1981;67;61 Pediatrics

Tania Gunn, Elena R. Reece, Katherine Metrakos and Eleanor Colle

Depressed T Cells Following Neonatal Steroid Treatment

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PEDIATRICS Vol. 67 No. 1 January 1981 61
Depressed T Cells Following Neonatal Steroid
Treatment
Tania Gunn, MD, Elena R. Reece, MD, Katherine Metrakos, MD, and
Eleanor Colle, MD
From the Departments of Neonatology, Clinical Immunology, Electroencephalography
and Endocrinology, McGill University, and Montreal Children s Hospital Research
Institute, Montreal
ABSTRACT. Forty-four patients received two doses of
12.5 mg/kg of hydrocortisone or placebo on the first day
of life in attempted therapy for respiratory distress syn-
drome. Follow-up studies were performed on survivors at
5 years of age in ten steroid-treated and seven placebo-
treated respiratory distress syndrome subjects. There
were no significant differences in growth, inteffigence
tests, or neurologic examinations in the patients assessed.
Abnormal EEGs are present in both groups. Immunologic
tests showed no differences in lymphocyte counts, im-
munoglobulin levels, diphtheria and tetanus antibody
titers, or complement components. Diminished percent-
ages of T lymphocytes were found in steroid patients
(53% ) compared to control subjects (69% ). There were
also increased percentages of lymphocytes with C3 recep-
tors in steroid patients (20.1% ) compared to control pa-
tients (13.8% ). Episodes of otitis and/or pneumonia were
documented in eight of 1 1 steroid-treated patients be-
tween the ages of 1 and 5 years, compared to two of seven
patients in the placebo group in the same time period. It
is concluded that large doses of steroids on the first day
of life may induce lasting immunologic abnormalities and
may predispose to an increased incidence of infections.
Pediatrics 67:61-67, 1981; corticosteroids, T cells, respi-
ratory distress syndrom e, neonates.
The short history of neonatal medicine is replete
with therapeutic misadventures. Any new pharma-
cologic regimen must be carefully evaluated for
both unexpected side effects and long-term seque-
lae.
Received for publication Sep 26, 1978; accepted July 6, 1980.
Read in part at the 48th Annual M eeting of the Society for
Pediatric Research, New York, April 26-28, 1978.
Reprint requests to (ERR.) Department of Clinical Immunol-
ogy, M ontreal Childrens Hospital, M ontreal, Quebec H3H 1P3.
Dr Gunns present address: St Helens Hospital, Auckland, New
Zealand.
PEDIATRICS (ISSN 0031 4005). Copyright 1981 by the
American Academy of Pediatrics.
The efficacy of glucocorticoid treatment in accel-
erating the rate of lung development in late fetal
life has been shown by numerous animalt3 and
human studies.4 Potential toxicity for the fetus and
newborn infant may be inferred from the late effects
of neonatally administered corticoids found in ani-
mal studies. These studies have been reviewed re-
cently,5 and effects include impaired central ner-
vous system development71 diminished placental
growth,2 thymolymphatic cellular depletion,7t 6
lasting impairment of immunologic responsive-
ness,867 runting similar to that seen in neonatal
thymectomy,3 2#{176} and decreased life span with in-
creased infections.8
In 1971 a controlled trial using postnatal hydro-
cortisone in pharmacologic doses for infants with
the respiratory distress syndrome was carried out
in the neonatal intensive care unit of the M ontreal
Childrens Hospital and showed no benefit to the
steroid-treated infants.2 Blood levels of cortico-
steroids which exceeded 500 mg/100 ml in a few
infants were found in the steroid-treated group.
Pathologic findings from the infants who died in
the neonatal period showed a significant association
between intraventncular hemorrhage and steroid
treatment.22
Follow-up studies of the infants who survived for
the first year of life showed a trend toward an
increased incidence of neurologic and encephalo-
graphic abnormalities and a significant difference
in motor development in the steroid-treated infants
at 1 year of age.23
This paper presents continued follow-up investi-
gation of the children from the same study.
