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An
Pediatr
(Barc).
2014;
81(6)
:374---382
www.analesdepediatria.org
ORIGINAL
ARTICLE
Antenatal
corticosteroid
therapy
and
late
preterm
infant
morbidity
and
mortality

I.M.
Gázquez
Serrano
a
,
,
A.
Arroyos
Plana
a
,
O.
Díaz
Morales
b
,
C.
Herráiz
Perea
a
,
A.
Holgueras
Bragado
a
a
Servicio
de
Neonatología,
Hospital
Virgen
de
la
Salud,
Toledo,
Spain
b
Servicio
de
Pediatría,
Hospital
de
Antequera,
Antequera,
Málaga,
Spain
Received
6
November
2013;
accepted
27
January
2014
Available
online
29
October
2014
KEYWORDS
Late
preterm
infants;
Antenatal
corticosteroids;
Premature
Abstract
Introduction:
Late
preterm
infants
(34---36
weeks
gestation)
have
a
morbidity
rate
significantly
higher
than
those
born
at
term.
However,
few
interventions
have
been
undertaken
to
reduce
this
increased
morbidity
and
mortality.
Antenatal
corticosteroid
administration
could
be
an
effective
preventive
measure.
Objective:
The
aim
of
this
study
was
to
describe
the
morbidity
associated
with
late
prematurity
in
our
institution,
and
determine
if
there
are
differences
between
those
who
received
antenatal
corticosteroids.
Patients
and
methods:
A
prospective
observational
study
was
conducted
on
late
preterm
infants
born
in
a
tertiary
hospital
from
October
2011
until
September
2012.
Two
groups
were
formed
according
to
whether
or
not
they
had
received
antenatal
steroids.
The
rates
of
morbidity
and
mortality
for
each
of
the
groups
were
analysed
and
compared.
Results:
There
was
a
total
of
4127
live
newborns
during
the
study
period,
of
whom
3795
were
term
and
332
were
preterm
(the
overall
prematurity
rate
was
8.04%).
There
were
247
late
preterm
deliveries,
representing
6%
of
live
born
infants,
and
74.4%
of
all
premature
infants.
Of
late
preterm
infants,
63.2%
were
admitted
to
the
Neonatal
Unit
and
29.6%
had
received
antenatal
steroids.
The
incidence
of
admission
to
the
Neonatal
Unit
and
Neonatal
Intensive
Care,
transient
tachypnea,
need
for
respiratory
support
in
the
form
of
continuous
positive
pressure
airway
and
oxygen
therapy,
incidence
of
hypoglycemia,
feeding
difficulty,
and
jaundice
requiring
phototherapy
were
significantly
higher
(
P
<
0.05)
in
the
late
preterm
group
that
did
not
receive
antenatal
steroids.

Please
cite
this
article
as:
Gázquez
Serrano
IM,
Arroyos
Plana
A,
Díaz
Morales
O,
Herráiz
Perea
C,
Holgueras
Bragado
A.
Corticoterapia
prenatal
y
morbimortalidad
del
prematuro
tardío:
estudio
prospectivo.
An
Pediatr
(Barc).
2014;81:374---382
Corresponding
author.
E-mail
addresses:
isabelgazquezserrano@gmail.com
,
nebito82@hotmail.com
(I.M.
Gázquez
Serrano).
2341-2879/©
2013
Asociación
Espa
̃
nola
de
Pediatría.
Published
by
Elsevier
España,
S.L.U.
All
rights
reserved.
Prenatal
corticosteroids
late
preterm
375
Conclusions:
Our
finding
suggests
that
the
administration
of
antenatal
corticosteroids
to
patients
at
risk
of
34---36
weeks
delivery
could
significantly
reduce
the
cost
and
acute
morbidity
associated
with
late
preterm
birth.
©
2013
Asociación
Espa
̃
nola
de
Pediatría.
Published
by
Elsevier
España,
S.L.U.
All
rights
reserved.
PALABRAS
CLAVE
Prematuro
tardío;
Corticoides
prenatales;
Prematuro
Corticoterapia
prenatal
y
morbimortalidad
del
prematuro
tardío:
estudio
prospectivo
Resumen
Introducción:
Se
define
al
prematuro
tardío
como
al
recién
nacido
de
34
a
36
semanas
de
gestación.
Este
grupo
presenta
mayor
riesgo
de
complicaciones
que
los
nacidos
a
término.
Sin
embargo,
son
pocas
las
intervenciones
que
se
realizan
para
reducir
esta
mayor
morbimortalidad.
La
administración
prenatal
de
corticoides
podría
ser
una
medida
preventiva
eficaz.
Objetivo:
Describir
la
morbilidad
asociada
a
la
prematuridad
tardía
y
determinar
si
existen
diferencias
en
los
prematuros
tardíos
que
recibieron
corticoides
prenatales.
Pacientes
y
métodos:
Estudio
observacional
prospectivo
de
los
prematuros
tardíos
nacidos
en
un
hospital
terciario
desde
octubre
de
2011
a
octubre
de
2012.
Se
clasificaron
en
2
grupos,
según
hubiesen
o
no
recibido
corticoides
prenatales,
y
se
compararon
las
tasas
de
morbimortalidad
entre
los
2
grupos.
Resultados:
La
tasa
de
prematuridad
global
fue
del
8,04%,
de
los
cuales
el
74,4%
(n
=
247)
fueron
prematuros
tardíos.
