FETAL AND NEONATAL

MEDICINE RichardE. Behrman,Editor

Growth and development in children recovering

from bronchopulmonary dysplasia

0 f 2 6 patients with bronchopulmonary dysplasia, 20 (77%) survived and were followed prospectively f o r
two years post-term. Lower respiratory tract infections occurred in 17 of the 20 children (85%), and
required hospitalization in ten (50~ during the first and in four (20%) during the second year. A t two
years post-term only two patients had significant respiratory symptoms at rest, but 78% had residual
radiographic changes. The average weight and height at term were at or below the third percentile.
Growth occurred at an accelerated rate with improvement o f respiratory symptoms, with average weight
reaching the third to tenth percentile f o r both sexes, and tenth to twenty-fifth percentile for height in
the boys and the twenty-fifth percentile for the girls by two years post-term. Growth retardation was
associated with severe and prolonged respiratory dysfunction. Fifteen (75%) were free o f major
developmental defects. Five had mean Bayley scores < 85 at 18 months post-term; one also had
hydrocephalus. Developmental outcome seems related to perinatal and neonatal events rather than to
the presence or absence o f BPD.

T. M a r k e s t a d , M . D . , and P. M . F i t z h a r d i n g e , M . D . , T o r o n t o , O n t . , C a n a d a

BRONCHOPULMONARY DYSPLASIA is a serious com-
plication of ventilation in the newborn infant. The actual
incidence varies from 5 to 38%, depending on the specific
diagnostic criteria used. 1-8 However, in all reports the
mortality rate has been high, ranging from 25 to 39%;
most deaths occur during the first seven months of life
and usually during the initial hospitalization.4, ~, 8
In spite of the importance of the disease, very little has
been published regarding the prognosis for the survivors.
Most of the children with BPD studied by Harrod et aP
and by Northway 1~ were clinically free of cardiopulmo-
nary symptoms by three years. There is a discrepancy,
however, between these two studies regarding neurologic
sequelae, with Harrod et al reporting none and Northway
finding 34% with significant and 29% with minor handi-
cap.
The purpose of this paper is to report the growth
From the Research Institute of the Hospital For Sick
Children and the Department o f Pediatrics, University
of Toronto.
Supported in part by the Medical Research Council
Grant No. MA 6458.
*Reprint address: Director, Neonatal Follow-up Program,
Hospital For Sick Children, 555 University Ave., Toronto,
Ont., Canada M5G 1XS.
pattern, cardiopulmonary status, and the incidence of
neurodevelopmental defects in a group of 20 BPD survi-
vors followed prospectively from birth for a minimum of
two years.
Abbreviations used
BPD: bronchopulmonary dysplasia
RDS: respiratory distress syndrome
IPPV: intermittent positive pressure ventilation
FI%: functional inspired oxygen concentration
MATERIALS AND METHODS
For the diagnosis of BPD, all the following criteria had
to be fulfilled: (1) Primary lung disease requiring positive
pressure ventilation within the first three days of life; (2)
continued respiratory insufficiency because of pulmonary
pathology, requiring oxygen supplementation to maintain
Pa% > 50 mm Hg beyond 30 days of life; and (3)
radiographic changes progressing to a pattern of alternat-
ing areas of focal emphysema and atelectasis,7 persisting
for at least 30 days.
During 1974-1977, 26 patients developed BPD, repre-
senting 2.4% of all admissions with respiratory distress
syndrome and 3.7% of all ventilated infants with RDS.
General management and respiratory support followed

The Journal o f P E D I A T R I C S 597

0022-3476/81/040597+06500.60/0 9 1981 The C. V. Mosby Co. Vol. 98, No. 4, pp. 597-602
598 Markestad and Fitzhardinge The Journal of Pediatrics
April 1981

97th
15- Male ...... ~ . - - ~ ' "
100-~ Male
. T.--- 50th ~ 97th
.-" T ...---r 9 3rd .--"" -T 50th
,o- / T.-"l._---r- I s~*~ ,T ~'~'~ ~ i
/ " . T / ; ~ " ' I '' 1 " .-;T<*,-'" x
,/T/';" I / ./-r~" 0" I
5- / /O,"
",," |
| .1_
1,o
./,T_';'?
0" .a_
",,"i
T,
E
o
F- 0 I ! ! i J.
"l- 32 40 I l ] i
I--
ILl (..9
97th Z
15 - Female ...~....-~"
-~ 1OO- Female
97th
, .-" ---T 50th