PATIENTS AND METHODS
Of the original 44 patients admitted to the study,
22 received 12.5 mg/kg of hydrocortisone in two
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62 DEPRESSED T CEL L S FOL L OW ING NEONA TA L STEROID TREA TMENT
d o s es 12 hours apart in the first day of life and 22
received placebo. The neonatal courses of the two
groups were similar. Fourteen infants in each group
survived the neonatal period and 12 infants in each
group were available for study at 1 year of age.
Th es e children have been followed at yearly in-
tervals in the neonatal follow-up clinic with records
of interim infections, measurements of height,
w ei g h t , and head circumference, and neurologic and
developmental examinations.
A t 4 years of age 12 children from the steroid
group and ten of the placebo group were still fol-
lowed in the clinic. Of the 12 surviving placebo-
treated children who were evaluated at 1 year of
age, ten were studied completely for four years but
only seven were still available for study at 5 years
of age. At this time weight index and height index
were calculated for each child from the expected
date of delivery and the formula: weight (height)
index = weight (height)/age24 with percentiles from
the Stuart grid25 and age from estimated date of
conception. The head circumferences were plotted
on the Nelihaus grid.26
The children were retested with psychometric
evaluations using the W echsler Preschool and Pri-
mary Scale of I ntelligence (W PPSI ),27 and Bender-
Ges t al t , s c o r ed ac c o r d i n g to Koppitz, or Rutger s
A Drawing Age? Electroencephalograms were re-
peated and were interpreted without knowledge of
steroid treatment status. Each abnormal tracing
was classified according to severity and the abnor-
mality described as, focal, paroxysmal, asymmetri-
cal, or epileptiform.
Im m u n e c o m p et en c e was reassessed at 5 years of
age. Total lymphocyte counts were estimated from
the peripheral white blood cell and differential
counts. Levels of the complement components C3
and C4 were determined by radial immunodiffusion
u s i n g commercial plates. Ci-esterase inhibitor and
Clq levels were estimated by Ouchterlony double
diffusion. Assessments of B-cell function included
protein electrophoresis, determinations of I gG, I gA,
1gM , and I gD using commercial plates and I gE by
paper radioimmunosorbent test (PRI ST, Pharma-
cia). Antibodies to tetanus and diphtheria were
measured by hemagglutination. Cell-mediated im-
m u n i t y was assessed by intradermal delayed skin
tests using dermatophytin, purified protein denva-
tive, Ca ndida , streptokinase, and streptodornase
(V aridase), and histoplasmin or tetanus toxoid. T-
and B-cell quantitation was performed utilizing
mononuclear cells separated from heparimzed
whole blood by Ficoll-Hypaque density gradient
centrifugation.3#{ 176} The cell suspension was washed in
medium 199 and incubated with latex particles for
one hour at 37 C.3 M onocytes ingesting latex were
not counted when lymphocyte subpopulations were
q u an t i t at ed . This incubation also allowed labile
membrane immunoglobulin to elute from cells with
Fc receptors.32 T lymphocytes (E-RFC) were iden-
tified by the formation of rosettes with sheep red
cells.33 Receptors for the third component of com-
plement (C3) were detected by the adherence of
fluoresceinated Sa lmonella typhi, sensitized with
human complement, to lymphocytes. Fc receptors
were determined by rosette formation of lympho-
cytes with human type 0 Rh+ red cells sensitized
with Ripley anti-CD antiserum. Surface mem-
brane immunoglubulin (SmI G) was detected with
fluoresceinated antisera, both polyvalent and spe-
cific for individual heavy and light chains.36 All
studies were performed without knowledge of the
patients treatment status.
RES UL T S
Of the 12 surviving children who had received
hydrocortisone and were evaluated at 1 year of age,
1 1 were studied completely for five years. Reports,
including neurologic evaluation were obtained from
another hospital for one other boy who is retarded,
hyperactive, and mute with moderate spastic diple-
gia. This boy probably had an intracranial hemor-
rhage in the neonatal period. The 1 1 other steroid-
treated and seven placebo-treated children studied
at 5 to 6 years of age had normal neurologic exam-
inations.