Precisaron
ingreso
el
63,2%
(n
=
156),
suponiendo
el
17%
del
total
de
ingre-
sados
y
el
20,6%
de
los
ingresos
en
la
unidad
de
cuidados
intensivos
neonatales.
Recibieron
corticoides
prenatales
el
29,6%
(n
=
73).
La
incidencia
de
ingreso
en
neonatología
y
cuidados
intensivos
neonatales,
la
presencia
de
taquipnea
transitoria,
hipoglucemia,
intolerancia
diges-
tiva,
ictericia,
asistencia
respiratoria
en
forma
de
presión
positiva
continua
en
la
vía
respiratoria
nasal,
oxigenoterapia,
sueroterapia
y
fototerapia
fueron
significativamente
superiores
(p
<
0,05)
en
el
grupo
que
no
recibió
corticoides
prenatales.
Conclusiones:
La
morbilidad
de
los
prematuros
tardíos
de
nuestro
medio
es
significativamente
inferior
en
los
que
recibieron
corticoides
prenatales,
por
lo
que
podría
ser
útil
prolongar
su
administración
más
allá
de
las
34
semanas.
©
2013
Asociación
Espa
̃
nola
de
Pediatría.
Publicado
por
Elsevier
España,
S.L.U.
Todos
los
dere-
chos
reservados.
Introduction
Preterm
birth
is
the
primary
cause
of
perinatal
morbidity
and
mortality
in
developed
countries.
In
the
past
few
years,
the
rate
of
preterm
births
and
the
rate
of
survival
of
pre-
mature
babies
have
both
increased.
Late
preterm
infants
(LPIs),
born
between
34
+0
and
36
+6
weeks
of
gestational
age,
constitute
the
most
frequent
group
(amounting
to
75%
of
total
premature
births)
and
the
one
that
has
increased
most
significantly.
1 --- 3
Overall,
they
are
at
lesser
risk
than
babies
born
at
lower
gestational
ages,
but
recent
studies
have
shown
that
due
to
their
immaturity,
their
morbidity
and
mortality
is
greater
than
those
of
babies
born
at
term.
4 --- 6
Although
they
are
a
high-risk
group,
few
routine
interven-
tions
have
been
established
to
reduce
their
higher
rates
of
morbidity
and
mortality.
One
of
the
interventions
that
has
most
contributed
to
improve
the
prognosis
of
preterm
NBs
is
the
antenatal
administration
of
corticosteroids.
7
However,
the
foetal
lung
is
considered
to
be
mature
at
34
weeks
of
gestation,
at
which
point
administration
of
corticosteroids
is
no
longer
indicated.
As
a
result,
few
studies
have
evaluated
the
effect
of
antenatal
corticosteroids
in
the
late-preterm
population.
8---10
We
set
the
following
goals
to
assess
the
effect
of
ante-
natal
corticosteroids
in
LPIs
in
our
centre:
to
describe
the
morbidity
associated
to
late
prematurity
and
to
determine
if
there
are
differences
in
the
infants
exposed
to
antena-
tal
corticosteroids,
as
well
as
the
associated
prevalence,
aetiology,
and
obstetric
conditions.
Population
and
methods
We
conducted
a
prospective
observational
study
the
main
purpose
of
which
was
assessing
whether
antenatal
admin-
istration
of
corticosteroids
in
LPIs
had
an
effect
on
their
outcomes.
We
selected
all
patients
born
alive
at
34
+0
to
36
+6
weeks
of
gestation
in
our
hospital
in
a
one-year
period
(Octo-
ber
1st,
2011
to
September
30th,
2012).
Gestational
age
was
determined
by
obstetric
criteria,
based
on
the
first
day
of
the
last
menstrual
period
or
on
the
ultrasound
scan
of
the
first
half
of
the
pregnancy.
We
calculated
the
overall
rate
of
preterm
birth
and
the
rate
of
late
preterm
birth
in
the
period
under
study.
We
classified
the
selected
NBs
in
2
groups:
(a)
those
that
had
been
exposed
to
antenatal
corticosteroids
(prenatal
administration
of
one
or
two
12-mg
doses
of
betamethasone
376
I.M.
Gázquez
Serrano
et
al.
24
h
apart)
and
(b)
those
that
had
not
been
exposed.
We
col-
lected
this
information
by
reviewing
medical
records.
The
exclusion
criteria
were
death
before
or
during
birth,
pres-
ence
of
major
congenital
malformations,
and
presence
of
a
confirmed
or
suspected
genetic
or
metabolic
disorder.
We
analysed
the
following
variables
for
the
entire
sam-
ple
and
for
each
of
the
groups:
admission
to
the
neonatal
unit
and/or
the
neonatal
intensive
care
unit
(NICU);
length
of
hospital
stay;
mortality;
relevant
complications
dur-
ing
pregnancy;
mode
of
delivery;
immediate
resuscitation
and
perinatal
period;
respiratory
disorders
(hyaline
mem-
brane
disease,
transient
tachypnoea
of
the
newborn
[TTNB],
meconium
aspiration
syndrome,
and
pneumothorax)
requir-
ing
respiratory
support
in
the
form
of
nasal
continuous
positive
airway
pressure
(CPAP)
or
mechanical
ventilation
and
administration
of
surfactant.
We
also
analysed
the
inci-
dence
of
jaundice
requiring
phototherapy,
hypoglycaemia,
digestive
intolerance,
need
for
fluid
therapy
and
parenteral
nutrition,
and
sepsis
confirmed
by
clinical
examination
and
blood
culture.
