Objective
We sought to assess the independent effect of perinatal factors on the risk for bronchopulmonary dysplasia (BPD) in very-low-birthweight infants.
Study Design
This was a population-based observational study. Data were prospectively collected by the Israel Neonatal Network. Multivariable analyses identified independent risk factors for BPD.
Results
Of 12,139 infants surviving to a postmenstrual age of 36 weeks, 1663 (13.7%) developed BPD. BPD was independently associated with young maternal age (odds ratio [OR], 1.53), maternal hypertensive disorders (OR, 1.28), antepartum hemorrhage (OR, 1.26), male gender (OR, 1.41), non-Jewish ethnicity (OR, 1.23), birth defects (OR, 1.94), small for gestational age (GA) (OR, 2.65), and delivery room resuscitation (OR, 1.86). Stratified analysis by GA groups showed that postdelivery resuscitation had a more pronounced effect with increasing maturity.
Conclusion
Perinatal factors and pregnancy complications were independently associated with development of BPD in very-low-birthweight infants. Most risk factors identified were consistent within GA groups.
Bronchopulmonary dysplasia (BPD) is a common chronic respiratory disorder affecting approximately 20-40% of very-low-birthweight (VLBW) infants. Advances in the medical care of VLBW infants have led to decreased mortality rates, however, this has not been accompanied by a similar decline in the rate of BPD. Despite the introduction of therapies and ventilatory strategies aimed at improving respiratory outcomes, the rate of BPD has remained constant or has even increased.
For Editors’ Commentary, see Contents
Both prenatal and neonatal factors have been shown to be associated with BPD. Gestational age (GA) is possibly the strongest factor associated with BPD. Prior to 23 weeks’ gestation, 100% of surviving infants develop BPD, whereas the risk decreases to <1% in infants of >30 weeks’ gestation. Furthermore, the severity of BPD is inversely proportional to both GA and to birthweight (BW). An increased risk of BPD has been associated with prenatal factors such as maternal hypertension, chorioamnionitis, and lack of antenatal steroid therapy as well as with neonatal factors including postdelivery resuscitation, being born small for GA (SGA), and others.
BPD is an important health issue that is associated with increased morbidity during the neonatal intensive care unit stay and after discharge, prolonged hospital length of stay, increased mortality, and long-term respiratory and neurodevelopmental morbidities.
Therefore, our aim was to assess the effect of potential perinatal risk factors on the development of BPD in a large national cohort of VLBW infants and to evaluate the impact of these risk factors at different gestational weeks. Identification of perinatal risk factors for BPD may enable early interventions aimed at prevention and thus decrease the burden of this disease.
Materials and Methods
This population-based observational study was performed on data obtained from the Israel National VLBW Infant Database ( Appendix ). The study was approved by the institutional review board of the Sheba Medical Center.
The Israel National VLBW Infant Database
Data were prospectively collected by the Israel Neonatal Network on VLBW newborn infants (BW ≤1500 g) born in Israel in the years 2000 through 2010. All 28 neonatal departments in Israel participated in the data collection as previously described. The data collected included: demographic details, antenatal and perinatal history, postdelivery status, neonatal diagnoses, medical and surgical treatments, and outcome at discharge. A prestructured form was completed for each infant, checked for logic errors, and if necessary, returned to the participating center for clarification. Interhospital transfers were followed up by the database coordinator until final discharge home. Birth hospital and patient identification remain confidential by consensus agreement of all participating centers. All departments used an operating manual and standard definitions based on those of the Vermont-Oxford Trials Network. Data were collected on all infants until death or discharge home.
Study population
During the period from 2000 through 2010 the database included records of 14,120 VLBW infants without lethal malformations, born at GA 24-32 weeks. Of the initial cohort, 1981 infants died before attaining the postmenstrual age (PMA) of 36 weeks. Thus, the final study population comprised 12,139 VLBW infants of GA 24-32 weeks who were alive at 36 weeks’ PMA.
