Schmidt B, Asztalos EV, Roberts RS, Robertson CMT, Sauve RS, Whitfield MF, for the Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators . Impact of Bronchopulmonary Dysplasia, Brain Injury, and Severe Retinopathy on the Outcome of Extremely Low-Birth-Weight Infants at 18 MonthsResults From the Trial of Indomethacin Prophylaxis in Preterms. JAMA. 2003;289(9):1124-1129. doi:10.1001/jama.289.9.1124
Author Affiliations: Departments of Pediatrics (Dr Schmidt) and Clinical Epidemiology and Biostatistics (Dr Schmidt and Mr Roberts), McMaster University, Hamilton, Ontario; Department of Pediatrics, University of Toronto, Toronto, Ontario (Dr Asztalos); Child Health Outcomes Unit, Glenrose Rehabilitation Hospital, Edmonton, Alberta (Dr Robertson); Departments of Pediatrics and Community Health Sciences, University of Calgary, Calgary, Alberta (Dr Sauve) and Department of Department of Pediatrics, University of British Columbia, Vancouver (Dr Whitfield).
Context Despite more than 2 decades of outcomes research after very preterm
birth, clinicians remain uncertain about the extent to which neonatal morbidities
predict poor long-term outcomes of extremely low-birth-weight (ELBW) infants.
Objective To determine the individual and combined prognostic effects of bronchopulmonary
dysplasia (BPD), ultrasonographic signs of brain injury, and severe retinopathy
of prematurity (ROP) on 18-month outcomes of ELBW infants.
Design Inception cohort assembled for the Trial of Indomethacin Prophylaxis
in Preterms (TIPP).
Setting and Participants A total of 910 infants with birth weights of 500 to 999 g who were admitted
to 1 of 32 neonatal intensive care units in Canada, the United States, Australia,
New Zealand, and Hong Kong between 1996 and 1998 and who survived to a postmenstrual
age of 36 weeks.
Main Outcome Measures Combined end point of death or survival to 18 months with 1 or more
of cerebral palsy, cognitive delay, severe hearing loss, and bilateral blindness.
Results Each of the neonatal morbidities was similarly and independently correlated
with a poor 18-month outcome. Odds ratios were 2.4 (95% confidence interval
[CI], 1.8-3.2) for BPD, 3.7 (95% CI, 2.6-5.3) for brain injury, and 3.1 (95%
CI, 1.9-5.0) for severe ROP. In children who were free of BPD, brain injury,
and severe ROP the rate of poor long-term outcomes was 18% (95% CI, 14%-22%).
Corresponding rates with any 1, any 2, and all 3 neonatal morbidities were
42% (95% CI, 37%-47%), 62% (95% CI, 53%-70%), and 88% (64%-99%), respectively.
Conclusion In ELBW infants who survive to a postmenstrual age of 36 weeks, a simple
count of 3 common neonatal morbidities strongly predicts the risk of later
death or neurosensory impairment.
Health professionals and parents of very preterm infants fear the development
of bronchopulmonary dysplasia (BPD), brain injury, and severe retinopathy
of prematurity (ROP) because these neonatal morbidities are risk factors for
neurosensory impairment in childhood. Bronchopulmonary dysplasia has been
associated with low psychomotor development index scores on the Bayley Scales
of Infant Development II,1,2 neurologic
abnormalities3 including cerebral palsy,4 and poor mental development.2,3 Ultrasonographic
signs of brain injury such as severe periventricular and intraventricular
hemorrhage, periventricular leukomalacia, and ventriculomegaly also increase
the risks of mental2,5 and motor2- 7 impairments.
Severe ROP is associated with later visual impairment7,8 and
functional disability.9 However, it has remained
uncertain to what degree the presence or absence of 1 or more of these neonatal
complications affects the overall prognosis of very preterm infants who survive
to near term. A better understanding of the predictive value of these neonatal
morbidities would improve the ability to counsel parents and to anticipate
We undertook this study to examine the individual and combined prognostic
impact of BPD, brain injury, and severe ROP on the 18-month outcome of extremely
low-birth-weight (ELBW) infants who survive to a postmenstrual age of 36 weeks.
Infants with birth weights of 500 to 999 g were enrolled in the international
Trial of Indomethacin Prophylaxis in Preterms (TIPP) between 1996 and 1998.10 The research ethics boards of all 32 participating
clinical centers (located in Canada, the United States, Australia, New Zealand,
and Hong Kong) approved the trial protocol, and written informed consent was
obtained from a parent or guardian of each infant. Since infants who die early
in their course in the neonatal intensive care unit cannot develop the morbidities
of interest, only infants who survived to a postmenstrual age of 36 weeks
were eligible for the current study.