Finally,
we
analysed
all
these
parameters
for
each
ges-
tational
age
and
birth
weight
group
to
determine
whether
there
were
any
significant
differences
between
infants
that
had
been
exposed
to
corticosteroids
and
infants
that
had
not.
We
compared
the
frequency
of
each
of
the
parameters
under
study
in
each
of
the
2
groups.
The
statistical
analysis
was
performed
using
SPSS
version
18.0
for
Windows.
Quanti-
tative
variables
are
expressed
as
mean
±
standard
deviation
and
maximums
and
minimums.
Qualitative
variables
are
expressed
as
absolute
frequencies
(
n
)
and
relative
frequen-
cies
(%).
We
compared
the
groups
using
the
chi
squared
test
on
contingency
tables
and
Fisher’s
exact
test
when
any
of
the
expected
frequencies
was
below
5.
Results
In
the
period
under
study
(October
1,
2011
to
September
30,
2012)
there
were
4127
NBs
born
alive,
of
whom
3795
were
born
at
term
and
332
born
preterm,
with
an
over-
all
annual
preterm
birth
rate
of
8.04%.
Among
the
latter
group,
247
were
late
preterm,
amounting
to
6%
of
live
births
and
74.4%
of
all
preterm
births.
Of
all
late
preterm
NBs,
63.2%
were
admitted
to
the
neonatal
unit
(17%
of
all
admit-
ted
NBs),
for
hospital
stays
lasting
a
mean
of
14.70
+
11.4
(3---90)
days.
Among
them,
28.2%
required
admission
to
the
NICU
for
a
mean
length
of
hospital
stay
of
7.11
±
10.4
(1---70)
days,
amounting
to
20.6%
of
the
total
number
of
NBs
admit-
ted
to
the
NICU.
None
of
the
PTIs
died
during
the
neonatal
period.
Table
1
describes
the
general
characteristics,
the
obstet-
ric
and
perinatal
history,
and
the
overall
morbidity
in
the
neonatal
period
of
the
PTIs
included
in
this
study.
The
PTIs
in
the
study
(
n
=
247)
were
divided
into
2
groups
according
to
the
antenatal
administration
of
corti-
costeroids.
Antenatal
corticosteroids
were
administered
in
29.6%
(
n
=
73),
and
98.6%
(
n
=
72)
of
them
received
a
com-
plete
course
(2
doses
of
betamethasone
24
h
apart
before
delivery).
The
mean
gestational
age
at
administration
was
31
+6
±
2
+2
(25---34
+1
)
weeks.
The
mean
time
elapsed
from
administration
to
delivery
was
27.2
±
15.4
(0---65)
days.
In
Table
1
General
characteristics,
obstetric
and
perinatal
history,
and
overall
morbidity
of
late
preterm
infants.
Total
Absolute
frequency
(
n
=
247)
Percentage
(%)
General
characteristics
Gestational
age
34
weeks
49
19.8
35
weeks
65
26.3
36
weeks
133
53.8
Birth
weight
2543(
±
496)
g
Male
sex
112
45.3
Gestation
Maternal
age
35
years
105
42.5
HBP
38
15.4
Diabetes
28
11.3
Primiparous
115
46.6
Twin
gestation
59
23.9
IVF
19
7.7
IUGR
54
21.9
TPL
52
21.1
PROM
111
44.9
Delivery
Onset
Spontaneous
144
58.3
Induced
103
41.7
Mode
Vaginal
165
67.6
Caesarean
82
32.4
Requiring
resuscitation
30
12.1
Overall
morbidity
TTNB
50
20.2
HMD
13
5.3
Pneumothorax
1
0.4
PHT
3
1.2
Oxygen
therapy
16
6.5
CPAP
46
18.6
CMV
17
6.9
Surfactant
therapy
14
5.7
Hypoglycaemia
19
7.7
Digestive
intolerance
106
42.9
Fluid
therapy
95
38.5
NEC
1
0.4
Parenteral
nutrition
36
14.6
Phototherapy
125
50.6
Confirmed
sepsis
8
3.2
CMV:
conventional
mechanical
ventilation;
CPAP:
continuous
positive
airway
pressure;
HBP:
high
blood
pressure;
HMD:
hyaline
membrane
disease;
IVF:
in
vitro
fertilisation;
IUGR:
intrauterine
growth
restriction;
NEC:
necrotising
enterocolitis;
PHT:
pul-
monary
hypertension;
PROM:
premature
rupture
of
membranes;
TPL:
threatened
preterm
labour;
TTNB:
transient
tachypnoea
of
the
newborn.
the
12.5%
women
that
received
a
full
course,
delivery
occurred
within
7
days
from
its
administration.
We
found
no
significant
differences
between
the
groups
in
most
of
their
perinatal
histories
and
outcomes
(
Table
2
).
Prenatal
corticosteroids
late
preterm
377
Table
2
Comparative
study
of
perinatal
history
and
outcomes
according
to
administration
of
antenatal
corticosteroids
in
late
preterm
infants.