10- ,- _-- T 3rd 80- . . . . . . I T 1 2 1 ~ I ~,~et 50th

/ ~.,.. / O.~ ~ I
-r..."*j-T'~'J/'~"T551"~
e....- are
/" W
," ~'~ I .......O"
T .'?'-
I
I •
" / " ..o .[ l --12--",..-- J
5-//-r/" / /'/o i"l _L
60- 9 tt'T;"~-u
f * | ,,..-'
~ "-
~,o .1_
o
.J_
I
.3.
0 P I I t I 40 I I I q L
0 6 12 18 24 0 6 12 18 24
AGE IN MONTHS POST TERM AGE IN MONTHS POST TERM
Fig. 1. Weight measurements from term. The mean _+ 2 SD for Fig. 2. Crown-heel measurements from term. The mean _+ 2 SD
the study sample are plotted against the Stuart graph. for the study sample are plotted against the Stuart graph.

Table I. Survivors of BPD: Early clinical features in 20 expected date of delivery (post-term). A full physical and
patients a neurodevelopmental examination were done at each
visit. Physical measurements were recorded on the stan-
Mean Range No. %
dard grids of Stuart and Reed" and of Nellhaus. '3
Gestational age (wk) 31.1 25-36 Respiratory rate, presence of chest retractions, and abnor-
Birth weight (gm) 1,661 830-2,600 mal auscultatory findings were recorded at each visit. At
Male:Female ratio 4:1
18 months post-term, a psychometric assessment using the
Number of patients with
Severe asphyxia 15 75 Bayley Scales of Infant Development14 was performed by
RDS 20 100 the clinical psychologist, without prior knowledge of the
Pulmonary air leaks 13 65 neonatal history. All patients were screened clinically for
Patent ductus arteriosus 13 65 hearing loss. Complete audiometric examinations were
Apnea 10 50
done on suspect cases. Eye examinations were performed
Seizures 6 30
Cardiac arrest 3 15 in the neonatal intensive care unit and repeated at nine to
Necrotizing enterocolitis 3 15 12 months in all except three patients by an ophthalmol-
ogist using indirect ophthalmoscopy. A three-point scale
of parental socioeconomic status was determined on the
basis of the father's occupation and education: Class
the practice of the neonatal intensive care unit and have I--professional or executive with university or equivalent
been described earlier." All the surviving infants were education; Class II-technical or skilled labor, clerical,
seen at three-month intervals from the expected term date and middle management with high school education;
the first year, and every six months during the second Class III-unskilled labor or unemployed with grade
year. All the results are expressed in terms of age from the school equivalent.
Volume 98 Growth and development in BPD 599
Number 4

Table II. Survivors of BPD: Duration of respiratory support, CO2 retention, time to regain
birth weight, and initial hospital stay (days)

Duration in days
Mean I +_ SD Range
IPPV 13.3 8.7 4- 32
IPPV + CPAP 19.4 13.8 6- 63
Ft% > 0.80 1.3 3.3 0- 15
FI% > 0.40 13.5 21.3 3- 95
FI% > 0.21 85.9 50.3 30-190
Pco2 --> 50 mm Hg 52.3 33.1 10-114
Regained birth weight 29.2 6.7 18- 40
Hospitalization 143.0 81.0 60-360

