Bronchopulmonary dysplasia in very low birth weight infants.

Abstract

The developments in newborn care have enabled many more very low birth weight premature infants to live. The aim of our study was to determine the risk factors for bronchopulmonary dysplasia (BPD) development by evaluating mild and moderate/severe BPD in extramural neonates with a birth weight <1501 g.
A case-control study was conducted between January 1, 2004- December 31, 2006 at the Dr. Sami Ulus Children's Hospital Neonatal Intensive Care Unit. Patients with BPD and without BPD were compared. Bronchopulmonary dysplasia was diagnosed and classified according to the Bancalari criteria. One-hundred and six (106) extramural premature infants with a birth weight <1501 g and admitted to the Neonatal Unit in the first three days of life and survived for more than 28 postnatal days were included. Patients with multiple congenital anomalies and complex cardiac pathologies were excluded. The maternal and neonatal risk factors, clinical features, mechanical ventilation treatment were compared. The principal risk factors for BPD development were analyzed and followed by logistic regression test.
The diagnosis was mild BPD in 27 of the 106 patients and moderate/severe BPD in 29. The incidence of BPD was 52.8%. Fifty of 106 patients had no BPD. Analysis of risk factors revealed that gestational age < or =28 weeks (p=0.019), birth weight < or =1000 g (p=0.007), hypothermia (p=0.003), acidosis (p=0.003) and hypotension (p=0.005) at admission, respiratory distress syndrome (RDS) ( p<0.001), mechanical ventilation therapy (p<0.001), surfactant therapy (p=0.005), higher amount of mean fluid therapy on 7(th) days (p=0.008), nosocomial infection (p<0.001), higher amount of mean packed red cell transfusions (p<0.001) and more than two packed red cell transfusions (p=0.033) were risk factors associated with the development of BPD. Multivariant logistic regression analysis showed acidosis at admission (OR 5.12, 95%CI 1.17-22.27, p=0.029), surfactant treatment (OR 7.53, 95%CI 2.14-26.45, p=0.002), nosocomial infections (OR 4.66, 95%CI 1.27-17.12, p=0.02) and PDA (OR 9.60, 95%CI 2.23-41.22, p=0.002) were risk factors increasing the severity of BPD.
The most important risk factors for BPD development in our study were RDS and nosocomial infections while the presence of acidosis at admission, surfactant administration, nosocomial infections and the presence of PDA were the most important risk factors regarding BPD severity. Presence of acidosis at admission as a risk factor emphasized the importance of suitable transport conditions for premature infants.

Full text

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Correspondence and Reprint requests : Nihal Demiral, Sami
Ulus Cocuk Hastanesi, Telsizler, 06090, Ankara, Turkey.
[DOI- -10.1007/s12098- -009- -0110- -5]
[Received April 25, 2008; Accepted December 05, 2008]
Original Article
Bronchopulmonary Dysplasia in Very Low Birth Weight
Infants
Nihal Demirel, Ahmet Yagmur Bas and Ayesegul Zenciroglu
Department of Neonatology, Dr. Sami Ulus Children Hospital, Ankara, Turkey
ABSTRACT
Objective. To determine the risk factors for development of bronchopulmonary dysplasia (BPD) by evaluating mild and
moderate/severe BPD in extramural neonates with a birth weight <1501 g. Methods. A case-control study was conducted
between January 1, 2004- December 31, 2006. Patients with BPD and without BPD were compared. Bronchopulmonary
dysplasia was diagnosed and classified according to the Bancalari criteria. One-hundred and six (106) extramural
premature infants with a birth weight <1501 g and admitted to the Neonatal Unit in the first three days of life and survived for
more than 28 postnatal days were included. Patients with multiple congenital anomalies and complex cardiac pathologies
were excluded. The maternal and neonatal risk factors, clinical features, mechanical ventilation treatment were compared.