Bronchopulmonary dysplasia, brain injury, and severe ROP were prespecified
secondary outcomes in the TIPP study. All data were collected prospectively
in a standardized fashion. Bronchopulmonary dysplasia was defined as the need
for supplemental oxygen at a postmenstrual age of 36 weeks.11 Cranial
ultrasonography was recommended between days 5 and 8, between days 21 and
28, and between 34 and 36 weeks postmenstrual age if the infant was still
in the study center. The scans were read locally. Copies of the written reports
were sent to the coordinating center. Several types of lesions were considered
as a group because they all indicate probable brain injury6;
these included echodense intraparenchymal lesions, periventricular leukomalacia,
porencephalic cysts, and ventriculomegaly with or without intraventricular
hemorrhage. This cluster of lesions includes periventricular and intraventricular
hemorrhages of grades 3 and 4.12 Retinopathy
was diagnosed according to the international classification.13,14 Unilateral
or bilateral ROP of stages 4 and 5 were considered severe. Infants were also
classified as having severe ROP if they received cryotherapy or laser therapy
in at least 1 eye. Infants were screened for ROP according to local nursery
In the TIPP study, the primary composite outcome was death before a
corrected age of 18 months or the presence in survivors of 1 or more of the
following: cerebral palsy, cognitive delay, hearing loss requiring amplification,
and bilateral blindness.10 The same long-term
composite outcome was used in the current analysis. All 18-month assessments
were performed prospectively according to a standardized protocol. Cerebral
palsy was diagnosed if the child had nonprogressive motor impairment characterized
by abnormal muscle tone and decreased range or control of movements. Cognitive
delay was defined as a Mental Development Index score below 70 (2 SDs below
the mean of 100) on the Bayley Scales of Infant Development II.15 The
score was assumed to be less than 70 if the child could not be tested due
to severe developmental delay. Sound field audiometry was performed to determine
the presence or absence of hearing loss. A central adjudication committee
blinded to any clinical data reviewed the audiological test results from all
infants with potential deafness whose hearing had not been amplified. Infant
blindness was defined as a corrected visual acuity less than 20/200. Follow-up
was targeted for a corrected age of 18 months, but the protocol allowed a
window of 18 to 21 months (12 to 21 months for audiometry). Efforts to conduct
assessments continued beyond a corrected age of 21 months to maximize completeness.
Home visits or assessments in nonstudy facilities were permitted when necessary.
The confirmation of either death or any 1 of the 4 types of impairment
determined the presence of the composite primary outcome, but its absence
required confirmation that the infant had survived without any impairment.
Since a single missing component of the follow-up assessment would result
in a designation of "missing" for the composite outcome, detailed a priori
criteria were used to define what constituted "adequate evidence" for the
presence or absence of each component of the primary outcome.10
Logistic function regression was used to investigate the relationship
between the 3 neonatal morbidities and the outcome at 18 months.16 Initially,
a stepwise model was constructed including 3 indicator variables for the presence
or absence of BPD, brain injury, and severe ROP. This model assumes that the
neonatal morbidities provide independent, additive prognostic information
on the log odds scale. The regression coefficient associated with each term
in the model is a log odds ratio. The potential for a lack of prognostic independence
among the neonatal morbidities was investigated by adding second-order interactions
(as product variables between pairs of neonatal morbidities) to the model.
The significance of the prognostic information of any term, or group of terms,
was tested using a χ2 test. A logistic model was also constructed
using the number of neonatal morbidities present. Exact 95% confidence intervals
were computed around the observed proportions of poor outcome at 18 months.
All analyses were carried out with SAS v6.12 (SAS Institute Inc, Cary, NC); P values were 2-sided and considered significant if <.05.
In the TIPP study, 1202 infants with a birth weight of 500 through 999
g were enrolled; 1003 survived to 36 weeks postmenstrual age. All neonatal
outcomes were known for 967 infants and adequate data for analysis of the
composite 18-month outcomes were available for 910. The baseline characteristics
of the 910 study infants and their mothers are summarized in Table 1. Overall, 323 infants (35%) had a poor outcome at 18 months.
Thirty-four infants (4%) died after a postmenstrual age of 36 weeks. Of the
876 survivors, 110 (13%) developed cerebral palsy, 229 (26%) had cognitive
delay, 20 (2%) had hearing loss requiring amplification, and 16 infants (2%)
had bilateral blindness.