RESULTS Table III. Respiratory sequelae: Severe respiratory signs

Mortality. Six patients (23%) died. Average age of
death was 3.5 months (range 15 days to eight months),
and all .died during the initial hospitalization. Treatment
was discontinued on the 2-week-old baby because of
severe intraventricular hemorrhage. The others died of
cardiopulmonary insufficiency secondary to BPD.
In Tables I and II are summarized the early clinical
features and therapy of the 20 survivors.
General health. The incidence of pulmonary symptoms
at rest and of lower respiratory tract infections declined
markedly during the first two years post-term (Table III).
The chest radiographs were improving in all, although
78% still had residual changes when last examined during
the second year post-term.
Three of ten examined had right ventricular hypertro-
phy on electrocardiogram during the second year post-
term, but only one child presented with signs of congestive
heart failure after initial hospitalization. This child had
cor pulmonale during the first part of her second year but
was asymptomatic by two years.
Growth. All patients had appropriate weight for gesta-
tional age at birth. Birth weight was regained by an
average of 29 days (range 18 to 40 days). At term the
average height and weight were below the third percentile
for the girls. The boys were at the third percentile for
height, but below in weight. Some "catch-up" growth
occurred in most patients over the next two years. At two
years post-term, weight for both sexes was at the third to
tenth percentile. 9 was at the tenth to twenty-fifth
percentile for boys and twenty-fifth percentile for girls
(Figs. 1 and 2). The head circumference had a normal rate
of growth, the average following close to the 50th percen-
tile for girls and slightly below for boys (Fig. 3).
In all but one patient, linear growth did not accelerate
until there was marked improvement in the resting
respiratory rate and clearing of the chest on auscultation.
Once these changes occurred there was a 3- to 4-month
(resting respiratory rate _> 45, chest retractions, or wheez-
ing), radiographic changes, and lower respiratory tract
infections (n = 20)
Age post-term
1 yr I 2 yr
I
Respiratory signs 8 2
Radiographic 18 14
Infections 17 10
Requiring admission 10 4
growth spurt which resulted in linear growth percentiles
moving from the third to the tenth to twenty-fifth percen-
tile (Fig. 2). There was a similar, although less pro-
nounced, pattern of accelerated weight gain (Fig. 1).
In seven of the patients the accelerated growth also
coincided with discharge to home from the hospital; the
one exception had a marked deceleration in linear growth
pattern at the time of clearing respiratory symptoms and
discharge home at one year of age. He had, however, a
severe central nervous system sequela (hydrocephalus)
causing a serious management problem.
At two years post-term, only five boys and one girl had
height at or above the fiftieth percentile. Four patients, all
boys, were growth retarded (height < third percentile).
Although their lengths at term were similar to those of the
rest of the group, these four had decelerating linear
growth during the first six to 12 months post-term. The
growth delay was associated with more severe lung
disease as reflected in duration of hypoxia, retention of
carbon dioxide, high-oxygen dependency, hospitalization,
and persistence of symptoms at one year post-term (Table
IV). There was, however, no significant difference in
gestational age, birth weight, duration of assisted ventila-
tion, time to regain birth weight, number of lower
respiratory tract infections, mean Bayley score, or socioec-
600 Markestad and Fitzhardinge
Table IV. A comparison of the clinical characteristics during the initial_hospitalization between
those survivors with persistent growth retardation (height < third percentile at two years
post-term) and those with normal height (height __>third percentile)
Height < 3rd (n = 4)
Mean ] SD
Duration in days with
Pa% < 40 mm Hg 4.4 • 2.0
Pco2 --> 50 mm Hg 88.5 • 31.2
Fl% > 0.40 32.8 + 38.8