M ean weight and height indices and head circum-
ferences are shown in Table 1. All measurements
for both groups are between the 25th and 50th
percentiles and are not significantly different. The
mean heights and weights of the parents (fathers:
173 8 cm, 77 10 kg; mothers:160 7 cm, 52
7 kg) were similar to the Canadian average.37
Table 2 shows the results of psychometric testing.
The mean I Q was 100.7 10.8 in the steroid group
and 108 1 1.3 in the control group; these scores
are not significantly different nor are the mean
verbal or performance scores from the W PPSI . The
mean Rutger or Bender-Gestalt scores also show no
significant differences between the two groups. The
s o c i o ec o n o m i c level was similar in the two groups.23
Not all of the children had started school yet. One
child in the placebo group has a history of poor
writing and poor fine motor coordination in school.
One child in the steroid group has both emotional
and learning problems, but two of his older brothers
also have severe learning problems.
EEG abnormalities are seen in both groups and
are shown in Table 3. One child in the steroid group
who has an active epileptogenic disturbance has
had no seizures. One child in the placebo group,
whose parents refused an EEG, has had a febrile
convulsion.
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TA B L E 1 . Growth at 1 and 4 Y ears of A ge i n Steroi d-Treated and Control Pati ents*
ARTICLES 63
-- Pati ents W ei ght I ndex Hei ght I ndex Head Ci rcumf erence
1 year of age
Steroi d-treated (12)t 0.93 0.27 0.97 0.18 47.2 1.0
Control (12) 0.98 0.4 0.99 0.18 46.6 1.5
4 y ear s of age
Steroi d-treated (12) 0.91 0.23 0.90 0.15 51.5 1.1
Control (10) 0.97 0.25 0.93 0.14 51.3 1.7
* V al ues are mean number (1 SD).
t Number of chi l dren i n each group i s shown i n parentheses.
TA B L E 2. Psychometri c Testi ng W PPSI * i n Steroi d-Treated and Control Pati ents
Pati ents Ful l I Q Scores V erbal Perf ormance Perceptual
Steroi d-treated (10) 107.1 10.8 101 104 2.5 mo
Control (7) 108.2 11.3 105 109 4.0 mo
S W echsl er Preschool and Pri mary Scal e of I ntel l i gence.
TA B L E 3. El ectroencephal ograms i n Steroi d-Treated and Control Pati ents
. - - Re f u s e d
Pati ents Epi l eptogen,c Paroxysmal I rregul ar Test Normal
Steroi d-treated (10) 2 0 1 1 6
Control (7) 0 1 3 2 * 1
* One f ebri l e convul si on.
IMMUNOL OGIC DA TA
The resul ts of i mmunol ogi c testi ng are shown i n
Tabl e 4 and the Fi gure. There were no si gni f i cant
di f f erences i n total l ymphocyte counts, l evel s of
i mmunogl obul i ns, di phtheri a and tetanus ti ters, or
compl ement components i n the two groups. A l l
chi l dren had at l east one posi ti ve del ayed ski n test.
Pati ents who had recei ved steroi ds had a si gni f i -
cantl y l ower percentage of E-RFC than the control
group: 53% and 69%, respecti vel y (P < .0005). I n
some pati ents decreased E-RFC percentages were
associ ated wi th hi gher percentages of cel l s wi th C3
receptors (20. 1%) than observed i n the adul t or
control groups (10.4% and 13.8%, respecti vel y, P <
.025) . No si gni f i cant di f f erences were observed i n
percentages of cel l s wi th surf ace i mmunogl obul i ns
or Fc receptors.
The number of i nf ecti ons between 1 and 5 years
of age was greater i n the steroi d group wi th ei ght of
1 1 p at i en t s h av i n g o t i t i s and/or x-ray proven pneu-
moni a compared to onl y two of seven pati ents i n
the control group havi ng oti ti s (Tabl e 5). One chi l d
i n each group has had asthmati c attacks.