During the neonatal period, 409 (45%) of the 910 infants in the analysis
cohort developed BPD, 194 (21%) had ultrasonographic evidence of brain injury,
and 89 (10%) had severe ROP. Each of these 3 neonatal morbidities was strongly
associated with a poor 18-month outcome (Table 2). Severe ROP showed the strongest association with 18-month
outcome but was a relatively uncommon neonatal finding. Bronchopulmonary dysplasia
was the most prevalent neonatal morbidity but somewhat less predictive of
long-term outcome than severe ROP or brain injury. Table 2 shows the association between each of the 3 morbidities
and the individual components of the composite 18-month outcome.
Table 3 summarizes the results
of fitting a logistic model to the 18-month outcome. This model contained
indicator variables for the 3 separate neonatal morbidities and estimated
the independent prognostic information that was provided by each of the neonatal
morbidities after adjustment for any intercorrelation. Each of the morbidities
had a significant effect on the risk of poor outcome at 18 months. In addition,
none of the second-order interactions between pairs of neonatal morbidities
was significant. The P value for interactions as
a whole was .36. This suggests that the 3 neonatal morbidities provided independent
prognostic information. This prognostic independence, together with the observation
that the odds ratios associated with each of the neonatal morbidities were
similar in size, implies that a very simple predictive model based solely
on the number of morbidities that are present would fit the observed data
well. The estimated coefficients for this model are shown in Table 3. The model suggests an odds ratio of 2.9 (95% confidence
interval, 2.4-3.5) for each additional neonatal morbidity.
Table 4 shows the observed
rates of poor 18-month outcome in subgroups of infants with different combinations
of neonatal morbidities, beginning with those infants who remained free of
all morbidities, and ending with the small group of infants who developed
all 3 morbidities. All possible combinations were considered, including single
morbidities and all possible pairs of morbidities. In the same table we also
show the corresponding rates of poor 18-month outcome that were predicted
by 2 logistic models, one including terms for the presence of the individual
morbidities and the other based solely on a count of the 3 morbidities. The
observed risk of poor long-term outcome was 18% (95% confidence interval,
14%-22%) in infants without any of the 3 neonatal morbidities. This increased
to an average risk of 42% (37%-47%) with any 1 of the morbidities, 62% (53%-70%)
with any 2, and 88% (64%-99%) with all 3. Each of the 3 morbidities, and each
pair of morbidities, contributed a comparable amount of prognostic information.
The logistic model with terms for the presence of the individual morbidities
generated probabilities of a poor 18-month outcome that fit the observed data
very closely (Table 4). Importantly,
almost the same predictive accuracy could be achieved with a model that is
based on a simple morbidity count (Table
4). The fit of this latter model is shown in Figure 1.
We also investigated whether the prognostic value of the morbidity count
was influenced by birth weight (500-749 vs 750-999 g), gestational age (≤26
vs ≥27 weeks), maternal race (white vs nonwhite), and maternal education
(completed high school vs less than high school). For each of these risk factors
we fitted a logistic model that contained terms for the direct effects of
the morbidity count, the respective risk factor, and an interaction. The prognostic
effect of the morbidity count remained strong (P<.001)
in all 4 models. None of the interactions was significant: the smallest P value for an interaction in these 4 analyses was .61.
This indicates that the morbidity count predicted the 18-month outcome equally
well in each of the 2 strata for birth weight, gestational age, maternal race,
and maternal education (Figure 2).
Birth weight (P = .002) and maternal race (P<.001) added prognostic information to the morbidity
count, but gestational age (P = .74) and maternal
education (P = .93) did not (Figure 2).
Bronchopulmonary dysplasia, ultrasonographic signs of brain injury,
and severe ROP were each only modest predictors of a poor long-term outcome
in this international cohort of ELBW infants who survived to a postmenstrual
age of 36 weeks. However, we found that these 3 neonatal morbidities contributed
similarly and independently from each other to the prediction of the infants'
status at a corrected age of 18 months. Therefore, it was possible to develop
a very simple predictive model based solely on the number of neonatal morbidities.
Counting whether an infant had none, any 1, any 2, or all 3 of these neonatal
morbidities greatly improved the prediction of a late death or of survival
with neurosensory impairment.