The principal risk factors for BPD development were analyzed and followed by logistic regression test. Results. The
diagnosis was mild BPD in 27 of the 106 patients and moderate/severe BPD in 29. The incidence of BPD was 52.8%. Fifty
of 106 patients had no BPD. Analysis of risk factors revealed that gestational age ≤28 weeks (p=0.019), birth weight ≤1000
g (p=0.007), hypothermia (p=0.003), acidosis (p=0.003) and hypotension (p=0.005) at admission, respiratory distress
syndrome (RDS) ( p<0.001), mechanical ventilation therapy (p<0.001), surfactant therapy (p=0.005), higher amount of mean
fluid therapy on 7th days (p=0.008), nosocomial infection (p<0.001), higher amount of mean packed red cell transfusions
(p<0.001) and more than two packed red cell transfusions (p=0.033) were risk factors associated with the development of
BPD. Multivariant logistic regression analysis showed acidosis at admission (OR 5.12, 95%CI 1.17–22.27, p=0.029),
surfactant treatment (OR 7.53, 95%CI 2.14–26.45, p=0.002), nosocomial infections (OR 4.66, 95%CI 1.27–17.12, p=0.02)
and PDA (OR 9.60, 95%CI 2.23–41.22, p=0.002) were risk factors increasing the severity of BPD. Conclusion. The most
important risk factors for BPD development in our study were RDS and nosocomial infections while the presence of
acidosis at admission, surfactant administration, nosocomial infections and the presence of PDA were the most important
risk factors regarding BPD severity. Presence of acidosis at admission as a risk factor emphasized the importance of
suitable transport conditions for premature infants. [Indian J Pediatr 2009; 76 (7) : 695-698] E-mail: nihalelmaci@yahoo.
com
Key words: Bronchopulmonary dysplasia; Neonatal chronic lung disease; Very low birth weight infants; Respiratory distress
syndrome; Acidosis
Bronchopulmonary dysplasia is a chronic lung disease
developing in premature infants that requires treatment
with oxygen and/or positive pressure ventilation. The
American National Health Institute has grouped BPD as
mild, moderate or severe according to the 28 days or
more of oxygen requirement and postconceptional 36th
week oxygen dependency.1
Immaturity, barotrauma and oxygen toxicity are seen
as the most important risk factors for BPD development.
However, these factors do not explain the development
of BPD in infants with mild Respiratory Distress
Syndrome (RDS) and who do not require mechanical
ventilator treatment, bringing to mind a role for other
factors in the etiopathogenesis.2
This study was conducted to determine neonatal and
perinatal risk factors associated with BPD in
extramural VLBW neonates admitted in a tertiary
neonatal unit. The maternal and neonatal risk factors,
clinical features were also compared between
moderate/severe BPD, mild BPD and control groups.
MATERIAL AND METHOD
This study is a case-control study carried out at the Dr.
Sami Ulus Children’s Hospital Newborn Clinic
between January 1, 2004 and December 31, 2006 on
infants with a birth weight <1501 g. Our hospital has
Indian Journal of Pediatrics, Volume 76—July, 2009 695

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Nihal Demiral et al
696Indian Journal of Pediatrics, Volume 76—July, 2009
no obstetrics department and all the patients
hospitalized in our unit are outborn. Our study group
consisted of patients with oxygen requirement and/or
nasal continuous positive airway pressure (CPAP)/
Positive pressure ventilation (PPV) requirement at
admission. The case group consisted of extramural
preterm infants with a birth weight <1501 grams, with
a postnatal age≤3 days at admission and who
continued to require oxygen after the postnatal 28th
day. Control infants were extramural infants with a
birth weight <1501 g, with a postnatal age ≤3 days at
admission and who did not require oxygen after the
postnatal 28th day. Patients with a major congenital
anomaly, complex cardiac anomaly and chromosomal
abnormality were also excluded.
