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Prenatal and postnatal risk factors for developing bronchopulmonary dysplasia

Abstract

Aim. To determine prenatal and postnatal risk factors for developing bronchopulmonary dysplasia in infants < 30 weeks of gestational age.
Methods. Over a 22-month period, 115 newborns were enrolled in the study. Details including gestational age, sex, birth weight, prenatal steroids, surfactant treatment, ventilatory support, days of postnatal oxygen requirement, late onset sepsis/pneumonia, air leaks, patency of ductus arteriosus, and fluid intake were collected. The presence of chorioamnionitis was diagnosed by histological examination. Commercial ELISA kits were used for the determination of the IL-6 and IL-8 levels.
Results. Twenty-five infants developed BPD and 90 were enrolled in the non BPD group. Lower gestational age and male sex increased the risk for BPD. There was no difference in the presence of chorioamnitis and the level of IL-6 and IL-8 measured in cord blood and gastric aspirate between the groups. Intubation in the delivery room (resuscitation), need for surfactant treatment, mechanical ventilation, late onset sepsis/pneumonia, increased oxygenation index increased the risk for BPD after adjustment for GA and gender.
Conclusion. In our cohort of infants with GA < 30 weeks exposure to prenatal inflammation did not increase the risk for BPD. However, low gestational age, male sex, need for resuscitation, mechanical ventilation and late onset sepsis were major risk factors for BPD development.

Key words: premature infant, bronchopulmonary dysplasia, respiratory distress syndrome, chorioamnionitis, interleukin 6, interleukin 8

Introduction

Bronchopumonary dysplasia (BPD) was first described by Northway in 1967 (1) reporting clinical and radiographic changes in the lungs of preterm infants who had respiratory distress syndrome (RDS) and who were treated with oxygen and mechanical ventilation. Beside risks of mechanical ventilation (duration, volu-, barotrauma and oxidative stress) also nosocomial infections and patent ductus arteriosus had been clearly identified as risk factors for BPD development (2,3,4). The study from Watterberg et al. (5) in 1996 established that that the presence of chorioamnionitis (CHA) was associated with lower incidence of RDS and higher of BPD, indicating that lung injury can start before birth. Later studies confirmed that CHA (6,7,8) funisitis (9), and fetal inflammatory response syndrome (10,11) were associated with increased incidence of BPD; however, results were not reproduced in some later studies (12,13). It has been suggested that the association between CHA and BPD is more complicated (14). Van Marter et al. (15) introduced “multiple hit” theory. They established that CHA does not increase the incidence of BPD by itself, but only in combination with already known risk factors for BPD, such as mechanical ventilation longer than 7 days and exposure to postnatal infection.
Most of the published studies were focused on identifying either prenatal or postnatal risk factors. The aim of this study was to identify prenatal and postnatal risk factors in a cohort of infants with GA < 30 weeks.

