Full text of DOI:10.1007/BF03345508

J. Endocrinol. Invest. 25: 759-764, 2002
Adrenocortical function and chronic lung disease of
pre-maturity: An unresolved problem?
C. Romagnoli, C. Latella, E. Zecca, P. Papacci, and G. Tortorolo
Department of Pediatrics, Division of Neonatology, Catholic University of Sacred Heart, Rome, Italy
ACTH concentrations at the 14th (p=0.006 for F
and p=0.020 for ACTH) and at the 21st (p=0.008
for F and p=0.024 for ACTH) day of life, while
no significant differences were detected at the
28th day of life. The response to ACTH stimula-
tion test was similar between the NOCLD and
CLD group. These data demonstrate the lack of
any significant association between adrenal in-
sufficiency and CLD and discourage the use of
baseline or stimulated plasma F levels to predict
the development of CLD in pre-term infants.
(J. Endocrinol. Invest. 25: 759-764, 2002)
©2002, Editrice Kurtis
ABSTRACT. The aim of this study was to investi-
gate the relationship between adrenocortical
function and chronic lung disease (CLD) of pre-
term infants. Plasma F and ACTH were measured
at 7, 14, 21 and 28 days of life in 25 pre-term in-
fants with gestational age ≤32 weeks and birth
weight ≤1,250 g. Fourteen infants developed
CLD (CLD group) and 11 recovered without CLD
(NOCLD group). Response to ACTH stimulation
was tested on days 7 and 28. The results show
that at the 7th day of life plasma F and ACTH lev-
els were similar in the NOCLD and CLD group.
CLD group had significantly higher plasma F and
INTRODUCTION
sufficiency as a F level <414 nmol/l (15 μg/dl) while
Merz et al. (8) have chosen a much lower cut-off of
83 nmol/l (3 μg/dl). This observational study was
designed to evaluate the adrenocortical function in
pre-term infants from the 7th to the 28th day of life
and to investigate its relationship with the devel-
opment of CLD.
There is no evidence of clinical adrenocortical in-
sufficiency in term infants after birth, but inadequate
F concentrations in stressed pre-term infants have
been reported in the first week of life (1-3). Short-
term suppression of the pituitary-adrenal axis oc-
curs in pre-term infants whose mothers received an-
tenatal corticosteroids (4, 5) and some Authors have
reported an insufficient adrenocortical function in
pre-term infants developing hyaline membrane dis-
ease (6) or suffering from severe circulatory prob-
lems (7). An association between delayed matura-
tion of adrenocortical function and the develop-
ment of chronic lung disease (CLD) has been sug-
gested in some papers (1, 2) but other Authors
failed to find any adrenal insufficiency in pre-term
infants with ongoing CLD (8). The definition itself
of “normal” levels for baseline F concentrations in
pre-term infants is still somewhat controversial.
Morning F levels <138 nmol/l (5 μg/dl) are sugges-
tive of adrenal insufficiency (9, 10); however, Korte
et al. (2) have recently defined adrenocortical in-
METHODS
Infants with birth weight <1,250 g and gestational age <32
weeks, admitted to the Neonatal Intensive Care Unit between
January and October 1998 and still ventilated at the 7th day of
life, were eligible for enrollment into this prospective, observa-
tional study. Neonates with severe congenital malformations or
suspected chromosomal aberrations were excluded from the
study. This study was approved by the Department of Pediatrics
Ethics Committee and parents’ informed consent was obtained.
Basic clinical variables were recorded, including measurements
of heart and respiratory rates, arterial BP and oxygen saturation,
ventilation and oxygen requirements. All infants were in incubators
with servocontrol of temperature and with >60% relative humid-
ity. Parenteral nutrition was begun in the first 36 h of life, accord-
ing to a regimen which enabled the fluid intake to be progres-
sively built up from 60 to 150 ml/kg/day during the first week of
life. Enteral feeding was begun as an infant’s vital signs were sta-
ble, usually within the first week of age, while parenteral nutrition
was gradually reduced as the volume of milk feeding increased,
stopping when 100 kcal/orally were well tolerated. All infants were
ventilated with time cycled pressure limited ventilators; a single
dose of 200 mg/kg of surfactant was given to babies affected by
Key-words: Pre-maturity, adrenocortical function, chronic lung disease.