Definitions
The GA in completed weeks was defined as the best estimate based on last menstrual period, obstetric history and examination, prenatal ultrasound, or early postnatal physical examination. SGA was defined as a BW <10th percentile for GA according to the sex-specific growth charts of Kramer et al. Ethnicity was recorded according to birth certificate registration. BPD was defined as clinical evidence of BPD together with the requirement of oxygen therapy at 36 weeks’ PMA. Definitions of the perinatal variables included in the analysis have been previously reported in detail. Prolonged rupture of membranes was considered as rupture of membranes >12 hours before delivery. The diagnosis of amnionitis was clinically established. Respiratory distress syndrome (RDS) was diagnosed clinically and confirmed by chest x-ray. Delivery room resuscitation included endotracheal intubation, chest compressions, or epinephrine administration. Noninvasive ventilation included continuous positive airway pressure and/or synchronized intermittent mandatory ventilation applied nasally only.
Statistical analysis
The association between antenatal and neonatal variables and BPD was tested using a χ 2 test for categorical variables and a 2-sample t test for continuous variables. All tests were 2-sided and P values of < .05 were considered significant. Multivariable logistic regression analyses were used to identify the independent perinatal risk factors for BPD in the total population and in 4 GA groups separately (24-25, 26-27, 28-29, and 30-32 weeks). The multivariable analyses were adjusted for maternal variables (age, ethnicity, multiple pregnancy, diabetes, hypertensive disorders, premature labor, prolonged rupture of membranes, amnionitis, antepartum hemorrhage, and cesarean delivery) and for neonatal variables (GA, SGA, sex, delivery room resuscitation, and first-week sepsis). Results of the multivariable analyses are presented as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Statistical analyses were performed using statistical software (SAS, version 9.2; SAS Institute Inc, Cary, NC).
Results
During the 11-year study period, data were collected on 14,120 VLBW infants born between 24-32 weeks’ gestation. The outcomes of the VLBW infants by GA groups are shown in the Figure . Of the 14,120 infants, 1981 died <36 weeks’ PMA. The mortality rates decreased from 55.1% at 24-25 weeks’ GA to 2.7% at 30-32 weeks’ GA. The combined outcome of mortality or survival with BPD was 77.5% in the 24- to 25-week group and decreased to 6.7% in the 30- to 32-week group. Among the 12,139 survivors at 36 weeks’ PMA, a total of 1663 infants (13.7%) were diagnosed with BPD.
The perinatal characteristics of VLBW infants with and without BPD are compared in Table 1 . Among the infants with BPD, mothers were significantly younger, more were non-Jewish, and more had antepartum hemorrhages. Fewer pregnancies were conceived by fertility treatments and there was a lower percent of multiple births in the BPD group. Antenatal steroid therapy and delivery mode were similar in the 2 groups. The infants with BPD were of lower GA and BW, and a higher proportion was SGA, of male gender, and required delivery room resuscitation ( Table 2 ). Infants with BPD had received more intensive respiratory support.