Bronchopulmonary dysplasia was diagnosed
according to the Bancalari criteria. Patients with an
oxygen requirement ≥30% and/or nasal continuous
positive airway pressure (CPAP)/Positive pressure
ventilation (PPV) requirement at the postconceptional
36th week were considered to have severe and those with
an oxygen requirement of 21–30% were considered to
have moderate BPD. Patients who continued to require
oxygen after the postnatal 28th day but not on the 36th
week were considered to have mild BPD. The patients
were classified as moderate/severe BPD, mild PBD and
control.1,3 The maternal and neonatal risk factors and
clinical features were compared between the BPD group
and the control group first and then moderate/ severe
BPD was compared to mild BPD and control group. As
so the risk factors associated with BPD severity were also
evaluated. Maternal age <20, >35, absence of antenatal
follow, antenatal steroid, smoking in pregnancy,
preeclampsia/eclampsia, chorioamnionitis, cesarean
section, male gender, gestational age ≤28 weeks, birth
weight≤1000 grams are the risk factors.
Clinical features: Hypothermia, acidosis and
hypotension at admission, RDS, mechanical ventilation
treatment, surfactant treatment, mean fluid treatment
(ml/kg/day) on 7th day, patent ductus arteriosus,
nosocomial blood stream infection and/or nosocomial
pneumonia (nosocomial infection), mean packed red
cell transfusion, >2 packed red cell transfusions. A body
temperature <36 ºC (axillary) at presentation was
evaluated as hypothermia while a blood pressure value
less than 2 standard deviations of normal according to
the gestational and postnatal age was evaluated as
hypotension.4 Acidosis was pH <7.2 and hypoxemia
was PaO2< 40–50 mm Hg with FiO2 > 0.6–0.7. The normal
arterial oxygen saturation was accepted as 88–95%.4
Treatment: Infants requiring mechanical ventilator
received surfactant while infants who only needed
nasal CPAP support did not. All infants received
restrictive fluid management that produced a negative
fluid and sodium balance at first.
Statistical Analysis
The difference of the means between the groups was
compared with the Student’s t or Mann Whitney U test
when the number of independent groups was 2 (the control
and BPD groups). The estimated relative risk (OR) was
calculated with a confidence interval (CI) of 95%. When the
number of independent groups was more than 2
(moderate/severe BPD, mild BPD, control group) the
significance of the difference between the variance of the
continuously measured data between the groups was
analyzed with the One Way Variance Analysis (ANOVA) or
the Kruskal Wallis test. When both test statistics were found
to be significant, the Tukey or the Kruskal Wallis multiple
comparison tests were used to determine the source of the
difference. The chi square or Fisher’s Exact tests were used for
categorical comparisons. The results found to be significant
between the three groups according to the chi square tests
were corrected with the Bonferoni correction applied for the
multiple comparison tests between groups. Logistic
Regression Analysis was used to analyze whether the
multiple effects of the variables found to significant in
predicting the development of BPD. “P<0.05” meant that the
results were considered statistically significant. Any variable
whose univariable test had a p value <0.25 was accepted as a
candidate for the multivariable model along with all
variables of known clinical importance. Once the variables
have been identified, we begin with a model containing all of
the selected variables
Since this is a case control study, data obtained from
the remaining subjects after making the exclusion
according to the predefined criteria is included in the
database and studied.
RESULTS
A total of 312 extramural infants, admission age
between 0-28 days, birth weight ≤1500 g were admitted.
The number of infants weighing <1501 grams who
presented in the first 3 days of life and lived and were
monitored long enough for BPD criteria to be applied
was 106 and 56 (52.8%) of them had BPD. These 106
infants made up the present study group. Mild BPD
developed in 48.2% of the total number of 56 patients
with BPD, moderate BPD in 7.1% and severe BPD in
44.7%. The present study group consisted of 64.3%
males and 35.7% females. The mean pregnancy
duration of our cases was 28.98±2.21 weeks in the BPD
group and 30.0±1.91 weeks in the control group and
the difference was significant (p=0.012). The mean birth
weight was 1154.82±238.17 g in the BPD group and
1281.30±161.20 g in the control group and the
difference was significant (p=0.009). There was no
difference by mean pregnancy duration and mean birth
weight between the moderate/severe BPD and mild

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Bronchopulmonary Dysplasia in Very Low Birth Weight infants
Indian Journal of Pediatrics, Volume 76—July, 2009697
BPD (p>0.05). The patients weighed ≤1000 gram in
28.6% of the cases and 1001–1500 g in 71.4%. Table 1
shows the evaluation of the maternal, neonatal and
clinical risk factors between the control group and the
BPD group. The maternal age (<20 or >35 yr) was a
significant risk factor compared to mild BPD in the
moderate/severe BPD group (p<0.05). The BPD group
had significantly higher incidence compared to the
control group of 7th day mean fluid amount (p=0.008)
and mean packed red cell transfusions (p<0.001).