Correspondence: Prof. Costantino Romagnoli, Divisione di Neonatologia,
Largo A. Gemelli 8, 00168 Roma, Italia.
E-mail: cromagnoli@rm.unicatt.it
Accepted April 26, 2002.
759

Adrenal function and CDL of pre-maturity
which ACTH was administered iv at a dose of 250 μg/1.73 m2
BSA. A second blood sample was drawn for F analysis 2 h after
the ACTH injection. The magnitude of response to ACTH (ꢀ-F)
was calculated by subtracting the basal from the stimulated val-
ue and, on this basis, ꢀ-F percent was also calculated. Consi-
dering 2 different definitions of normal response to ACTH in
pre-term infants, the number of patients with stimulated F con-
centrations >414 nmol/l (2) and the number of patients with ꢀ-
F>248 nmol/l (15) was calculated.
respiratory distress syndrome (RDS). Ibuprofen as lysine salt was
given iv as prophylactic treatment of patent ductus arteriosus
(PDA) during the first 3 days of life (11). None of the studied ba-
bies received inotropes or steroids before and during the study
period. The diagnosis of CLD was made at the 28th day of life, ac-
cording to the following criteria: 1) need for supplemental oxy-
gen to maintain PaO2 >50 mmHg or oxygen saturation >90%; 2)
abnormal radiological findings (12-14). The diagnosis of oxygen
dependence at 36 weeks of post-conceptional age was also con-
sidered.
Statistics
Statistical analyses were performed by Mann Whitney test for
continuous variables and by Fisher’s exact test for discrete vari-
ables. Relationship between baseline plasma F concentrations
and the peak response or incremental rise resulting from stimu-
lation were assessed using Pearson’s correlation test. A p value
<0.05 (two-tailed) was considered to be statistically significant.
Cortisol and ACTH measurements
Plasma F and ACTH levels were measured at 7, 14, 21 and 28
days after birth. The blood samples for ACTH and F analyses
were collected in EDTA, transferred to microcentrifuge tubes
and spun at 2000 g for 5 min, then plasma was promptly sepa-
rated and frozen for shipment. All determinations were per-
formed in duplicate. ACTH was measured by specific IRMA
(Nichols Institute Diagnostic, San Juan Capistrano, CA, USA).
The intraassay coefficients of variation were 2-4% and the in-
terassay coefficients of variation were 8-9.7%. F levels were de-
termined in plasma extracts by RIA (Diagnostic Products, Fa.
Biermann, Bad Nauheim, Germany), the cross-reaction with cor-
tisone being <0,2%. The intra-assay coefficients of variation were
2.1-5.1% and the interassay coefficients of variation were 6.2-
8.5%. The lowest limit of detection was 20 nmol/l.
RESULTS
Twenty-eight infants were enrolled in the study, but
3 were excluded from the analysis because of in-
complete hormonal data. Fourteen neonates de-
veloped CLD (CLD group) and eleven did not (NO-
CLD group). Population characteristics are shown
in Table 1. Perinatal data and major neonatal mor-
bidity were similar between the 2 groups, except
for CLD at 28 days of life, O2 dependence at 36
weeks of post-conceptional age, time spent on oxy-
gen and ventilation. All infants suffering from PDA
ACTH stimulation test
An ACTH stimulation test was performed at the age of 7 and 28
days. All tests were performed between 08:00 h and 10:00 h. A
blood sample was drawn for baseline F concentration, after
Table 1 - Perinatal data and major neonatal morbidity. Values are expressed as mean SD (range) or number (%).