DISCUSSION
A l though thi s f ol l ow-up study was desi gned to
address the maj or categori es of l ong-term sequel ae
reported i n ani mal s gi ven neonatal steroi ds, i t was
surpri si ng to the authors to f i nd di mi ni shed per-
centages of E-RFC at 5 years of age i n chi l dren who
had recei ved steroi ds on the f i rst day of l i f e. M an,
al ong wi th monkeys and gui nea pi gs, has been con-
si dered rel ati vel y resi stant to steroi d ef f ects on the
i m m u n e s y s t em . Cl aman et al eval uated steroi d-
i nduced thymocyte l ysi s i n humans, mi ce, and
gui nea pi gs and f ound human thymocytes rel ati vel y
resi stant to thi s treatment. However, the thymo-
cytes of the youngest subj ect studi ed (age 11
months) demonstrated greater suscepti bi l i ty to l ysi s
than thymocytes of ol der subj ects. Reducti on i n
thymi c si ze wi th oral steroi d admi ni strati on has
al so been demonstrated radi ol ogi cal l y i n human
neonates.39 Eval uati on of cardi othymi c/thoraci c ra-
ti os i mmedi atel y af ter bi rth i n these i nf ants and i n
those who recei ved prenatal steroi ds 40,41 reveal ed
a sl i ghtl y more rapi d decl i ne i n cardi othymi c/tho-
raci c rati os i n postnatal l y steroi d-treated i nf ants
compared to those gi ven pl acebo, whi l e i n prena-
tal l y treated i nf ants the cardi othymi c/thoraci c ra-
ti o was greater i n pati ents who devel oped respi ra-
tory di stress syndrome, but no ef f ect of steroi ds was
found.
Human and ani mal studi es have shown di verse
ef f ects of gl ucocorti coi ds on bl ood l eukocyte ki net-
i cs and f uncti on. T-l ymphocyte numbers and f unc-
ti on are more suscepti bl e to thei r ef f ects than are B
l ymphocytes, al though many of the ef f ects on cel l -
medi ated i mmune f uncti ons are secondary to the
rel ati ve steroi d sensi ti vi ty of the monocyte-macro-
phage system.42 I t i s thought that T cel l s devel op
resi stance to f uncti onal ef f ects of steroi ds, i n part
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because of maturati onal changes i n the thymus43
and the di f f erenti ati ng ef f ects of thymi c hormones,45
0 and i n part because of f urther di f f erenti ati on af ter
E! exposure to anti gen.46 I n mature mi ce, thymectomy
i i or corti sone admi ni strati on l eads to no detectabl e
l ong-term ef f ects.47 Conversel y, l ow concentrati ons
.5 of steroi ds i n vi tro have been shown to enhance
0 thymocyte di f f erenti ati on rather than to cause cy-
: . : . ,: totoxi ci ty,48 and gl ucocorti coi d antagoni sts i nterf ere
0 wi th the normal ontogeny of cel l -medi ated i mmune
f uncti on.49
c The l ong-term i mpl i cati ons of the i mmunol ogi c
:g f i ndi ngs i n these pati ents are not readi l y apparent
C,, ; C\t as vari ous di sorders are associ ated wi th di mi ni shed
numbers of T cel l s, i ncl udi ng i mmunodef i ci ency
states, autoi mmune di sorders, mal i gnanci es, and
Lt Lt acute i nf ecti ons. A nul l popul ati on i s suggested by
;; ; the f ai l ure to i denti f y l arge percentages of the cel l s
- - - f rom several steroi d-treated chi l dren by the tech-
ni ques uti l i zed. That the associ ati on of di mi ni shed
E-RFC and el evated numbers of cel l s wi th compl e-
. ment receptors may i ndi cate an earl y T cel l popu-
,: ; lation i s supported by a recent report that compl e-
ment receptors may be a marker of earl y T cel l s i n
. man. #{ 176} A ddi ti onal l y young mi ce i nj ected wi th cor-
.2 ti sone demonstrate a rel ati ve enri chment of C3
L) - 2 receptor-beari ng thymocytes.5
The i ncreased i nci dence of bronchopneumoni a
. and oti ti s medi a i n the chi l dren who recei ved hy-
c drocortisone was, agai n, unexpected. El uci dati on of
- - ? g whether thi s was a chance occurence, as the num-
bers of chi l dren i n each group are smal l and the
- i nci dence of chi l dhood i nf ecti ons i s wi del y vari abl e,
- or secondary to the therapy depends on f urther
. . : caref ul f ol l ow-up of these chi l dren and others who
, V V recei ve steroi ds at an earl y age.