Variable
Group
A:
received
corticosteroids,
n
(%)
Group
B:
no
corticosteroids,
n
(%)
P
a
Total
73
174
HBP
10
(14)
28
(16)
0.634
Diabetes
3
(4)
25
(14)
0.02
Primiparous
41
(56)
74
(43)
0.074
Number
of
foetuses
Single
55
(75)
133
(76)
0.854
Twin
18
(25)
41
(24)
IVF
9
(12)
0
(6)
0.077
IUGR
12
(16)
42
(24)
0.182
TFD
10
(14)
44
(25)
0.044
PROM
31
(42)
80
(46)
0.613
TPL
27
(37)
25
(14)
<0.0001
Onset
of
labour
Spontaneous
35
(48)
108
(62)
0.052
Induced
37
(52)
66
(38)
Mode
of
delivery
Vaginal
50
(68)
116
(67)
0.413
Caesarean
22
(30)
58
(33)
0.105
Resuscitation
5
(7)
25
(14)
HBP:
high
blood
pressure;
IUGR:
intrauterine
growth
restriction;
IVF:
in
vitro
fertilisation;
PROM:
premature
rupture
of
membranes;
TFD:
threatened
foetal
distress;
TPL:
threatened
preterm
labour.
a
Statistical
significance
levels
obtained
using
the
chi
squared
test
on
contingency
tables.
Table
3
Comparative
study
of
morbidity
and
mortality
and
required
interventions
in
late
preterm
infants
by
antenatal
corti-
costeroid
administration.
Variable
Group
A:
exposed
to
corticosteroids,
n
(%)
Group
B:
no
corticosteroids,
n
(%)
P
a
Total
73
174
Morbidity
TTNB
2
(2.7)
48
(28)
<0.0001
HMD
1
(1.4)
12
(7)
0.116
PHT
0
3
(2)
0.557
Pneumothorax
0
1
(0.6)
1.000
Hypoglycaemia
0
19
(11)
0.003
Digestive
intolerance
14
(19)
92
(53)
<0.0001
NEC
0
1
(0.6)
1.000
Jaundice
14
(19)
111
(64)
<0.0001
Required
intervention
28
(38)
128
(74)
<0.0001
Neonatal
unit
admission
6
(8)
38
(22)
0.01
NICU
admission
0
16
(9)
0.004
Oxygen
therapy
4
(5)
42
(24)
0.001
CPAP
2
(3)
15
(9)
0.096
CMV
1
(1)
13
(8)
0.071
Surfactant
10
(14)
85
(49)
<0.0001
Fluid
therapy
6
(8)
30
(17)
0.067
Parenteral
nutrition
14
(19)
111
(64)
<0.0001
CMV:
conventional
mechanical
ventilation;
CPAP:
continuous
positive
airway
pressure;
HMD:
hyaline
membrane
disease;
NEC:
necrotising
enterocolitis;
NICU:
neonatal
intensive
care
unit;
PHT:
pulmonary
hypertension;
TTNB:
transient
tachypnoea
of
the
newborn.
a
Statistical
significance
levels
obtained
using
the
chi
squared
test
on
contingency
tables.
378
I.M.
Gázquez
Serrano
et
al.
Table
4
Comparative
study
of
morbidity
and
required
interventions
by
gestational
age.
Age
34---34
+6
weeks
35---35
+6
weeks
36---36
+6
weeks
Total
49
65
133
Variable
n
(%)
n
(%)
n
(%)
P
a
Morbidity
TTNB
20
(41)
7
(26)
13
(10)
<0.0001
HMD
10
(20)
2
(3)
1
(0.8)
<0.0001
PHT
1
(2)
1
(1.5)
1
(0.8)
0.751
Hypoglycaemia
5
(10)
5
(8)
9
(7)
0.742
Digestive
intolerance
44
(90)
35
(64)
27
(21)
<0.0001
Jaundice
44
(90)
46
(71)
35
(26)
<0.0001
Sepsis
3
(6)
3
(5)
2
(2)
0.226
Required
intervention
Oxygen
therapy
8
(16)
6
(9)
2
(1.5)
0.001
CPAP
25
(51)
14
(22)
7
(5)
<0.0001
CMV
11
(22)
3
(5)
3
(2)
<0.0001
Surfactant
11
(22)
2
(3)
1
(0.8)
<0.0001
Fluid
therapy
35
(71)
34
(62)
26
(20)
<0.0001
Parenteral
nutrition
20
(41)
8
(12)
8
(6)
<0.0001
CMV:
conventional
mechanical
ventilation;
CPAP:
continuous
positive
airway
pressure;
HMD:
hyaline
membrane
disease;
PHT:
pulmonary
hypertension;
TTNB:
transient
tachypnoea
of
the
newborn.
a
Statistical
significance
levels
obtained
using
the
chi
squared
test
on
contingency
tables.
The
results
of
the
comparative
study
of
both
groups
for
neonatal
morbidity
and
required
interventions
are
shown
in
Table
3
.
The
rate
of
admission
to
the
neonatal
unit
was
signifi-
cantly
higher
(74%
vs
38%)
in
LPIs
that
had
not
been
exposed
to
antenatal
corticosteroids.
The
rate
of
NICU
admission
was
also
significantly
higher
in
this
group
(22%
vs
8%).
All
the
diseases
associated
to
late
preterm
birth
were
less
fre-
quent
in
the
group
exposed
to
antenatal
corticosteroids,
and
the
differences
were
significant
for
TTNB,
the
presence
of
hypoglycaemia,
digestive
intolerance,
and
jaundice
requir-
ing
phototherapy.
The
need
for
respiratory
support
by
means
of
oxygen
therapy
and
nasal
CPAP
and
the
need
for
fluid
ther-
apy
and
parenteral
nutrition
were
also
significantly
higher
in
the
groups
of
LPI
that
were
not
exposed
to
antenatal
corticosteroids.
