developing brain derived from
mounting experimental evidence is that of an inverse-U–shaped curve, because
 Steroids and Brain Injury 197

both insufficient glucocorticoid exposure and accentuated or prolonged exposure

exert an array of deleterious effects mediated by either low MR occupancy or by
high GR occupancy (Fig. 1). Conditions associated with excessive GR relative to
MR occupancy include: (1) administration of high doses or prolonged courses of hy-
drocortisone; (2) administration of dexamethasone at an advanced postmenstrual
age, when endogenous cortisol production had increased and HSD2 protection
decreased, which could exaggerate an already heightened GR occupancy by cortisol;
(3) administration of prolonged courses of dexamethasone that can suppress the HPA
axis and deplete local brain tissue cortisol, thereby reducing MR occupancy; (4)
administration of dexamethasone during conditions that impair elimination by the
multidrug resistance pump at the blood-brain barrier, such as during cerebral hypox-
ia/ischemia; and (5) early administration of a pure GR agonist dexamethasone when
endogenous cortisol levels for effective MR occupancy are deficient. The consequent
overall effects of steroids on the brain are dependent on the developmental stage,
duration of exposure, and the presence or absence of other disease processes in
the brain and/or body before or after the time of exposure. The effect of steroids on
the brain is also dependent on the dose and type of glucocorticoid used. This concept
has been proposed by many investigators, including De Kloet and colleagues,47 Dia-
mond and colleagues,68 McEwen,69 and Sousa and Almeida.49 These concepts could
provide a basis for clarifying the disparate effects of glucocorticoids observed in clin-
ical trials, and guiding future clinical strategies to maximize the beneficial effects of
steroids while minimizing the detrimental effects of glucocorticoid therapy.

Fig. 1. Inverse-U–shaped hypothesis as a guide for risk/benefit analysis of glucocorticoid

administration in experimental and clinical scenarios. Note that during the first few days
of life, although a degree of MR occupancy by hydrocortisone may be neurotrophic in pre-
mature infants, systemic side effects of very early administration of hydrocortisone
outweigh the potential benefits. See text for details.

CLINICAL PERSPECTIVES
Antenatal Steroids
The ability of a single antenatal course of glucocorticoids to accelerate fetal lung matu-
ration has been extensively documented by clinical trials.70,71 The 2 most frequently
used glucocorticoids are betamethasone and dexamethasone. Betamethasone has
slightly greater beneficial pulmonary effects compared with dexamethasone.72 Ante-
natal administration of glucocorticoids reduces the incidence and severity of respira-
tory distress syndrome and decreases the incidence of intraventricular hemorrhage,
necrotizing enterocolitis, and risk of mortality.70,71 Antenatal treatment with glucocor-
ticoids is also associated with a trend toward a lower incidence of cerebral palsy and
198 Malaeb & Stonestreet

less neurodevelopmental delays in childhood (relative risk, 0.49; 95% CI, 0.24–1.00).70
However, when the same course of antenatal steroids was repeated weekly, head
circumference at birth was smaller compared with that of infants whose mothers had
received a placebo.73 Children exposed to multiple courses of betamethasone tended
to have higher incidences of cerebral palsy74 and attention problems in later child-
hood.75 In addition, multiple courses of antenatal dexamethasone were associated
with an increased risk of periventricular leukomalacia and neurodevelopmental impair-
ment at 2 years of age.76 These findings suggest that glucocorticoids can have bene-
ficial effects when given over short intervals, whereas prolonged GR occupancy
potentially results in CNS injury and impaired development.

POSTNATAL STEROIDS: EARLY ADMINISTRATION

In several clinical trials, both hydrocortisone and dexamethasone have been adminis-
tered to premature infants early in the first week of life,1 based on the assumption by
some investigators that sick premature infants could have relative adrenal insuffi-
ciency.77–79 The existence of this condition remains controversial, and appreciation
of the net benefit from this approach has been guarded at best. These studies have
suggested occasional improvement and better neurologic outcomes after hydrocorti-
sone treatment than after dexamethasone treatment, especially in infants exposed to
chorioamnionitis.80–82 However, glucocorticoid administration during the first week of
life has also been associated with an increased incidence of intraventricular hemor-
rhage and gastrointestinal perforation.80,83 Infants treated with dexamethasone early
after birth also have been reported to have smaller head circumferences and lower
weights at 36 weeks’ postmenstrual age; higher incidences of cerebral palsy; and
developmental delays later in life compared with placebo-treated infants.84,85 In
contrast, the risk for cerebral palsy was not increased in premature infants treated
with hydrocortisone in the first week of life.1,86 Nonetheless, these complications
outweigh the neurotrophic benefits of MR occupancy by hydrocortisone, and have
limited the use of glucocorticoids shortly after birth.