Bronchopulmonary dysplasia, brain injury, and severe ROP are known risk
factors for poor long-term outcome in very preterm infants,1- 9 which
is why we chose those 3 morbidities as predictor variables in the present
study. Indeed, our individual estimates of risks associated with either BPD,
ultrasonographic lesions that signify brain injury, and severe ROP were comparable
with those reported recently by others.2- 4,9,17 However,
the clinical usefulness of these individual risk estimates is limited by their
relatively modest predictive accuracy.18 For
example, 53% of infants in our cohort who developed BPD had a favorable 18-month
outcome. Conversely, 26% of infants without BPD nevertheless later died or
survived with neurosensory impairment. Moreover, many very preterm infants
acquire multiple morbidities rather than just a single neonatal morbidity,
yet it has remained uncertain whether the associated risks for long-term outcome
are independent. We have now shown that they are. Compared with children who
have no morbidity, having only 1 of the 3 morbidities approximately doubles
the risk of a poor 18-month outcome, while having 2 morbidities approximately
An obvious question is whether birth weight or gestational age influences
the prognostic value of the morbidity count. Not surprisingly, the prevalence
of morbidity was higher in the lower birth weight and gestational age strata.
For example, only 27% of infants with birth weights of 500 to 749 g remained
free of any of the 3 morbidities, compared with 51% of infants with birth
weights of 750 to 999 g. However, it is noteworthy that our prediction model
applied equally well to both birth weight and both gestational age strata.
Importantly, the observed rates of a poor 18-month outcome in children who
remained free of all 3 neonatal morbidities were very similar in the 2 subgroups
of smaller and bigger infants. This was also true for the 2 subgroups of infants
with lower and higher gestational ages. It follows that even very tiny and
immature infants have a good probability of a favorable long-term outcome
if they survive the immediate neonatal period without serious morbidities.
Recently, Doyle and the Victorian Infant Collaborative Study Group19 reached a similar conclusion. Therefore, although
birth weight and gestational age influence the risk of acquiring neonatal
morbidities, the latter appear to affect more directly the causal pathways
that lead to poor long-term outcome.
The morbidity count prediction model also performed equally well in
the subgroups of infants born to white and to nonwhite mothers. However, maternal
race had an important effect on the observed rates of poor outcome at each
of the 4 counts of neonatal morbidities. This effect of race on the prevalence
of a poor 18-month outcome is consistent with previous studies that identified
maternal race directly2 or as a component of
a social risk score3 to be a predictor of cognitive
outcome at 18 to 20 months in mixed-race populations of ELBW infants. In our
study, cognitive delay was most influenced by maternal race, but late death
and cerebral palsy were also observed more frequently in children born to
There are several reasons why our inception cohort was especially suited
for this study. These strengths include the size and international scope of
the cohort as well as the fact that all children were born very recently and
during a period of only 2 years. Moreover, all children received prospective
standardized assessments, and the loss to follow-up rate at 18 months was
However, it could also be argued that our study sample may not be representative
of all ELBW infants who are admitted to a neonatal intensive care unit because
our cohort was assembled for a clinical trial. However, both the baseline
characteristics at trial entry and the rates of neonatal and 18-month outcomes
are comparable with other recent multicenter cohorts of ELBW infants that
were not derived from a trial population.2,20 It
is also pertinent that the trial intervention, indomethacin prophylaxis, did
not affect the rate of poor outcome at 18 months.10
Finally, we need to stress that we did not select our 3 prognostic variables
from a larger set. We planned a priori only to examine the prognostic effects
of BPD, brain injury, and severe ROP. Therefore, we chose not to split our
study cohort into derivation and validation samples. Our results were statistically
strong. Nevertheless, the separate verification of our prediction model in
different populations of ELBW infants would be desirable.
Whenever neurosensory impairment is used to measure the outcome of very
preterm infants and the effectiveness of neonatal intensive care, it is necessary
to remember that impairment may not be an accurate predictor of functional
limitations and disability in later childhood.21 A
child without impairment at 18 months may have learning difficulties at school
age, while a child with impairment may function well. Nevertheless, cerebral
palsy, cognitive delay, hearing loss, and blindness are important and commonly
reported adverse outcomes after very preterm birth.2,20,22 Parents
want to know whether these outcomes are likely to affect their children. Therefore,
clinicians need valid evidence that allows them to estimate the risk of impairment
with reasonable accuracy. We report that, in ELBW infants who survive to a
postmenstrual age of 36 weeks, the prediction of late death or of survival
with neurosensory impairment is greatly improved by a simple count of 3 common
neonatal morbidities: BPD, brain injury, and severe ROP. This new finding
should improve our ability to counsel parents and to anticipate special needs.