The
comparative
analysis
by
gestational
age
showed
sig-
nificant
differences
on
a
week
to
week
basis,
with
a
clear
decrease
of
morbidity
as
gestational
age
increased
(
Table
4
).
All
the
pathologies
and
needs
for
interventions
were
less
frequent
in
neonates
who
had
been
exposed
to
antenatal
corticosteroids
at
any
gestational
age,
and
once
again
the
decrease
was
significant
for
TTNB,
digestive
intolerance,
jaundice
requiring
phototherapy,
fluid
therapy,
and
nasal
CPAP
(
Table
5
).
Lastly,
when
we
analysed
the
data
by
birth
weight
we
confirmed
that
there
is
increased
risk
at
lower
birth
weights,
especially
of
feeding
difficulties
and
the
need
for
fluid
ther-
apy
and
parenteral
nutrition,
which
were
significantly
more
frequent
(
Table
6
).
Morbidity
was
higher
in
all
LPIs
that
were
not
exposed
to
antenatal
corticosteroids,
although
the
differences
were
only
significant
for
infants
with
birth
weights
below
2000
g,
which
constituted
the
largest
group
(
Table
7
).
Discussion
Consistent
with
the
reviewed
literature,
the
overall
rate
of
preterm
birth
in
our
hospital
during
the
period
under
study
was
8.04%.
Within
this
group,
74.4%
of
patients
belonged
to
the
LP
subgroup.
These
data
are
in
agreement
with
those
published
in
most
developed
countries,
where
increasing
trends
have
also
been
reported.
1,11,12
Some
of
the
underlying
causes
are
the
older
age
of
primiparous
mothers,
multi-
ple
pregnancies,
assisted
reproductive
technology,
and
an
increase
in
the
indications
for
induced
labour
and
scheduled
caesarean
delivery.
In
this
study,
42.5%
of
the
mothers
were
35
or
more
years
old;
46.6%
were
primiparous
mothers;
7.7%
of
pregnancies
were
the
result
of
assisted
reproduction;
24.1%
of
pregnancies
were
multiple
gestations;
and
41.7%
of
deliveries
were
induced
due
to
maternal
or
foetal
indica-
tions,
figures
that
are
consistent
with
those
reported
in
the
literature.
13---17
These
results
make
sense
considering
that
all
these
factors
are
interrelated.
Advanced
maternal
age
is
associated
with
a
higher
risk
of
obstetric
complications,
which
are
often
indications
for
the
early
termination
of
pregnancy,
and
is
more
frequently
associated
with
the
need
for
assisted
reproduction
technologies,
which
increase
the
probability
of
a
multiple
pregnancy.
In
our
study,
63.2%
of
LPIs
were
admitted
to
the
neona-
tal
unit,
and
28.2%
required
intensive
care,
giving
rise
to
a
considerable
number
of
hospital
admissions,
as
this
group
is
the
largest
among
preterm
infants.
They
account
for
17%
of
the
total
NB
admissions,
and
for
20.6%
of
NICU
admissions.
The
general
criteria
for
admission
in
our
hospital
are
having
a
gestational
age
of
34
weeks
or
less;
or
having
a
gestational
age
of
more
than
34
weeks
and
a
birth
weight
below
2300
g
or
suffering
from
any
disease
that
requires
monitoring
and/or
treatment.
Prenatal
corticosteroids
late
preterm
379
Table
5
Comparative
study
of
morbidity
and
required
interventions
by
gestational
age
and
administration
of
antenatal
corticosteroids.
Variable
TTNB,
n
(%)
HMD,
n
(%)
Hypoglycaemia,
n
(%)
Digestive
intolerance,
n
(%)
Jaundice,
n
(%)
Sepsis,
n
(%)
34---34
+6
weeks
(n
=
49)
CS
(
n
=
14)
1
(7)
1
(7)
0
10
(71)
10
(71)
0
No
CS
(
n
=
35)
19
(54)
9
(26)
5
(14)
34
(97)
34
(97)
3
(9)
P
a
0.002
0.244
0.303
0.019
0.019
0.548
35---35
+6
weeks
(n
=
65)
CS
(
n
=
17)
1
(6)
0
0
3
(18)
4
(23)
1
(6)
No
CS
(
n
=
48)
16
(33)
2
(4)
5
(10)
32
(67)
42
(88)
2
(4)
P
a
0.029
1.000
0.315
<0.0001
<0.0001
1.000
36---36
+6
weeks
(n
=
133)
CS
(
n
=
42)
0
1
(1)
0
1
(2)
0
0
No
CS
(
n
=
91)
13
(14)
1
(1)
9
(10)
26
(29)
35
(39)
2
(2)
P
a
0.009
1.000
0.057
<0.0001
<0.0001
1.000
Variable
Oxygen,
n
(%)
CPAP,
n
(%)
CMV,
n
(%)
Surfactant,
n
(%)
Fluid
therapy,
n
(%)
Parenteral
nutrition,
n
(%)
34---34
+6
weeks
(n
=
49)
CS
(
n
=
14)
0
2
(14)
1
(7)
1
(7)
7
(50)
5
(36)
No
CS
(
n
=
35)
8
(23)
23
(66)
10
(29)
10
(29)
28
(80)
15
(43)
P
a
0.085
0.001
0.143
0.143
0.08
0.646
35---35
+6
weeks
(n
=
65)
CS
(
n
=
17)
0
1
(6)
0
0
2
(12)
1
(6)
No
CS
(
n
=
48)
6
(13)
13
(27)
2
(4)
2
(4)
32
(67)
7
(15)
P
a
0.327
0.009
1.000
1.000
<0.0001
0.669
36---36
+6
weeks
(n
=
133)
CS
(
n
=
42)
0
1
(2)
0
0
2
(12)
0
No
CS
(
n
=
91)
2
(2)
6
(7)
1
(1)
1
(1)
32
(67)
8
(9)
P
a
1.000
0.43
1.000
1.000
<0.0001
0.056
CMV:
conventional
mechanical
ventilation;
CPAP:
continuous
positive
airway
pressure;
CS:
corticosteroids;
HMD:
hyaline
membrane
disease;
TTNB:
transient
tachypnoea
of
the
newborn.
a
Statistical
significance
levels
obtained
using
the
chi
squared
test
on
contingency
tables.