Hospital stay in days 216.0 + 102.0
Patients with respiratory 4 4
distress at 1 yr
post term
onomic class. Except for the patient with hydrocephalus,
these children had accelerated growth rate during their
second year.
Central nervous system sequelae. One patient had
hydrocephalus. No other major neurologic defects
occurred. The mean Bayley score (average of mental
developmental index and psychomotor developmental
index) at 18 months post-term was 88.9 (range 50 to
101.5). Of the five patients with mean Bayley scores less
than 85, two were severely retarded with scores below 70.
Two of the children with scores less than 85 showed
accelerated development between 18 and 36 months
post-term. One of these was severely retarded at 18
months (Bayley 64) but had been repeatedly hospitalized
during her first 1~ years post-term because of cardiopul-
monary failure. Her developmental quotient at two and
three years was 68 and 83, respectively. The second child
had repeated respiratory tract infections during the first
year; his score rose from 77 at 18 months to 80 at two
years and 85 at three years. A similar developmental spurt
did not occur in the higher score group.
The early hospital course of the five patients with mean
Bayley score < 85 was compared with that of the rest of
the group. Low Bayley scores were associated with a
prolonged need for oxygen supplementation and hospital-
ization, and with recurrent apnea in the neonatal period
(Table V). Four of the five patients were asphyxiated at
birth, but this was not significantly different from the
others. Two of them, however, had severe metabolic
acidosis with pH of 6.82 and 6.87, respectively, after birth,
including the patient with a major CNS defect. There was
no significant difference in socioeconomic class, gestation-
al age, birth weight, duration of hypoxia, hypercarbia,
assisted ventilation, time to regain birth weight, or severity
of later pulmonary disease, as judged by the necessity for
subsequent hospital stays or by respiratory symptoms at
The Journal of Pediatrics
April 1981
Height > 3rd (n = 16)
Mean I SD
1.3 + 1.2 < 0.001
43.3 _+ 27.4 < 0.01
6.8 • 2.8 < 0.01
123.0 • 63.0 < 0.05
< 0.05
one year post-term. Mild seizures occurred in four of the
higher score group and in the two with very low arterial
pH in the lower score group. All had normal electroen-
cephalograms and none had seizures beyond the neonatal
period. Three patients had a short episode of cardiac
arrest during the neonatal period. One was retarded with
a mean Bayley score of 64; the others had scores above 85
at 18 months post-term.
Behavior problems, short attention span, and/or hyper-
activity were reported in four patients at 18 months
post-term; two were in the higher score group.
Sensory defects. One patient had severe myopia (more
than - 2 diopters) at one year; she had had retrolental
fibroptasia in the neonatal period. Two patients had
strabismus without visual defects. No cases of sensorineu-
ral hearing loss were detected.
DISCUSSION
All the patients were referred to our neonatal intensive
care unit from hospitals without a perinatal center. Less
than optimal perinatal management, delay in treatment
and the trauma of transport may have contributed to the
high incidence of birth asphyxia and severe neonatal
hypoxia in our patients. These factors probably also
contributed to the severity of early lung disease 1~ a n d
subsequently to a more complicated neonatal course. Our
incidence of BPD in infants with respiratory distress
syndrome is, however, similar to that found by Truog et
aP and less than the 8% reported by Northway. ~~Our 3.5%
incidence of BPD in the ventilated group is considerably
lower than the commonly found 15 to 35%.TM
A high, but decreasing occurrence of respiratory symp-
toms and lower respiratory tract infections during the first
two years of life has also been found by others, ~. 10. ~7 but
the actual incidence is not stated in these reports. Harrod
et al e found that 13 of 15 patients with BPD did not have
Volume 98 Growth and development in BPD 60 1
Number 4