| Variable | BPD group (N = 1663), n (%) | No BPD group (N = 10,476), n (%) | P value |
|---|---|---|---|
| Maternal age, y | < .0001 | ||
| 15-24 | 442 (26.6) | 1994 (19.0) | |
| 25-34 | 908 (54.6) | 6177 (59.0) | |
| 35-39 | 233 (14.0) | 1645 (15.7) | |
| ≥40 | 80 (4.8) | 658 (6.3) | |
| Multiple birth | 603 (36.3) | 4518 (43.1) | < .0001 |
| Non-Jewish ethnicity | 569 (34.2) | 2875 (27.5) | < .0001 |
| Maternal education (≥13 y) | 623 (38.6) | 4688 (46.4) | < .0001 |
| Fertility treatment | 488 (29.5) | 3630 (34.7) | < .0001 |
| First-trimester antenatal care | 1428 (85.9) | 9086 (86.7) | .34 |
| Maternal hypertensive disorders | 329 (19.8) | 2141 (20.5) | .56 |
| Maternal diabetes | 91 (5.5) | 757 (7.2) | .01 |
| Premature labor | 892 (53.7) | 5633 (53.8) | .91 |
| Amnionitis ± PROM | < .0001 | ||
| No amnionitis + PROM (<24 h) | 1277 (79.0) | 8430 (83.0) | |
| No amnionitis + PROM (≥24 h) | 201 (12.4) | 1140 (11.2) | |
| Amnionitis | 138 (8.5) | 591 (5.8) | |
| Antepartum hemorrhage | 365 (22.0) | 1590 (15.2) | < .0001 |
| Antenatal steroids | .45 | ||
| None | 400 (24.1) | 2669 (25.5) | |
| Partial | 281 (16.9) | 2718 (16.4) | |
| Complete | 980 (69.0) | 6073 (58.1) | |
| Cesarean delivery | 1217 (73.2) | 7796 (74.4) | .30 |
| Variable | BPD group (N = 1663), n (%) | No BPD group (N = 10,476), n (%) | P value |
|---|---|---|---|
| Gestational age group, wk | < .0001 | ||
| 24-25 | 417 (25.1) | 416 (4.0) | |
| 26-27 | 594 (35.7) | 1685 (16.1) | |
| 28-29 | 436 (26.2) | 3310 (31.6) | |
| 30-32 | 216 (13.0) | 5065 (48.3) | |
| Birthweight group, g | < .0001 | ||
| <1000 | 1176 (70.7) | 2613 (24.9) | |
| 1000-1500 | 487 (29.3) | 7863 (75.1) | |
| Male sex | 996 (59.9) | 5161 (49.3) | < .0001 |
| Birth defects | 169 (10.2) | 651 (6.2) | < .0001 |
| Small for gestational age | 384 (23.1) | 2131 (20.3) | .01 |
| Delivery room resuscitation | 1113 (66.9) | 3425 (32.7) | < .0001 |
| 1-min Apgar score | < .0001 | ||
| 0-3 | 337 (20.7) | 864 (8.4) | |
| 4-7 | 806 (49.6) | 3721 (36.2) | |
| 8-10 | 482 (29.7) | 5700 (55.4) | |
| Sepsis, 0-3 d | 42 (2.5) | 168 (1.6) | .007 |
| Sepsis, 4-7 d | 165 (9.9) | 667 (6.4) | < .0001 |
| Respiratory distress syndrome | 1549 (93.1) | 6647 (63.5) | < .0001 |
| Respiratory support | < .0001 | ||
| Oxygen only or none | 1 (0.1) | 2060 (19.7) | |
| Noninvasive ventilation a | 76 (4.6) | 2742 (32.6) | |
| Conventional | 795 (47.8) | 4044 (48.1) | |
| High-frequency ventilation | 791 (47.6) | 1630 (19.4) | |
| Surfactant | 1428 (85.9) | 4850 (46.3) | < .0001 |
Rates of BPD by perinatal variables and the multivariable analysis of perinatal factors associated with BPD are presented in Table 3 . The rates of BPD in the GA groups were 50.1% at 24-25 weeks, 26.1% at 26-27 weeks, 11.6% at 28-29 weeks, and 4.1% at 30-32 weeks. High rates of BPD were present in infants of young mothers (18.1%); in the presence of amnionitis (18.9%) or antepartum hemorrhage (18.7%); and among infants with birth defects (20.6%), with early sepsis (20.0%), or requiring delivery room resuscitation (24.5%). In the multivariable analysis, young maternal age (<25 years) was associated with a 1.53-fold risk of BPD (95% CI, 1.33–1.77). BPD was independently associated with maternal hypertensive disorders (OR, 1.28; 95% CI, 1.07–1.52), antepartum hemorrhage (OR, 1.26; 95% CI, 1.08–1.46), male gender (OR, 1.41; 95% CI, 1.26–1.59), non-Jewish ethnicity (OR, 1.23; 95% CI, 1.09–1.40), presence of birth defects (OR, 1.94; 95% CI, 1.59–2.38), SGA (OR, 2.65; 95% CI, 2.24–3.12), and delivery room resuscitation (OR, 1.86; 95% CI, 1.63–2.11). The risk for developing BPD was markedly related to the GA. As compared to the 30- to 32-week group, infants of 24-25 and 26-27 weeks’ GA had a 25.2-fold (95% CI, 20.0–31.8) and an 8.78-fold (95% CI, 7.23–10.7) risk, respectively, for BPD. Multivariable analyses of variables associated with BPD stratified by GA groups were therefore also performed ( Table 4 ). In the 24-25 weeks’ gestation group only antepartum hemorrhage and SGA were independently associated with an increased risk of BPD. Young maternal age, male gender, presence of birth defects, SGA, and delivery room resuscitation were associated with an increased risk of BPD in the GA groups of 26-27, 28-29, and 30-32 weeks. Postdelivery resuscitation had a more pronounced effect with increasing maturity and was most strongly associated with BPD in the 30- to 32-week group (OR, 3.38; 95% CI, 2.97–5.34). Maternal hypertension was associated with an increased risk of BPD at 26-27 and 28-29 weeks.