The moderate/severe BPD and mild BPD were
compared for clinical features. The moderate/severe
BPD group showed a significant difference (p<0.05) for the
following risk factors: hypotension at admission, acidosis
at admission, presence of RDS (p<0.001), mechanical
ventilator treatment, surfactant administration, 7th day
mean fluid amount, presence of PDA, presence of
nosocomial infection, number of average packed red cell
transfusions and more than two packed red cell
transfusions. The BPD group had a higher mean number
of ventilator treatment days (6.93 ±9.76 vs 2.78 ± 0.97,
p=0.024) and number of patients staying on the ventilator
for more than 4 days (14 vs 0, p=0.014) compared to the
control group. The number of infants required mechanical
ventilator treatment, the mean number of ventilator
treatment days and number of patients staying on the
ventilator for more than 4 days was higher in the
moderate/severe BPD group than mild BPD (p<0.05).
Table 2 shows the evaluation of multiple effects of
significant risk factors between the case and control
groups. The mild BPD and control groups were
combined and compared with the moderate/severe BPD
groups to determine the risk factors influencing the
development of moderate/severe BPD (Table 3).
DISCUSSION
The modern developments in neonatology have
increased the survival rate of very low birth weight
infants but the BPD incidence has also increased. A
multi-center study by the Neonatal Research Network
has reported the incidence of BPD in infants with a
birth weight of 1500 g or less as 3-43%, a wide range.1
Immaturity, barotrauma and oxygen toxicity are seen
as the most important risk factors for BPD development.
However, these factors do not explain the development
of BPD in infants with mild RDS and who do not
require mechanical ventilator treatment, bringing to
mind a role for other factors in the etiopathogenesis.2
Hypothermia, systemic hypotension and acidosis cause
pulmonary hypertension by resulting in pulmonary
vasoconstriction. We found the presence of
hypotension, hypothermia and acidosis findings in the
patients at presentation to be factors increasing the risk
of BPD development. Since the present study included
extramural infants, the development of hypotension,
hypothermia and acidosis may be due to inappropriate
transport conditions, especially for infants under risk. The
development of RDS increases the BPD risk while BPD
may develop without RDS1. We found a significantly
higher rate of RDS in the patients with BPD compared to
the control group and in the moderate/severe BPD patients
TABLE 1. Characteristics of Maternal- neonatal Risk Factors, and Clinical
Variables With and Without BPD
Risk factorsCasesControls
(%95 CI)
Odds Ratiop
Maternal age
<20, >35
Absence of
antenatal follow
Antenatal steroid
Smoking in
pregnancy
Preeclampsia
/eclampsia
Chorioamnionitis
Cesarean section
Male gender
Gestational age
≤28 wk
Birth weight
≤1000 g
Hypothermia at
admission
Acidosis at
admission
Hypotension at
admission
Respiratory distress
syndrome
Mechanical
ventilation treatment 29 (%51.8)
Surfactant treatment
Patent ductus
arteriosus
Nosocomial
infection
>2 packed red cell
transfusions
12 (%21.4) 10 (%20)1.09 (0.42–2.79)0.856
38 (%67.9)
8 (%14.3)
38 (%76.0) 0,67 (0.28–1.57)
15 (%30)2.56 (0.98–6.73)
0.353
0.05
11 (%19.6) 9 (%18)1.11 (0.42–2.96) 0.829
1 (%1.8)
10 (%17.9)
20 (%35.7)
36 (%64.3)
1 (%2)
5 (%10)
19 (%38)
24 (%48)
0.89 (0.05–14.6)
1.96 (0.62–6.18)
0.91 (0.41–1.99)
1.95 (0.89–4.25)
1.00
0.247
0.808
0.091
27 (%48.2)13 (%26)2.65 (1.17–6.02)0.019
16 (%28.6)4 (%8) 4.6 (1.42–14.89) 0.007
24 (%42.9) 8 (%16)3.98 (1.6–9.9) 0.003
19 (%33.9)5 (%10)4.6 (1.6–13.6) 0.003
13 (%23.2)2 (%4) 7.26 (1.5-34) 0.005