Table V. Clinical characteristics of survivors with mean

Bayley scores < 85 and _> 85 at 18 months PT
601 Male
Mean Bayley score
- <85 >--85 ..... 97th
(n 5) (n 15) 5O
= = , -~-~r'- .... ~fS---- ~ 50th
I ......,.-- o ..... ,. . . . . -• 3rd
Mean [ SD Mean [ SD P
Duration (days) o
40 -I .//i ...-.a-
FI% > 0.21 125.8 + 56.7 72.6 _+ 39.1 < 0.05 /'~,-L"
Hospitalization
Number of patients with
210.0 • 96.0 117.0 4- 60.0 < 0.05 (.9
Z I/
nr"
recurrent apnea 5 5 < 0.05 u,J 1
30 t l t I
pH < 7.00 2 0 < 0.01
L9
a:: 60- Female
L..)

any increased incidence of lower respiratory tract infec- <

uJ
tion and were completely asymptomatic beyond one year T
50- - ......... T.r 97th
of age, despite abnormal chest radiographs and increased ~.~-~ -- .... 9 5Oth
alveolar-arterial differences of Po~. Their definition of -"T ..,o'-',* __-~ ...... 3rd
BPD may have included very mildly affected infants, as t'~?,~., '''~ ~
40- "O" .a..
evidenced by their high incidence of 68% of all infants /',,•
ventilated for RDS. The pulmonary status in our patients T/"/
will probably continue to improve. Johnson et aP found t_/
that none of 16 children with BPD had any'clinical signs 30 I t t i I
or symptoms of continous pulmonary dysfunction, 0 6 12 18 24
although four had episodic wheezing and ten had residual AGE IN MONTHS POST TERM
radiographic changes when last examined at the mean age Fig. 3. Head circumference measurements from term. The mean
of 5.7 years. Long-term pulmonary function, however, • 2 SD for the study sample are plotted against the Nellhaus
remains to be determined. graph.
The poor growth pattern in our patients is not the result
of prematurity or RDS per se. Even very small premature
infants free of severe neonatal disease regain birth weight increased workload of breathing, and emotional depriva-
in two to three weeks, reach normal heights and weights at tion from being severely ill and confined to a hospital bed
term, and later grow at the same velocity as infants born at for several months ~4 probably contributed to the growth
term. TM ~ Survivors of uncomplicated RDS have been failure. The prolonged periods of hypoxia in the growth
found to reach normal height and weight, 6.... ~ although retarded group probably reflect the severity of early
small premature infants tend to stay smaller than larger disease. Persistent hypoxia may also have a more direct
newborn infants. The growth pattern in our patients is effect on growth, as seen among children raised at high
very similar to that of term and preterm small-for- altitudes, ~ in cyanotic congenital heart disease, 26 and in
gestational-age infants, TM ~ of mechanically ventilated chronic asthma. 27
babies less than 1,500 gm, and of survivors with birth We have not determined the skeletal age in any of our
weights less than 1,000 gm? ~, ~7The small-for-gestational- patients and therefore do not know their growth potential.
age babies have intrauterine malnutrition. The other Previous experience with early growth failure indicates
groups all have in common a complicated neonatal course that they may stay small, 2~ although late catch-up growth
with difficulties in providingsufficient postnatal nutrition has been noted in patients after corrective surgery for
and a long time required to regain birth weight. cyanotic heart lesions. ~ The relatively low incidence of
Northway 1~ also found an increased incidence of growth major neurologic handicap and severe mental retardation
retardation in survivors of BPD at three years: (two of 20) is encouraging in view of the difficult perinatal
The decelerating growth velocity during the first six to and neonatal courses experienced by most of our patients.
12 months post-term in the four severely growth retarded The late accelerated psychomotor and mental develop-
children parallels a period of persistent severe respiratory ment in two of the five children with low Bayley scores
distress. High-caloric expenditure because of the indicates that some of the ill infants have the potential for
602 Markestad and Fitzhardinge
improvement when their general health permits increased
activity and fewer hospital admissions. Because of the
sample size and differences in referral patterns and
patient selection, it is difficult to compare our results with
those of others. In unselected populations of ventilated
neonates, developmental impairment has been reported
in 6 to 19%?, 20, 29. 39 In the two studies reporting the
neurologic status following BPD, the incidence of severe
developmental handicap has been 0 and 34%, respective-
ly?, 10
If the infant survives the acute stage of BPD, the
prognosis for future development compares favorably