| Variable | Infants with BPD, n/N (%) | Multivariable analysis, OR (95% CI) |
|---|---|---|
| Maternal age group, y | ||
| 15-24 | 442/2436 (18.1) | 1.53 (1.33–1.77) |
| 25-34 | 908/8085 (12.8) | 1.0 |
| 35-39 | 233/1878 (12.4) | 0.95 (0.80–1.13) |
| ≥40 | 80/738 (10.8) | 0.79 (0.60–1.03) |
| Singleton | 1060/7018 (15.1) | 1.0 |
| Multiple birth | 603/5121 (11.8) | 1.07 (0.94–1.22) |
| Jewish | 1093/8682 (12.6) | 1.0 |
| Non-Jewish | 569/3444 (16.6) | 1.23 (1.09–1.40) |
| Maternal hypertensive disorders | ||
| No | 1331/9655 (13.8) | 1.0 |
| Yes | 329/2470 (13.3) | 1.28 (1.07–1.52) |
| Maternal diabetes | ||
| No | 1566/11,265 (13.9) | 1.0 |
| Yes | 91/848 (10.7) | 1.01 (0.79–1.29) |
| Premature contractions | ||
| No | 770/5604 (13.7) | 1.0 |
| Yes | 892/6525 (13.7) | 0.93 (0.82–1.06) |
| Amnionitis ± PROM | ||
| No amnionitis + PROM (<24 h) | 1277/9707 (13.2) | 1.0 |
| No amnionitis + PROM (≥24 h) | 201/1341 (15.0) | 1.18 (0.98–1.41) |
| Amnionitis | 138/729 (18.9) | 1.14 (0.91–1.43) |
| Antepartum hemorrhage | ||
| No | 1296/10,169 (12.7) | 1.0 |
| Yes | 365/1955 (18.7) | 1.26 (1.08–1.46) |
| Cesarean delivery | ||
| No | 445/3124 (14.2) | 1.0 |
| Yes | 1217/9013 (13.5) | 1.09 (0.94–1.26) |
| Gestational age group, wk | ||
| 24-25 | 417/833 (50.1) | 25.2 (20.0–31.8) |
| 26-27 | 594/2279 (26.1) | 8.78 (7.23–10.7) |
| 28-29 | 436/3746 (11.6) | 3.56 (2.96–4.29) |
| 30-32 | 216/4281 (4.1) | 1.0 |
| Female | 667/5982 (11.1) | 1.0 |
| Male | 996/6157 (16.2) | 1.41 (1.26–1.59) |
| Birth defects | ||
| No | 1493/11,316 (13.2) | 1.0 |
| Yes | 169/820 (20.6) | 1.94 (1.59–2.38) |
| Small for gestational age | ||
| No | 1279/9624 (13.3) | 1.0 |
| Yes | 384/2515 (15.3) | 2.65 (2.24–3.12) |
| Delivery room resuscitation | ||
| No | 550/7601 (7.2) | 1.0 |
| Yes | 1113/4538 (24.5) | 1.86 (1.63–2.11) |
| Sepsis | ||
| 0-3 d | 42/210 (20.0) | 0.98 (0.66–1.44) |
| 4-7 d | 162/818 (19.8) | 1.11 (0.90–1.36) |
| No sepsis 0-7 d | 1459/11,111 (13.1) | 1.0 |
| Variable | BPD, n/N; OR (95% CI) | |||
|---|---|---|---|---|