Material and methods

All infants delivered at less than 30 weeks of gestation in the Ljubljana Maternity Hospital, a tertiary referral centre for premature infants in Slovenia, during the period from September 1st, 2000, to June 30th, 2002, were enrolled in the study. The eligibility criteria were: 1) inborn infant, 2) availability of placenta and cord blood, 3) written informed parental consent obtained, and 4) absence of obvious congenital malformation. The National Medical Ethics Committee approved the study. Details including gestational age, sex, birth weight, prenatal steroids, fluid intake, blood pressure, catecholamine, indomethacin and surfactant treatment, ventilatory support and days of postnatal oxygen requirement were collected. Gestational age was determined by the best obstetric estimate using the last menstrual period and/or early ultrasound assessment.
The placenta, including fetal membranes and umbilical cord, was examined microscopically for the presence of inflammation. CHA was defined as acute when ten or more polymorphonuclear leukocytes were found per high-power field in the amniotic and chorionic membranes, in the chorionic plate, and/or in the umbilical cord. Blood was collected from the umbilical cord immediately after birth, then centrifuged and stored at –70oC until cytokine immunoassay was performed. Commercial ELISA kits (Endogen-Pierce, Boston, USA) were used for determination of the IL-6 and IL-8 levels.
Gastric aspirate sample was collected at the time of delivery with a 5F orogastric feeding tube. Because of no reliable correction factor available (16), cytokine concentrations in gastric aspirates were expressed as volume concentrations (pg/ml or ng/ml).
Infants with RDS on artificial ventilation (FiO2 > 0.60 and oxygenation index (OI) > 20 (OI = (MAPxFiO2x100)/paO2, MAP mean airway pressure, FiO2 fraction of inspired oxygen, paO2 partial pressure of oxygen in arterial blood) were treated with exogenous surfactant (poractant alpha, Curosurf®, 100 mg/kg body weight). Pulmonary air leak (PAL) was confirmed by X-ray. Late onset sepsis/pneumonia (LOS/P) was confirmed by isolation of the organism from the blood or cerebrospinal fluid/tracheal aspirate later than 72 hours of life. Patent ductus arteriosus (PDA) was diagnosed clinically and confirmed by echocardiography.
BPD was diagnosed according to National Information Health Center as oxygen dependency at 36 weeks of GA. Target saturation was kept between 88-92 %.
Statistical analysis. The T-test or Mann-Whitney U test were used for comparison of continuous variables that were normally or not normally distributed. The Pearson chi-square test or Fisher’s exact test (both 2-sided) were used for comparison of categorical variables as appropriate. Logistic regressions were performed stratified by GA. The results were presented as mean ± standard deviation (SD) or median with interquartile range (IQR) or odds ratio (OR) with a 95 % confidence interval (CI). P value < 0.05 was selected to determine statistical significance. Statistical Package of Social Sciences, version 14.0 (SPSS Inc., Chicago, USA) was used for the statistical analyses.

Results

One hundred and fifteen infants (89.1 %) with GA < 30 weeks survived and met the eligibility criteria, from a total of 129 born during the study period. Among the survivors, 25 (21.7 %) infants developed BPD. Male infants comprised 53.0 % of the study group. Mean 1-minute Apgar score was 6 (range, 4−7) and mean 5-minute Apgar score was 7 (range, 6−8). Ninety-three (80.8%) infants received prenatal corticosteroids (39 incomplete and 54 complete courses).
General characteristics of the study group are shown in Table 1. Infants who developed BPD had lower birth weight and gestational age. The percentage of males was higher in the BPD group. The average length of hospitalization was 1.7 times longer in the BPD group when compared to the non BPD group, despite the average difference in GA between the groups being 1 week only. The mode of delivery, prenatal corticosteroid therapy, 1 and 5 min Apgar score and number of multiples did not differ between the groups. Figure 1 shows percentages for death, survival with BPD, and survival without BPD for each week of gestational age. In the group of infants with GA ≤ 24 weeks, survival without BPD was very low (7.1 %). This was followed with progressive increase in survival without BPD for each week of GA; survival without BPD in the group of infants with GA of 29 weeks already reached 83.3 %.
Table 2 shows the comparison of the level of measured cytokines between the BPD and non BPD group. There was no difference in clinical, histological chorioamnionitis, and funisitis between the study groups. The level of IL-6 and IL-8 in cord blood and gastric aspirate was also similar in both study groups. Separate analysis of all infants with analyzed placenta for the presence of histological chorioamnionitis showed that infants with histologicaly confirmed chorioamnionitis after adjustment for GA less likely developed RDS (OR 0.32 [0.14−0.76], p=0.009), however there was no difference in the development of BPD.
Table 3 shows the difference in resuscitation measures and ventilatory support between infants with BPD and infants without BPD. Infants who developed BPD were more often resuscitated in the delivery room, more often needed intubation and surfactant treatment. Infants who developed BPD were ventilated with higher maximal peak inspiratory pressure (MIP), and needed higher FiO2. The length of mechanical ventilation and oxygen supplementation was significantly longer in the BPD group when compared to non BPD group. Infants who developed BPD also had more PAL and more often suffered from LOS/P.
Table 4 shows that infants who developed BPD had more often echocadiographically confirmed PDA and had higher fluid intake on day 2 when compared to infants without BPD. The need for cathecholamine treatment was also higher in the BPD group.
Risk factors for BPD development calculated with regression multivariate model are presented in Figure 2. Factors that independently increased risk for BPD development were: need for intubation in the delivery room, level and length of mechanical ventilation support (MAP, MIP, OI), need for surfactant replacement treatment, the presence of PDA, and development of LOS/P.