with ventilated infants without the complication of BPD.
In view of this finding, aggressive support of the infant
with BPD is justified unless there is evidence of massive
intraventricular hemorrhage. Evaluation of the neurode-
velopmental status should be determined only after
marked improvement of the respiratory system has
occurred.
The authors thank Dr. B. Reilly of the Department of
Radiology for his invaluable assistance in reviewing all the chest
radiographs.
REFERENCES
1. Rhodes PG, Hall RT, and Leonidas JC: Chronic pulmonary
disease in neonates with assisted ventilation, Pediatrics
55:788, 1975.
2, Bancalari E, Abdenour GE, Feller R, and Gannon J:
Bronchopulmonary dysplasia: Clinical presentation, J PEDl-
ATR 95:819, 1979.
3. Troug WE, Pruitt JL, and Woodrum DE: Unchanged
incidence of bronchopulmonary dysplasia in survivors of
hyaline membrane disease, J PED1ATR92:261, 1978.
4. Edwards DK, Dyer WM, and Northway WH: Twelve years'
experience with bronchopulmonary dysplasia, Pediatrics
59:839, 1977.
5. Johnson JD, Malachowski NC, Grobstern R, Welsh D,
Daily WJR, and Sunshine P: Prognosis of children surviv-
ing with the aid of mechanical ventilation in the newborn
period, J PEDIATR84:272, 1974.
6. Tooley WH: Epidemiology of bronchopulmonary dyspla-
sia, J PEDIATR95:851, 1979.
7. Northway WH, Rosan RC, and Porter DY: Pulmonary
disease following respiratory therapy of hyaline-membrane
disease, N Engl J Med 276:357, 1967.
8. Wung J-T, Koons HH, Driscoll JM, and James LS: Chang-
ing incidence of bronchopulmonary dysplasia, J PEDIAXR
95:845, 1979.
9. Harrod JR, L'Heureux P, Wangensteen OD, and Hunt CE:
Long-term follow-up of severe respiratory distress syn-
drome treated with IPPB, J PEmATR 84:277, 1974.
10. Northway WH: Observations on bronchopulmonary dys-
plasia, J PEDIATR95:815, 1979.
The Journal of Pediatrics
April 1981
ll. Pape KE, Buncic RJ, Ashby S, and Fitzhardinge PM: The
status at two years of low-birth-weight infants born in 1974
with birth weights of less than 1,001 gm, J PEDIATR92:253,
1978.
12. Stuart HC, and Reed RB: Longitudinal studies of child
health and development, Pediatrics 24(Suppl):875, 1959.
13. Nellhaus G: Head circumference from birth to 18 years,
Pediatrics 41:106, 1968.
14. Bayley N: Bayley scales of infant development, New York,
1969, The Psychological Corporation.
15. Tooley WH: Hyaline membrane disease, Am Rev Respir
Dis 115:19, 1977.
16. Thompson T, and Reynolds J: The results of intensive care
therapy for neonates with respiratory distress syndrome, J
Perinat Med 5:149, 1977.
17. Fitzhardinge PM, Pape K, Arstikaitis M, Boyle M, Ashby S,
Rowley A, Netley C, and Swyer PR: Mechanical ventilation
of infants of less than 1,501 gm birthweight: Health, growth,
and neurologic sequelae, J PEDIATR88:531, 1976.
18. Fitzhardinge PM: Early growth and development in low-
birthweight infants following treatment in an intensive care
nursery, Pediatrics 56:162, 1975.
19. Stewart AL, and Reynolds EOR: Improved prognosis for
infants of very low birthweight, Pediatrics 54:724, 1974.
20. Dinwiddie R, Mellor DH, Donaldson SH, Tunstall ME, and
Russel G: Quality of survival after artificial ventilation of
the newborn, Arch Dis Child 49:703, 1974.
21. Fisch RO, Bilek MK, Miller LD, and Engel RR: Physical
and mental status at 4 years of age of survivors of the
respiratory distress syndrome, J PEDIATR84:497, 1975.
22. Fitzhardinge PM, and Steven EM: The small-for-date
infant. I. Later growth patterns, Pediatrics 49:671, 1972.
23. Commey JOO, and Fitzhardinge PM: Handicap in the
preterm small-for-gestational age infant, J PEDIATR94:779,
1979.
24. Powell GF, Brasel JA, and Blizzard RM: Emotional depri-
vation and growth retardation simulating idiopathic hypo-
pituitarism, N Engl J Med 276:1271, 1967.
25. Fasancho AR, and Baker PT: Altitute and growth: A study
of the patterns of physical growth of a high altitude
Peruvian Quechua population, Am J Phys Anthrop 32:279,
1970.
26. Strangway A, Fowler R, Cunningham K, and Hamilton R:
Diet and growth in congenital heart disease, Pediatrics
57:75, 1976.
27. Murray AB, Fraser BM, Hardwick DF, and Pirie GE:
Chronic asthma and growth failure in children, Lancet
2:197, 1976.
28. Page RE, Deverall PB, Watson DA, and Scott O: Height
and weight gain after total correction of Fallot's tetralogy,
Br Heart J 40:416, 1978.
29. Reynolds EOR, and Taghizadeh A: Improved prognosis of
infants mechanically ventilated for hyaline membrane dis-
ease, Arch Dis Child 49:505, 1974.
30. Marriage KJ, and Davis PA: Neurological sequelae in
children surviving mechanical ventilation in the neonatal
period, Arch Dis Child 52:176, 1977.