| 24-25 wk, 417/833 | 26-27 wk, 594/2279 | 28-29 wk, 436/3746 | 30-32 wk, 216/5281 | |
| Maternal age group, y | ||||
| 15-24 | 1.22 (0.85–1.73) | 1.51 (1.19–1.93) | 1.61 (1.24–2.10) | 1.76 (1.25–2.50) |
| 25-34 | 1.0 | 1.0 | 1.0 | 1.0 |
| 35-39 | 0.87 (0.57–1.32) | 0.85 (0.63–1.13) | 0.94 (0.69–1.29) | 1.29 (0.86–1.92) |
| ≥40 | 0.72 (0.37–1.37) | 0.72 (0.44–1.15) | 0.80 (0.50–1.28) | 1.21 (0.66–2.22) |
| Multiple birth | 1.12 (0.82–1.54) | 1.21 (0.97–1.52) | 1.03 (0.81–1.31) | 0.96 (0.70–1.33) |
| Non-Jewish | 1.28 (0.94–1.75) | 1.36 (1.10–1.68) | 1.05 (0.83–1.33) | 1.22 (0.90–1.66) |
| Maternal hypertensive disorder | 1.21 (0.64–2.26) | 1.68 (1.22–2.32) | 1.48 (1.10–1.99) | 0.70 (0.49–1.01) |
| Maternal diabetes | 1.08 (0.49–2.40) | 0.98 (0.64–1.50) | 0.81 (0.52–1.28) | 1.22 (0.74–2.00) |
| Premature contractions | 1.11 (0.80–1.53) | 0.89 (0.71–1.11) | 1.03 (0.80–1.32) | 0.86 (0.62–1.19) |
| Amnionitis ± PROM | ||||
| No amnionitis + PROM (<24 h) | 1.0 | 1.0 | 1.0 | 1.0 |
| No amnionitis + PROM (≥24 h) | 1.27 (0.82–1.95) | 1.22 (0.91–1.64) | 1.45 (1.05–2.01) | 0.51 (0.25–1.01) |
| Amnionitis | 1.41 (0.90–2.22) | 1.04 (0.72–1.50) | 1.22 (0.79–1.89) | 1.38 (0.67–2.85) |
| Antepartum hemorrhage | 1.42 (1.02–1.98) | 1.25 (0.98–1.60) | 1.18 (0.88–1.57) | 1.25 (0.84–1.86) |
| Cesarean delivery | 0.94 (0.70–1.27) | 1.05 (0.82–1.34) | 1.23 (0.92–1.64) | 1.11 (0.73–1.69) |
| Male sex | 1.25 (0.94–1.66) | 1.43 (1.17–1.74) | 1.48 (1.19–1.83) | 1.70 (1.27–2.27) |
| Birth defects | 1.30 (0.69–2.46) | 1.60 (1.09–2.37) | 2.42 (1.74–3.36) | 1.90 (1.28–2.82) |
| Small for gestational age | 3.68 (1.87–7.22) | 2.87 (2.08–3.97) | 3.42 (2.60–4.50) | 1.57 (1.15–2.13) |
| Delivery room resuscitation | 0.99 (0.68–1.44) | 1.35 (1.09–1.67) | 1.94 (1.56–2.39) | 3.98 (2.97–5.34) |
| Sepsis | ||||
| 0-3 d | 0.58 (0.27–1.25) | 0.82 (0.41–1.64) | 1.89 (1.02–4.49) | 0.93 (0.27–3.20) |
| 4-7 d | 1.65 (1.10–2.47) | 1.07 (0.77–1.48) | 0.83 (0.52–1.31) | 0.83 (0.41–1.67) |
| No sepsis 0-7 d | 1.0 | 1.0 | 1.0 | 1.0 |
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