In
the
past
decade,
numerous
studies
have
confirmed
that
these
infants,
due
to
their
immaturity,
have
higher
morbid-
ity
than
full-term
infants.
The
LPIs
in
our
study
had
rates
of
respiratory
disorders,
jaundice,
hypoglycaemia,
feed-
ing
difficulties,
and
sepsis
similar
to
those
reported
in
the
literature.
4,18---22
The
evidence
shows
that
pharmacological
induction
of
foetal
lung
maturity
by
means
of
corticosteroids
is
the
intervention
that
most
improves
the
prognosis
of
preterm
NBs.
Consequently,
Spanish
and
American
associations
of
obstetricians
and
gynaecologists
recommend
antenatal
administration
of
corticosteroids
to
pregnant
women
at
risk
of
preterm
delivery
between
24
and
34
weeks
of
gestation
in
order
to
reduce
the
incidence
of
acute
respiratory
dis-
tress
syndrome,
intraventricular
haemorrhage,
necrotising
enterocolitis,
and/or
neonatal
death.
23
In
our
study,
29.6%
(73)
of
LPIs
had
received
antena-
tal
corticosteroids,
and
admission
rates
were
significantly
higher
in
those
who
had
not
received
them,
both
for
the
neonatal
unit
(74%
vs
38%)
and
the
NICU
(22%
vs
8%).
Respiratory
disorders
are
among
the
most
frequent
mor-
bidities
associated
to
late
preterm
birth.
In
this
study,
27.1%
of
LPIs
developed
respiratory
complications,
with
TTNB
being
the
most
frequent
diagnosis
(20.2%).
This
high
incidence
could
be
due
to
abnormalities
or
delays
in
the
clearance
of
foetal
lung
fluid
after
birth.
Various
studies
pro-
pose
that
sodium
transport
across
the
alveolar
epithelium
is
the
main
mechanism
involved
in
foetal
lung
fluid
clearance,
one
which
develops
as
gestational
age
increases
and
that
becomes
particularly
important
in
the
last
weeks
of
preg-
nancy.
In
LPIs,
the
lower
number
as
well
as
the
immaturity
of
sodium
transport
mechanisms
may
be
involved
in
the
patho-
genesis
of
TTNB.
24
The
incidence
of
TTNB
in
the
no-steroids
group
of
LPIs
was
significantly
higher
than
in
the
steroid-
exposed
group:
28%
versus
2.7%
(
P
<
0
.
0001).
This
difference
may
be
explained
by
the
fact
that
only
corticosteroids
seem
to
stimulate
the
synthesis
and
activity
of
sodium
channels
in
the
alveolar
epithelium,
contributing
to
the
reabsorption
of
lung
fluid.
There
is
evidence
that
a
surge
of
endogenous
steroids
and
catecholamines
accompanies
term
gestation
and
spontaneous
vaginal
delivery,
and
that
these
hormonal
changes
are
necessary
for
foetal
maturation
and
to
prepare
the
foetus
to
transition
successfully
to
neonatal
life.
This
would
account
for
the
higher
incidence
of
TTNB
in
LPIs
who
380
I.M.
Gázquez
Serrano
et
al.
Table
6
Comparative
study
of
morbidity
and
required
interventions
by
birth
weight.
Birth
weight
<2000
g
>2000
g
P
a
Total
36
211
Variable
n
(%)
N
(%)
Morbidity
TTNB
11
(31)
39
(18)
0.096
HMD
3
(8)
10
(5)
0.412
PHT
0
3
(1)
1.000
Hypoglycaemia
6
(17)
13
(6)
0.041
Digestive
intolerance
35
(97)
71
(34)
<0.0001
Jaundice
33
(92)
92
(44)
<0.0001
Sepsis
2
(6)
6
(3)
0.329
Required
intervention
Oxygen
therapy
2
(6)
14
(7)
1.000
CPAP
12
(33)
34
(16)
0.014
CMV
4
(11)
13
(6)
0.285
Surfactant
4
(11)
10
(5)
0.129
Fluid
therapy
29
(81)
66
(31)
<0.0001
Parenteral
nutrition
24
(67)
12
(6)
<0.0001
VMC:
conventional
mechanical
ventilation;
CPAP:
continuous
positive
airway
pressure;
HMD:
hyaline
membrane
disease;
PHT:
pulmonary
hypertension;
TTNB:
transient
tachypnoea
of
the
newborn.
a
Statistical
significance
levels
obtained
using
the
chi
squared
test
on
contingency
tables.
have
not
been
exposed
to
corticosteroids,
especially
in
those
delivered
by
caesarean
section,
a
procedure
that
is
more
common
in
the
latter
group
(32.4%).