NOCLD (11)
CLD (14)
5/9
p
NS
Sex ratio, M/F
6/5
28.5 1.7 (27-32)
943 187 (700-1240)
5 (45.4)
Gestational age (weeks)
Birth weight (g)
27.9 1.5 (25-30)
881 253 (560-1210)
8 (57.1)
NS
NS
Small for gestational age
Prenatal steroids
NS
6 (54.6)
7 (50)
NS
Cesarean section
10 (90.9)
8 (72.7)
13 (92.8)
NS
Hyaline membrane disease
Patent ductus arteriosus
Acute renal failure
11 (78.6)
NS
2 (18.2)
2 (14.3)
NS
2 (18.2)
1 (7.1)
NS
Intracranial hemorrhage >2nd grade
0
2 (14.3)
NS
Sepsis
5 (45.5)
6 (42.9)
NS
Necrotising enterocolitis
Mechanical ventilation (days)
Oxygen therapy (days)
Chronic lung disease at 28 days
Oxygen at 36 weeks of postconceptional age
Retinopathy of prematurity stage 3-4
1 (9.1)
1 (7.1)
NS
9.1 6.3 (2.1–21.1)
14.9 8.8 (1.5-25.8)
0
34.1 14.2 (14.6-57.7)
54.9 22.3 (29.6-88.1)
14 (100)
<0.0001
<0.0001
0.0001
0.035
NS
0
4 (28.6)
2 (18.2)
2 (14.3)
CLD: chronic lung disease; F: female; M: male; NOCLD: without chronic lung disease.
760

C. Romagnoli, C. Latella, E. Zecca, et al.
Table 2 - F (nmol/l) and ACTH (pmol/l) plasma levels at 7th day of
Only one infant of the NOCLD group was ventilat-
ed at the 14th day of life and none was ventilated at
21st and 28th days. Among the CLD group, 14 in-
fants were ventilated at the 14th day, 13 and 10 in-
fants were still ventilated at the 21st and 28th day
of life respectively.
life. Values are expressed as mean SD (range) and as number (%).
NOCLD (11)
CLD (14)
p
F
262 122
(138-572)
288 160
(75–663)
NS
F<83 nmol/l
F>138 nmol/l
F< 414 nmol/l
ACTH
0
1 (7.1)
NS
NS
NS
NS
Table 2 shows plasma F and ACTH concentrations
at the 7th day of life. The mean F levels were simi-
lar in NOCLD and CLD group (262 122 nmol/l and
288 160 nmol/l, respectively). Groups were then
compared according to different cut-off F levels
considered for the very low birth infants at this age
of life. No babies of NOCLD group and just one
baby of CLD group had plasma F concentrations
<83 nmol/l. All infants of NOCLD group and 12:14
(85.7%) of CLD group had plasma F concentrations
>138 nmol/l. Ten infants out of 11 (90.9%) of NO
CLD group and 12:14 (85.7%) of CLD group had
plasma F concentrations <414 nmol/l. The mean
ACTH levels were 2.8 1.3 pmol/l in NOCLD group
and 4.1 2.9 pmol/l in CLD group and the differ-
ence was not significant.
11 (100)
10 (90.9)
12 (85.7)
12 (85.7)
2.8 1.3
(0.4–5.3)
4.1 2.9
(0.8–9.8)
CLD: chronic lung disease; NOCLD: without chronic lung disease.
had their ductus closed into the first 5 days of life.
Acute renal failure was diagnosed in 2 NOCLD and
1 CLD infants in the 2nd-3rd day of life and resolved
before the 7th day. Intraventricular hemorrhage was
detected at the US scan of the 3rd day of life. Sepsis
was diagnosed in 2 NOCLD babies and 3 CLD in-
fants in the first week of life, while 3 babies of each
group had the diagnosis of sepsis made in the 3rd
week of life. Necrotising enterocolitis was diag-
nosed at the 9th day in one CLD infant and at the
14th day in one NOCLD infant. The study groups
were significantly different for the duration of me-
chanical ventilation and oxygen therapy. All stud-
ied infants were still ventilated at the 7th day of life.
Figure 1 shows the weekly F and ACTH levels dur-
ing the first month of life. The CLD group had sig-
nificantly higher F and ACTH concentrations than
the NOCLD group at the 14th and at the 21st day
of life, while no significant differences were de-
tected at the 28th day of life.
500
250
No CLD
CLD
Table 3 - F data before and after 2 h ACTH stimulation test.
Values are expressed as mean SD (range) or as number (%).