30 (%53.6) 8 (%16)6.05 (2.4-15.2) <0.001
9 (%18)
6 (%12)
4.9 (2-11.9)
4.07 (1.48–11.2)
<0.001
0.005 20 (%35.7)
17 (%30.4) 8 (%16)2.29 (0.89 – 5.9)0.082
19 (%33.9)3 (%6)8.04 (2.2–29.8) <0.001
13 (%23.2)4 (%8) 3.47 (1.05– 11.49)0.033
TABLE 2.Evaluation of Risk Factors in Development of BPD With Logistic
Regression Test
VariablesRegression
coefficient
Standard
deviation
pOdds
ratio
%95 CI
Limits
Respiratory
distress syndrome1.855
Nosocomial
infection
0.495<0.01 6.3922.423–16.859
2.1570.690 0.0028.6432.233–33.443
TABLE 3. Evaluation of Risk Factors in Development of Severe BPD With
Logistic Regression Test
VariablesRegression
coefficient
Standard
deviation
pOdds
ratio
%95 CI
Limits
Acidosis at
admission
Surfactant
treatment
Nosocomial
infection
Patent ductus
arteriosus
1.6340.750 0.029 5.1221.178–22.273
2.0200.6410.0027.5362.147–26.458
1.5410.6630.0204.6681.272–17.128
2.2620.7430.0029.6052.238–41.226

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Nihal Demiral et al
698Indian Journal of Pediatrics, Volume 76—July, 2009
compared to the mild group. However, the lack of RDS in
46.4% of our BPD patients supports a role for other factors
in the etiopathogenesis. Surfactant administered infants
are at risk for lung disease development due to their
increased survival.5,6 Surfactant administration incidence
in the BPD group was 4 times than that of the control
group in the present study. We speculate that this
difference may be explained by the patients requiring
surfactant having severe RDS.
Patent ductus arteriosus increases pulmonary blood
flow and causes interstitial edema. The mechanical
ventilator and oxygen requirements increase as a result
and develop a foundation for BPD.7,8 We found a
significantly higher incidence of PDA in the moderate/
severe BPD group. Infections
prostaglandings that cause opening of the ductus and
the duration of ventilator use, thus causing BPD
development.9-11 Nosocomial
significantly higher in the moderate/severe BPD group
in the present study. The most important risk factors for
BPD development in the present study were RDS and
nosocomial infections while the presence of acidosis,
surfactant administration, nosocomial infections and
the presence of PDA were the most important risk
factors regarding BPD severity.
increase the
infections were
Several limitations of this study exist. In the present
study, it should be highlighted that these are only risk
factors, at best associated with development of BPD; they
could not be interpreted as causative factors because of the
study design. Also, the confidence intervals were wide even
in the risk factors found to be significant. Despite these
limitations, the present study has important implications for
future research into the risk factors for development and
severity of BPD in extramural VLBW infants. The evident
link between acidosis at admission and BPD should be
explored further.
CONCLUSION
It is important to prevent prematurity and nosocomial
infections to decrease the incidence of BPD. All our
patients were extramural
hypotension and acidosis at admission which were
and hypothermia,
significantly high in BPD group reveal inappropriate
transport of infants. The present study mention this
ongoing problem in developing countries of increase in
pulmonary morbidities in very low birth weight infants
who survived.
Contributions: Nihal Demiral and Ahmet Yagmur Bas and
Aysegul Zenciroglu were involved in management of patients,
designing of article and critical revision of the manuscript. Nihal
Demiral and Ahmet Yagmur Bas were also involved in review of
literature, data collection and drafting the manuscript.
Conflict of Interest: No
Role of Funding Source: No
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