25
In
our
study,
the
same
proportion
of
infants
with
TTNB
had
been
born
vaginally
and
by
caesarean
delivery.
In
each
group,
only
one
neonate
had
been
exposed
to
antenatal
corticosteroids.
Our
results
sug-
gest
that
antenatal
corticosteroids
reduce
the
risk
of
TTNB,
regardless
of
the
type
of
delivery.
This
issue
is
important
because
TTNB
is
a
frequent
complication
and
the
main
reason
for
hospital
admission
in
LPIs.
The
rate
of
morbidity
should
not
be
the
only
factor
in
deciding
which
is
the
gestational
age
at
which
administra-
tion
of
antenatal
corticosteroids
should
be
recommended,
(LPIs
have
a
lower
rate
of
respiratory
morbidity
than
preterm
infants
with
lower
gestational
ages);
the
total
number
of
patients
that
could
benefit
also
ought
to
be
considered.
As
noted
above,
LPIs
constitute
the
largest
group
of
preterm
infants,
and
antenatal
treatment
could
reduce
the
num-
ber
of
patients
admitted
to
the
NICU,
resulting
in
a
lower
socioeconomic
burden.
26---28
Likewise,
the
Cochrane
review
supports
antenatal
administration
of
corticosteroids
up
to
34
6+
weeks
of
gestation.
This
recommendation
is
based
on
the
reduction
in
the
incidence
of
respiratory
distress
syn-
drome
in
the
subgroup
of
preterm
infants
born
at
33---34
+6
weeks
of
gestation
exposed
to
antenatal
corticosteroids.
29
In
this
study,
the
incidence
of
hyaline
membrane
disease
was
very
low
in
both
groups,
and
we
found
no
significant
dif-
ferences
were
between
them.
However,
both
this
condition
and
surfactant
administration
were
more
frequent
in
LPIs
who
were
not
exposed
to
antenatal
corticosteroids,
which
Table
7
Comparative
study
of
morbidity
and
mortality
and
required
interventions
by
birth
weight
and
administration
of
antenatal
corticosteroids.
Variable
TTNB,
n
(%)
HMD,
n
(%)
Hypoglycaemia,
n
(%)
Digestive
intolerance,
n
(%)
Jaundice,
n
(%)
Sepsis,
n
(%)
<2000
g
(n
=
36)
CS
(
n
=
7)
1
(14)
1
(14)
0
7
(100)
6
(86)
0
No
CS
(
n
=
29)
10
(34)
2
(7)
6
(21)
28
(97)
27
(93)
2
(7)
P
a
0.400
0.488
0.317
1.000
0.488
1.000
>2000
g
(n
=
211)
CS
(
n
=
66)
1
(2)
0
0
7
(11)
8
(12)
1
(2)
No
CS
(
n
=
145)
38
(26)
10
(7)
13
(9)
64
(44)
84
(58)
5
(3)
P
a
<0.0001
0.033
0.011
<0.0001
<0.0001
0.668
Variable
Oxygen,
n
(%)
CPAP,
n
(%)
CMV,
n
(%)
Surfactant,
n
(%)
Fluid
therapy,
n
(%)
Parenteral
nutrition,
n
(%)
<2000
g
(n
=
36)
CS
(
n
=
7)
0
2
(29)
1
(14)
1
(14)
3
(43)
6
(86)
No
CS
(
n
=
29)
2
(7)
10
(34)
3
(10)
3
(10)
26
(90)
18
(62)
P
a
1.000
1.000
1.000
1.000
0.016
0.384
>2000
g
(n
=
211)
CS
(
n
=
66)
0
2
(3)
1
(2)
0
7
(11)
0
No
CS
(
n
=
145)
14
(10)
32
(22)
12
(8)
10
(7)
59
(41)
12
(8)
P
a
0.006
<0.0001
0.068
0.033
<0.0001
0.020
CMV:
conventional
mechanical
ventilation;
CPAP:
continuous
positive
airway
pressure;
CS:
corticosteroids;
HMD:
hyaline
membrane
disease;
TTNB:
transient
tachypnoea
of
the
newborn.
a
Statistical
significance
levels
obtained
using
the
chi
squared
test
on
contingency
tables.
Prenatal
corticosteroids
late
preterm
381
could
be
due
to
the
structural
and
functional
development
of
the
foetal
lung,
which
is
incomplete
in
this
gestational
age
group.
There
are
very
few
studies
on
the
probable
benefi-
cial
effect
of
antenatal
corticosteroid
administration
in
late
preterm
infants.
To
obtain
evidence
on
this
matter,
the
Maternal
Fetal
Medicine
Units
Network
is
conducting
a
prospective
multicentre
study
(Antenatal
Late
Preterm:
Randomized
Placebo-Controlled
Trial
[ALPS])
to
evaluate
the
administration
of
antenatal
corticosteroids
in
women
at
risk
of
preterm
delivery
between
34
and
36
+6
weeks
of
gestation,
which
will
be
completed
in
2014.
26
Respiratory
morbidity
is
not
only
the
primary
cause
for
admission
in
LPIs,
but
is
accompanied
by
additional
complications
such
as
digestive
intolerance,
which
may
or
may
not
be
associated
with
the
need
for
respiratory
support
measures,
fluid
therapy,
and
parenteral
nutrition.