NOCLD (11)
CLD (14)
First test (7th day)
Baseline F (nmol/l)
262 122
(138–572)
288 160
(75-663)
F 2 h after ACTH (nmol/l)
ꢀ F (nmol/l)
1136 468
(293–2072)
874 424
(121–1749)
364 198
(70–793)
1153 550
(374–2046)
800 399
(138–1382)
236 99
(58–368)
p=0.006
p=0.008
0
0
7
14
21
28
ꢀ F%
20
ꢀ F>248 nmol/l
10 (90.9)
10 (90.9)
13 (92.9)
13 (92.9)
Stimulated F>414 nmol/l
Second test (28th day)
Baseline F (nmol/l)
15
10
5
240 124
(69-438)
182 102
(20–327)
F 2 h after ACTH (nmol/l)
ꢀ F (nmol/l)
1010 307
(663–1605)
763 281
(505–1383)
418 265
(126–856)
1081 570
(172–2013)
898 527
(152–1797)
597 303
(155–1045)
p=0.002
p=0.024
ꢀ F%
0
0
7
14
21
28
ꢀ F>248 nmol/l
Stimulated F>414 nmol/l
10 (90.9)
11 (100)
13 (92.9)
13 (92.9)
Days of life
Fig. 1 - Weekly plasma cortisol and ACTH concentrations in the
first month of life. Values are expressed as mean SEM.
CLD: chronic lung disease; NOCLD: without chronic lung disease.
761

Adrenal function and CDL of pre-maturity
Table 3 shows the results of ACTH stimulation tests
performed at the 7th and at the 28th day of life. Every
baby showed an increase in F concentration 2 h af-
ter ACTH infusion. At the 7th day of life the mean
plasma F levels 2 h after ACTH administration and
ꢀ F (absolute and percent) were similar in the NO-
CLD and CLD groups. The number of babies who
showed an increase of plasma F level >248 nmol/l
and a stimulated plasma F level >414 nmol/l was al-
so similar: 10 infants (90.9%) in NOCLD group and 13
(92.9%) in CLD group. Baseline F levels were direct-
ly correlated to F concentrations 2 h after ACTH in-
fusion (r 0.653 for all data; r 0.5770 for NOCLD, and
0.5515 for CLD infants – p<0.05). Baseline F levels
were inversely correlated with percent increase of
plasma F after ACTH stimulation test (r=-0.5496 for
all data – p<0.01; r=-0.5833 for each studied group
– p<0.05) while no correlation was found between
baseline F plasma level and the mean absolute ꢀ F.
Similar results were found when ACTH stimulation
test was performed at 28 days of life.
decreases gradually over 14 to 28 days (22). Al-
though we found such a trend in NOCLD infants,
CLD group showed an increase of both F and
ACTH from the 7th to the 21st day of life. A possible
explanation for these results is that, at this time, in-
fants developing CLD have more stressing clinical
conditions and more aggressive therapeutic needs
(22-25). On the other hand, it can be hypothesized
that high cytokine levels (mainly interleukin-1) in tra-
cheobronchial fluids stimulate the release of corti-
cotropin-releasing factor and therefore F synthesis
in babies developing CLD (8). The decrease of plas-
ma F and ACTH concentrations observed in CLD
babies at the 28th of life could be correlated to the
end of the more aggressive phase of lung inflam-
mation.
Because the response to ACTH stimulation may
be more useful than basal F concentrations to test
adrenal function, the ACTH stimulating test has
been used to detect the adrenocortical insuffi-
ciency in the neonate (25, 26). Watterberg et al.
(1), examining the F response to ACTH stimula-
tion test, found a correlation between CLD and a
decreased response to ACTH, considered as ꢀ F
or number of infants whose plasma F increased
>248 nmol/l. Korte et al. (2), however, failed to
find a different response to ACTH test (stimulat-
ed F>414 nmol/l or increase of F level >193
nmol/l) in CLD and NOCLD pre-term infants. In
our study the response to ACTH stimulation test
performed at 7 days of life was similar in both
study groups. All study infants increased their F
concentration after ACTH administration and ꢀ F
2 h after ACTH injection was similar in CLD and
NOCLD infants. Similar results were found with
the ACTH stimulation performed at 28 days of life,
when the diagnosis of CLD was done.