Table 1. Characteristics of infants with and without BPD. Results as percentage (%) or mean (SD).

No BPD
(n=90)
BPD
(n=25)
p
Birth weight  (g) 1088 (212) 841 (216) <0.001
GA (wks) 27.5 (1.3) 26.4 (1.9) 0.001
male (%) 40.7 66.7 0.027
1-minute Apgar score6.712.00.30
5-minute Apgar score6.74.00.52
Prenatal dexamethason (%) 81.1 80.0 1.0
Vaginal delivery (%) 56.7 64.0 0.64
Multiple pregnancies (%) 25.1 32.6 0.61
Hospital days 63 (16) 110 (24) <0.001

GA, gestational age; BPD bronchopulmonary dysplasia.

Table 2. Comparison of the level of measured cytokines between the groups. Results as percentage or median with inter quartile range (IQR).

No BPD
(n=90)
BPD
(n=25)
p
Clinical CHA (%) 22.2 24.0 0.85
Histological
CHA (%)
43.0 43.7 0.96
Funisitis (%) 32.9 32.0 0.59
IL−6 cord
blood (pg/ml)
6.0
(1.9  − 23.2)
3.4
(1.2 − 28.2)
0.80
IL−8 cord
blood (pg/ml)
306
(98 − 1033)
424
(107 − 902)
0.92
IL−6 gastric
aspirate (ng/ml)
3.4
(0.5 − 13.5)
2.7
(0.3 − 14.1)
0.66
IL−8 gastric
aspirate (ng/ml)
21
(5 − 278)
31
(6 − 464)
0.93

CHA, chorioamnionitis; IL-6, interleukin-6; IL-8, interleukin-8.

Table 3. Differences in resuscitation measures and ventilatory support between infants without and with BPD. Results as percentage (%) or mean (SD).

No BPD
(n=90)
BPD
(n=25)
p
Resuscitation
in DR (%)
34.4 92.0 0.003
Intubation
in DR (%)
6.7 24.0 0.022
Mechanical
ventilation (%)
38.9 100 <0.001
Surfactant (%) 34.5 92.0 <0.001
PAL (%) 3.5 20.0 0.014
LOS/P (%) 10.4 68.0 <0.001
Max MIP (cm H2O) 21.9 (4.9) 25.3 (4.8) 0.012
Max PEEP (cm H2O) 3.5 (1.1) 3.7 (1.2) 0.48
Max MAP (cm H2O) 9.8 (2.5) 11.8 (2.2) 0.030
Max OI 12.0 (8.6) 18.9 (10.0) 0.013
Max FiO2; 49.6 (24.9) 69.3 (23.5) 0.002
Days of mechanical ventilation 7.1 (8.8) 37.1 (19.1) <0.001
Days on oxygen 20 (20) 105 (26) <0.001
First breathing room air (days) 4.5 (6) 62 (60) <0.001

DR, delivery room; FiO2, fraction of inspired oxygen; LOS/P, late onset sepsis/pneumonia; MAP, mean airway pressure; MIP, maximal inspiratory pressure; OI, oxygenation index; PAL, pulmonary air leak; PEEP, positive end-expiration pressure

Table 4. Patent ductus arteriosus, indomethacin and cathecholamine treatment and fluids during first three days in infants without and with BPD. Results in percentage (%) or mean (SD).

No BPD
(n=90)
BPD
(n=25)
p
PDA (%) 13.3 76.0 0.007
Indomethacin prophylactic (%) 61.3 92.0 0.006
Catecholamine treatment (%) 15.6 36.0 0.04
Day 1 fluids
(ml/kg BW)
89 (15) 92 (11) 0.32
Day 2 fluids
(ml/kg BW)
96 (10) 102 (13) 0.03
Day 3 fluids
(ml/kg BW)
106 (10) 107 (14) 0.56
Weight loss
on day 3 (%)
10.3 7.8 0.11

PDA, persistent ductus arteriosus; BW, body weight

{webgallery}Figure 1. Mortality and survival in infants with/without BPD with respect to GA at birth.{/webgallery}

{webgallery}

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