These
findings
are
corroborated
by
our
study,
as
our
results
showed
a
significant
reduction
not
only
in
the
risk
of
acute
respi-
ratory
diseases
(TTNB),
but
also
in
the
risk
of
developing
hypoglycaemia,
digestive
intolerance
and
jaundice,
and
of
needing
respiratory
support
(oxygen
therapy,
nasal
CPAP),
fluid
therapy
and
phototherapy
among
the
LPIs
exposed
to
antenatal
corticosteroids.
Thus,
based
on
our
results,
the
extension
of
antenatal
corticosteroid
administration
to
LPIs
would
be
an
effective
strategy
to
reduce
the
length
of
hos-
pital
stays
and
the
consumption
of
resources.
The
34-week
cutoff
is
still
an
arbitrary
one.
While
the
lung
is
traditionally
considered
to
have
reached
structural
and
biochemical
maturity
by
this
gestational
age,
our
data
are
not
consistent
with
this.
When
we
analysed
morbidity
by
gestational
age,
we
found
a
significant
reduction
in
risk
as
gestational
age
increased;
however,
the
beneficial
effect
of
antenatal
corticosteroid
treatment
was
observed
through-
out
the
late
preterm
period,
a
finding
that
was
independent
of
birth
weight.
Furthermore,
corticosteroids
not
only
affect
the
structural
and
functional
maturity
of
the
foetal
lung,
but
also
have
extrapulmonary
effects
that
contribute
to
the
maturation
of
different
organs
and
systems.
7,30,31
There
are
studies
that
do
not
support
the
antena-
tal
administration
of
corticosteroids.
The
observational
multicentre
study
by
Gyamfi-Bannerman
et
al.
32
did
not
show
an
association
between
antenatal
corticoid
expo-
sure
and
a
reduction
of
respiratory
morbidity
in
LPIs.
A
significant
limitation
of
this
study
was
that
none
of
the
mothers
were
given
corticosteroids
between
34
and
36
weeks
of
gestation,
and
that
the
time
of
administration
was
unknown,
a
factor
to
consider
given
that
the
effect
of
corticosteroids
decreases
with
the
passage
of
time.
In
our
study,
most
mothers
received
a
full
course
of
corticoste-
roids
before
34
weeks
of
gestation
(the
mean
gestational
age
at
administration
was
31
+6
±
2
+2
weeks).
The
time
elapsed
to
delivery
was
27.2
±
15.4
(0---65)
days,
and
birth
occurred
within
7
days
of
administration
in
12.5%
of
the
neonates.
Another
study
is
a
clinical
trial
in
Brazil
with
a
sample
of
320
women
between
34
and
36
weeks
of
gestation
who
were
given
a
course
of
corticosteroids
or
placebo.
The
rate
of
acute
respiratory
distress
syndrome
was
very
low
in
both
groups,
and
the
rate
of
TTNB
was
similar
and
high
in
both
groups,
so
the
study
did
not
reach
sufficient
power
to
detect
significant
differences.
33
Up
to
now,
no
clinical
trial
has
evaluated
the
long-term
effects
of
the
administration
of
antenatal
corticosteroids
in
the
late
preterm
period.
The
effects
described
most
frequently
are
growth
and
neurodevelopmental
disorders.
Animal
models
show
that
corticosteroids
induce
apoptosis
and
cell
death
in
the
brains
of
exposed
animals.
In
most
humans,
the
process
of
neuronal
cell
division
is
already
complete
by
24
weeks
of
gestation,
but
the
division
of
oligo-
dendrocytes,
the
main
cells
involved
in
myelin
synthesis,
is
not
complete,
as
they
grow
most
rapidly
between
34
and
36
weeks
of
gestation.
This
would
make
LPIs
more
vulnera-
ble
to
the
potential
adverse
neurologic
effects
of
antenatal
corticoids
than
more
preterm
infants.
34
A
recent
study
in
Sweden
suggests
that
the
beneficial
effects
of
antenatal
cor-
ticosteroids
extends
beyond
34
weeks
and
does
not
seem
to
increase
the
risk
of
adverse
neurologic
effects.
35
All
of
the
above
justifies
the
need
to
make
a
long-term
follow
up
of
this
large
group
of
preterm
infants,
and
to
conduct
more
studies
on
the
potential
adverse
effects
of
corticosteroids
before
making
a
definitive
recommendation.
One
of
the
most
feared
short-term
adverse
effects
is
the
potential
to
increase
the
risk
of
perinatal
infection
in
LPIs,
a
risk
that
increases
due
to
the
immaturity
of
their
immune
systems.
36
This
led
us
to
assess
and
compare
the
incidence
of
sepsis,
and
we
found
no
difference
between
groups.
Thus,
in
our
study,
the
use
of
antenatal
corticosteroids
did
not
increase
the
risk
of
infection
in
LPIs.
Conclusion
In
our
setting,
the
morbidity
of
LPIs,
and
respiratory
morbid-
ity
in
particular,
is
significantly
lower
in
those
that
had
been
exposed
to
antenatal
corticosteroids,
who
did
not
experi-
ence
adverse
effects
in
the
short-term.
If
an
absence
of
adverse
effects
in
the
long-term
is
confirmed,
it
may
be
useful
to
prolong
the
administration
of
antenatal
cortico-
steroids
beyond
34
weeks
of
gestation,
with
the
purpose
of
significantly
reducing
morbidity
and
mortality
rates,
the
length
of
hospital
stays,
the
need
for
admission
to
the
NICU,
the
use
of
resources,
and
the
socio-economic
burden
asso-
ciated
with
this
subset
of
the
population.
Conflicts
of
interest
The
authors
have
no
conflicts
of
interest
to
declare.
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