DISCUSSION
Pre-term infants admitted to neonatal intensive
care units are likely to have respiratory and circu-
latory problems requiring steroids administration
(7, 16). Steroids can be used to prevent or treat
CLD in pre-term infants (17-20). Some Authors re-
ported an adrenal insufficiency as a cause of CLD
in pre-term infants (1, 2) and suggested to treat
with exogenous glucocorticoids all babies with low
F level in the first week of life (2) or all infants at
high risk of CLD (21).
This observational study was designed to investi-
gate the adrenocortical function in pre-term infants
at high risk of CLD to test the hypothesis that
adrenocortical insufficiency is associated with the
development of CLD itself. For this reason, plasma
F and ACTH levels have been serially measured
during the first month of life and 2 ACTH stimula-
tion tests were performed at the age of 7 and 28
days of life. In contrast to the results of Korte et al.
(2), our data showed no relationship between plas-
ma F level at 7 days of life and the development of
CLD. In fact, at the end of the first week of life NO-
CLD and CLD groups showed similar plasma F and
ACTH levels; moreover, a similar number of infants
had F level lower than the cut-off suggested by
Korte et al. (2) or by Merz et al. (8).
These data suggest that CLD infants have no im-
paired adrenal reserves in comparison to NOCLD
babies.
In our study, the first ACTH stimulation test was per-
formed at the end of the first week of life because
at this age even the earliest gestation infants re-
cover the ability to have a normal response. We
used the rapid standard ACTH stimulation test (250
μg/1.73 m2 BSA) because it is still the procedure of
choice in such an instance (27), and plasma F was
measured 120 min after the ACTH administration
because the response is optimal at this time (28-
30). Low-dose ACTH test has been recently sug-
gested in neonates, with the aim to detect mild
adrenal insufficiency (29-31) but there is little ex-
perience with low-dose ACTH test in pre-term in-
fants (27). Furthermore a recent paper showed an
equal sensitivity between low and standard dose
Our serial data show a significant increase of plas-
ma F and ACTH levels at 14 and 21 days of life in
CLD babies as compared to NOCLD babies. A re-
cent study indicates that plasma F level in pre-term
infants increases from birth to 24 h of life and then
762

C. Romagnoli, C. Latella, E. Zecca, et al.
4. Ng P.C., Wong G.W.K., Lam C.W.K., et al. Pituitary-adrenal
response in preterm very low birth infants after treatment
with antenatal corticosteroids. J. Clin. Endocrinol. Metab.
1997, 82: 3548-3552.
ACTH test in detecting hypothalamic-pituitary-
adrenal axis impairment in adults (32). In our opin-
ion the dose we used was able to detect a signifi-
cant adrenocortical impairment and it is hard to be-
lieve that a decreased biochemical responsiveness
could be so able to influence lung inflammation and
pulmonary outcome as a clinically relevant adrenal
impairment. Our data demonstrate the lack of any
significant association between adrenal insufficien-
cy and CLD and discourage the use of both base-
line and stimulated plasma F levels to predict the
development of CLD in pre-term infants.
It remains to discuss the usefulness of the study of
adrenocortical function in determining the thera-
peutic approach. It goes without saying that dex-
amethasone is effective in treating and preventing
CLD in high risk infants (17-20) and a recent paper
has demonstrated that early treatment with low-dose
hydrocortisone increases survival without CLD (21).
It is difficult, however, to identify those babies
needing treatment with exogenous glucocorticoids
to prevent CLD looking at the available literature,
because data are not univocal and reliable tests to
detect the real need for glucocorticoid therapy are
still to be found (27). Pre-term infants with incoming
CLD could be unable to increase F production to
levels that are appropriate for the degree of their in-
flammation, rather than be affected by real adrenal
insufficiency. In fact, the significant plasma F in-
crease that we found in CLD infants at 14 and 21
days of life can indicate that chronic inflammation of
respiratory tract was able to stimulate spontaneous
F secretion but not with the magnitude requested
to staunch the developing CLD.
5. Banks B.A., Cnaan A., Morgan M.A., et al. Multiple
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