POSTNATAL STEROIDS: ADMINISTRATION AFTER THE FIRST WEEK OF LIFE

Glucocorticoids have also been used after the first week of life in several regimens to
treat sick premature infants with pulmonary insufficiency and/or hypotensive
shock.2,87,88 Delayed administration of dexamethasone is associated with glycosuria,
hypertension, and gastrointestinal bleeding, but not with perforation.2 Moreover, an
increased incidence of severe retinopathy of prematurity and abnormal neurologic ex-
aminations is seen on follow-up, warranting further scrutiny.2,88

POSTNATAL STEROIDS: MODERATELY EARLY VERSUS DELAYED ADMINISTRATION

A systematic review of clinical trials further compared developmental outcomes of

premature infants after receiving dexamethasone courses beyond the first week of
life, and focused on the timing of treatment onset.89 Studies were stratified into trials
with a moderately early onset between 1 and 2 weeks of life or delayed onset of treat-
ment beginning after 3 weeks of life. In the trials with the moderately early treatment
onset, an inverse relationship was found between the dose of dexamethasone and
risk of the combined outcome of mortality and/or cerebral palsy, and of a motor devel-
opmental index less than –2 standard deviations below the mean. The negative
regression correlation coefficient suggests a decreased risk for neurodevelopmental
impairment with dexamethasone if treatment is started moderately early (ie, between
 Steroids and Brain Injury 199

7 and 14 days of life). However, an increased risk for hypertension, hyperglycemia,

gastrointestinal bleeding, hypertrophic cardiomyopathy, and infection was seen.87
In contrast, delaying the initiation of therapy beyond 21 days of age was associated
with a trend toward incremental increases in the risk of the combined outcome of mor-
tality and/or cerebral palsy with increasing dexamethasone doses. Similarly, a recent
large multicenter prospective cohort study of very premature infants born with birth
weights less than 1000 g receiving dexamethasone starting late at 5.1  2.1 weeks
of life showed that an increase of each 1-mg/kg dose was associated with a 40% in-
crease in the risk for cerebral palsy and a 2-point reduction on the mental develop-
mental index. Treatment after 33 weeks’ postmenstrual age was associated with
even greater harm.90
In summary, these studies support the contention that the age at onset of treatment
could influence the effects of steroids on the developing CNS in infants. The relation-
ships among the dose and duration of treatment with systemic steroids and their ef-
fects on neurologic outcomes, potential beneficial effects on pulmonary outcomes,
and/or systemic side effects are complex and need further investigation in large-
scale randomized controlled clinical trials.89

POSTNATAL STEROIDS: PROLONGED TREATMENT

In one controlled trial, prolonged courses of dexamethasone were given to preterm in-
fants born at birth weights of 1250 g or less and gestational ages of 30 weeks or less
who were dependent on mechanical ventilation and oxygen at 2 weeks of age.91 The
starting dosage of 0.5 mg/kg/day was tapered over 42 days. Follow-up at 15 months
of age showed normal neurologic examinations and Bayley developmental index
scores greater than 83 in 7 of the 9 infants after dexamethasone, but in only 2 of 5 after
placebo treatment, favoring beneficial effects for dexamethasone (P<.05). However,
another randomized controlled trial administered a 42-day tapering course of dexa-
methasone to more mature preterm infants born with birth weights of 1500 g or less
beginning between 15 and 25 days of age, with an initial dosage of 0.25 mg/kg/
day.92 Follow-up at 12 months of age found more abnormal neurologic findings and in-
stances of cerebral palsy (25% vs 7%; adjusted odds ratio, 5.3; 95% CI, 1.3–21.4) in the
dexamethasone-treated infants compared with those treated with placebo. Taken
together, these findings suggest that the critical developmental window for optimal
benefits from postnatal treatment with glucocorticoids in sick premature infants is
before 32 weeks’ postmenstrual age and beginning within the second week of life
(Box 4).90–92

Box 4
Critical developmental window for optimal benefits from postnatal glucocorticoid
administration

 Less than 32 weeks’ postmenstrual age in sick premature infants

 Beginning in the second week of life

HYDROCORTISONE AND THE PREMATURE INFANT

Hydrocortisone is often prescribed for sick premature infants after the first week of life
as an alternative to dexamethasone and betamethasone, with the goal of improving
pulmonary outcomes and preserving neurologic function. Hydrocortisone therapy
200 Malaeb & Stonestreet

has been reported to improve severe capillary leak lung syndrome in ventilated pre-
term infants.93 Extremely low-birth-weight infants receiving hydrocortisone after the
second week of life had similar extubation rates and improved somatic growth
compared with those receiving betamethasone.94 Preservation of regional brain vol-
umes at term-equivalent age was observed after treating ventilator-dependent infants
with low-dose hydrocortisone for a week, suggesting the potential safety of hydrocor-
tisone.95–97 The effectiveness of low-dose hydrocortisone in suppressing the evolution
of bronchopulmonary dysplasia (BPD) and the safety of higher doses must be
confirmed in clinical trials.86