There were no di f f erences i n hei ght, wei ght, or
. head ci rcumf erence at 1 year or 4 years of age
. c 1 i between corti costeroi d-treated chi l dren and the
control group. There were al so no si gni f i cant di f f er-
. ences i n the resul ts of psychometri c testi ng or i n
c the general behavi or of the chi l dren at 5 years of
2 age. School perf ormance wi f i be eval uated as the
E S chi l dren progress through school .
. c The di f f erences i n motor ski l l s f ound at 1 year by
- = Fi tzhardi nge et al 23 i n the steroi d-treated group
c were not apparent at 5 years of age. The resul ts of
. the mean perf ormance and verbal scores were not
: si gni f i cantl y di f f erent i n the two groups. No di f f er-
ences were apparent i n testi ng f or perceptual prob-
- l ems but the chi l dren are sti f i too young f or thi s to
be f ul l y assessed. The EEG resul ts showed an i n-
. ! crease i n severe abnormal i ti es i n the steroi d-treated
2W group, but one chi l d i n the control group had a
: 7 f ebri l e convul si on, and an EEG was ref used. There
I>< I>< were abnormal EEGs f ound i n f our of 12 steroi d-
I- & L) treated chi l dren at 1 year of age. There are no
64 DEPRESSED T CELLS FOLLOW ING NEONATAL STEROID TREATMENT
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E-RFC Fc C3 Sm IG
100 35
I N.o n at al s t er o i d t r .at .d
90 30 0 N.onatal controls
. 0 A #{149} A d u l t c o n t r o l s
- 80
25
E

C
;
; 70 20 -
a #{149} 0
T oo#{224}
: 0
8 #{149} A
60 A 15 #{ 149} I
. A #{ 149} I A 0
L - #{149}1 0A
: s o A I A A . -
10 _00 A A 0A A
0
. I 0 #{149}. 0 A
& - A #{ 149}#{ 176} A A #{ 149} . 0 A
I 00 A
A . A
I
40
A
A o
I
30 0 o A
p0.0005 p< 0.025
Fi g u r e. L ymphocyte surf ace markers. Percentage of l ymphocytes expressi ng Fc and C3
receptors and beari ng surf ace-membrane i mmunogl obul i ns represented on the same scal e.
ARTICLES 65
TABLE 5. Infections Between the Ages of 1 and 5 Y ears i n Steroi d-Treated and Control
Pati ents
Steroi d-tre
Control (7)
Pati ents
ated (11)
Pneumoni a
3
. . .
Oti ti s M edi a
6
2
Upper Respi ratory
I nf ecti ons Onl y
3
5
cl i ni cal ef f ects correl ated wi th these changes at thi s
ti me.
The chi l dren recei vi ng steroi ds were al l prema-
turel y born. The mean pl asma l evel s of corti sol
resul ti ng were greater than 100 mg/100 ml f or 48
hours f ol l owi ng i nj ecti on as compared wi th val ues
of 30 mg/100 ml f or the stressed pl acebo-treated
i nf ants. The most f requentl y used steroi d prepara-
tions i n the treatment of the f etus and newborn, at
thi s ti me, are dexamethasone and betamethasone
admi ni stered to the mother, of ten on a schedul e
which requi res weekl y repeti ti on of the dose. Data
on peak l evel s of the steroi ds measured f ol l owi ng
bi rth of the i nf ant52 are di f f i cul t to compare wi th
those f ound i n thi s study because of di f f erences i n
pl asma protei n and ti ssue bi ndi ng, durati on of ac-
ti on, and vari abl e esti mates of comparabl e poten-
ci es of vari ous steroi d anal ogues.
RELEVANCE
The f i ndi ng of di mi ni shed T cel l s at 5 years of
age i n chi l dren who recei ved steroi ds on the f i rst
day of l i f e emphasi zes the i mportance of ongoi ng
f ol l ow-up i nvesti gati ons to assess the l ong-term ef -
f ects of steroi ds i n i nf ants who recei ve them at an
earl y age or prenatal l y. Si nce corti costeroi d ef f ects
in devel opi ng organi sms vary dependi ng on the age
of admi ni strati on and dose admi ni stered, caref ul
strati f i cati on of study popul ati ons by gestati onal
age and steroi d dosage shoul d be a cardi nal f eature
of such studi es.
SUMMARY
A t 5 years of age ten chi l dren who recei ved hy-
drocorti sone on the f i rst day of l i f e i n attempted
therapy of respi ratory di stress syndrome and seven
pl acebo-treated i nf ants were assessed f or growth,
psychometri c testi ng, neurol ogi c status, el ectroen-
cephalograms, i mmunol ogi c status, and i nci dence
of i nf ecti ons. Di mi ni shed percentages of T cel l s
were f ound i n chi l dren who had recei ved steroi ds,
associ ated i n some wi th i ncreased percentages of
cel l s wi th compl ement receptors. There was al so an
i ncreased number of i nf ecti ons i n steroi d-treated
chi l dren. I t i s concl uded that even bri ef therapy
wi th corti costeroi ds i n i nf ants may resul t i n l asti ng
i mmunol ogi c i mpai rment.
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66 DEPRESSED T CELLS FOLLOW ING NEONATAL STEROID TREATMENT
ACKNOWLEDGMENT
Thi s work was supported by the Nathan Stei nberg
Fami l y Foundati on.
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THE S AD F ATE O F DR MIC HAE L UNDE R WO O DS WIDO WE D DAUG HTE R
The most advanced writer on diseases of children in the 18th century,
according to G. F. Still, was M ichael Underwood. He was the first to describe
sclerema neonatorum, apneic attacks in the newborn, malignant familial jaun-
dice of the newborn, and the first to write about congenital heart disease of
children. His Tr eati se on the Di seases of Chi l dr en (1784) passed through at
least 17 editions and remained in favor for more than 60 years; the last American
edition appeared in 1842.
Unfortunately, Underwood apparently received no royalties from his textbook
and died without being able to provide for his widowed daughter. Friends tried
to help her by putting together a book entitled Extr acts fr om the Di ar y of the
Late Mi chael Under wood, M.D. (1823) that would then be sold to subscribers.
I n the prospectus for this book Underwood s friends poignantly described
their reasons for publishing this book as follows:
It is confidently hoped that the Friends of the late Dr Underwood, and more especially
those in the Profession who are acquainted with the estimable works which he published
on the Diseases and Disorders of Children & c. wifi feel an interest in the case of his
widowed Daughter, who now stands in need of the benevolent exertions of her Friends.
She is in her fiftieth year, and is borne down by an accumulation of troubles, arising
partly from the loss of relatives and friends, and partly from serious mental debility,
which frequently incapacitates her for the humble and precarious employment of
needlework, in which she is at other times engaged. Thus reduced, she has at length
consented to make an appeal to the liberality of her Friends and humbly to solicit their
kind support of the Publication now projected, which she hopes will enable her to raise
a small sum to provide her with a few comforts in the decline of life. The situation of the
applicant is the more painful to her feelings from the recollection of those enjoyments,
and even indulgences, which in the plenitude of her father s fame, she had the happiness
to experience.2
As far as I can determine, approximately 500 copies of the book were sold to
subscribers. I doubt whether the profit made from this sale was large enough to
really benefit Dr Underwood s daughter.
Noted by T.E.C., Jr, M D
R E F E R E NC E S
1. Still GF: The Hi stor y ofPaedi atr i cs. London, Oxford University Press, 1931, pp 476-477.
2. Extr acts fr om the Di ar y of the Late Mi chael Under wood, M.D. London, Hatchard and Son,
1823.
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1981;67;61 Pediatrics
Tania Gunn, Elena R. Reece, Katherine Metrakos and Eleanor Colle
Depressed T Cells Following Neonatal Steroid Treatment

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