EFFECT MODIFICATION BY RISK OF BPD

Premature infants requiring continued respiratory support beyond 36 weeks’ post-

menstrual age are at high risk for developing cerebral palsy.98 Glucocorticoids can
reduce the risk of chronic lung disease. Therefore, it is reasonable to assume that
steroid therapy can have indirect benefits for infants at high risk for developing
BPD, by mitigating their risk of brain damage via attenuating the severity of their
chronic lung disease. Occasionally, the benefits of reducing the severity of BPD
could outweigh the risks of neurologic impairment resulting from the untoward ef-
fects of steroid therapy. On the other hand, the use of steroids in infants at low
risk for developing BPD could unnecessarily expose infants to the adverse side
effects of steroids. A meta-regression analysis conducted by Doyle and col-
leagues99 found that for every 10% increase in the rate of chronic lung disease, a
2.3% decrease occurred in the risk of cerebral palsy (95% CI, 0.3%–4.3%) as a
result of steroid therapy. A significant steroid-related benefit was observed only
when the incidence of chronic lung disease exceeded 65%. Therefore, the challenge
is to identify infants at high risk for BPD early in their course and administer a dose of
glucocorticoid that can attenuate the progression of BPD (Box 5).

Box 5
Clinical challenges

 Identify infants at high risk for BPD early in their course

 Administer a dose of glucocorticoid that impacts BPD progression while at the same time
minimizes glucocorticoid-related brain injury

PREDICTING RISK OF BPD

A recent large prospective cohort study of newborns of extremely low gestational age
found 3 distinct patterns of respiratory disease in the first 2 postnatal weeks (see
Fig. 2).100 The incidence of chronic lung disease was 67% in infants with early and
persistent pulmonary dysfunction. Other studies have observed that a low cortisol
level in the first week of life predicts a slightly higher probability of chronic lung dis-
ease or death at 36 weeks’ postmenstrual age, particularly in infants with elevated
illness scores.101–103 Hydrocortisone treatment increased survival without BPD in
infants with basal serum cortisol values less than a median of 140 nmol/L.104 When
considering these findings together, one could speculate that postnatal glucocorti-
coid therapy may be beneficial when administered shortly after the first week of life
to premature infants with early and persistent pulmonary dysfunction (Box 6).
 Steroids and Brain Injury 201

Fig. 2. Speculative predictive analysis for risk of death or cerebral palsy after postnatal gluco-
corticoid therapy according to pattern of respiratory disease in premature infants. Patterns of
respiratory disease during the first 2 postnatal weeks among newborns with extremely low
gestational age show that the incidence of chronic lung disease was 67% in infants with early
and persistent pulmonary dysfunction. Doyle et al99 observed significant steroid-related
benefit only when the incidence of chronic lung disease exceeded 65%. These data suggest
that the risk of cerebral palsy may be reduced if postnatal glucocorticoids are given to sick
premature infants with early and persistent pulmonary dysfunction whose risk for developing
BPD may exceed 65%, particularly if they also have low basal levels of cortisol. This predictive
analysis must be validated in randomized clinical trials. CLD, chronic lung disease; EPPD, early
and persistent pulmonary dysfuntion; FiO2, fraction of inspired oxygen; PD, pulmonary
dysfunction. (Adapted from Laughon M, Allred EN, Bose C, et al. Patterns of respiratory dis-
ease during the first 2 postnatal weeks in extremely premature infants. Pediatrics
2009;123(4):1124–31; with permission.)

Box 6
Most beneficial time frame for administration of postnatal glucocorticoid therapy

 Administered shortly after first week of life to premature infants born before 30 weeks of
gestation
 To infants with signs of early and persistent pulmonary dysfunction, particularly if clinical or
serologic signs of relative adrenal insufficiency are evident

SUMMARY

The relationship between glucocorticoids and neurodevelopmental impairment is com-

plex. A thorough understanding of the underlying physiology of the positive and nega-
tive effects of glucocorticoids on the developing brain based on the concept of the
inverse-U–shaped hypothesis is essential when deciding whether to treat a sick prema-
ture infant with glucocorticoids. Clearly, steroids play a major role in supporting brain
development. Most probably, some infants could benefit from antenatal and postnatal
administration of steroids. Ideally, the decision to treat should ensure the maximum
respiratory benefit from steroids at the lowest neurologic risk, and at the same time
avoid any serious systemic complications. This article suggests the following: (1) gluco-
corticoid therapy should be restricted to premature infants born before 30 weeks’
gestation in whom findings suggest a high risk (>65%) for developing BPD, (2) the first
course of postnatal steroids should be considered at approximately day 14 of life, and
202 Malaeb & Stonestreet

(3) the nature and dose of steroids used should be consistent with doses shown in clin-
ical studies to be effective in improving survival and pulmonary outcomes. This
approach must be validated in controlled trials. Of particular interest are 2 ongoing
multicenter randomized placebo-controlled trials105,106 investigating the use of moder-
ately early hydrocortisone to prevent BPD in preterm infants. The results of these
studies may provide a better understanding of the efficacy and safety of this approach.

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