Bronchopulmonary Dysplasia

Infants born alive at NRN centers in 2003–2007 with GAs of 22 0/7 to 28 6/7 weeks and BWs of 401 to 1500 g were studied, including those with congenital anomalies. These infants were part of the NRN VLBW registry.1 (link)–6 (link)
Research personnel collected maternal pregnancy/delivery data soon after birth and infant data from birth to death, discharge/transfer, or 120 days of age (“status”). For infants with prolonged hospitalizations, limited information was collected up to 1 year. Definitions for maternal and infant characteristics were provided in a manual of operations. GA was determined as the best obstetric estimate by using ultrasonography and/or the date of the last menstrual period. Intrauterine growth restriction, defined as BW of <10th percentile for gender and GA, was determined by using growth charts published by Alexander et al.9 (link) Morbidities were defined in earlier publications,1 (link)–6 (link),10 (link),11 (link) including respiratory distress syndrome, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), early-onset and late-onset sepsis, necrotizing enterocolitis, patent ductus arteriosus, and retinopathy of prematurity (ROP). Respiratory distress syndrome was defined on the basis of clinical features and oxygen or respiratory support for ≥6 of the first 24 hours.
Three definitions of BPD were used, namely, traditional BPD (supplemental oxygen use at postmenstrual age [PMA] of 36 weeks); BPD determined by using the National Institutes of Health Workshop severity-based diagnostic criteria,12 (link) and BPD determined according to physiologic definition.13 (link) Surviving infants who were discharged or transferred before PMA of 36 weeks were classified on the basis of their status at 36 weeks, if status information was available, or oxygen use at discharge/transfer, if status information was not available. Unless noted otherwise, BPD refers to the traditional definition.
Revisions to data collection in 2006 included questions about maternal chorioamnionitis, placental pathologic conditions, nitric oxide use, and ibuprofen use and expanded data collection on birth resuscitation and neurologic, pulmonary, and ophthalmologic outcomes. In addition to ophthalmologic examination results and interventions, the following outcomes, defined in the manual of operations, were recorded: favorable in both eyes, severe ROP in either eye, or undetermined in either eye without severe ROP in either eye. Complete definitions are included in a footnote to Table 6. The registry was approved by the institutional review boards at each center.

Preterm labor was diagnosed by the presence of regular uterine contractions (at least 3 in 30 minutes) and documented cervical changes in patients with a gestational age between 20 and 36 6/7 weeks. Preterm delivery was defined as birth prior to the 37^th week of gestation. MIAC was defined as either a positive culture for bacteria in AF or the detection of microbial footprints for either viruses or bacteria, using polymerase chain reaction (PCR) coupled with electrospray ionization mass spectrometry (ESI-MS) (Ibis® technology - Athogen, Carlsbad, CA). Intra-amniotic inflammation was diagnosed when AF IL-6 concentration was ≥ 2.6 ng/mL.^{72 (link),155 (link)} Microbial-associated intra-amniotic inflammation was defined as the presence of MIAC with intra-amniotic inflammation. Sterile intra-amniotic inflammation was diagnosed when the AF IL-6 concentration was ≥ 2.6 ng/mL and there was no evidence of microbial footprints for viruses or bacteria (negative AF culture and no detection of microbial footprints using PCR/ESI-MS).
Composite neonatal morbidity was defined as the presence of: respiratory distress syndrome, bronchopulmonary dysplasia, grade III or IV intraventricular hemorrhage, periventricular leukomalacia, proven neonatal sepsis, necrotizing enterocolitis or perinatal mortality. The diagnostic criteria of these complications have been previously reported.^{156 (link)} Acute placental inflammation was diagnosed based on the presence of inflammatory cells in the chorionic plate, chorioamniotic membranes (histologic chorioamnionitis),^{157 (link)-159 (link)} and/or umbilical cord (funisitis).^{157 (link),158 (link)}

Gestational age was determined by the last menstrual period and confirmed by ultrasound examination, or by ultrasound examination alone if the sonographic determination of gestational age was not consistent with menstrual dating. Preterm prelabor rupture of membranes was diagnosed with a sterile speculum examination with documentation of pooling of amniotic fluid in the vagina in association with a positive nitrazine test and/or and positive ferning tests when necessary. Clinical chorioamnionitis was diagnosed when maternal temperature was elevated to 37.8° C and two or more of the following criteria were present: uterine tenderness, malodorous vaginal discharge, maternal leukocytosis (>15,000 cells/mm³), maternal tachycardia (>100 beats/min), and fetal tachycardia (>160 beats/min) [58 (link),59 (link)].
The presence of microorganisms in the amniotic cavity was defined according to the results of AF culture and PCR/ESI-MS (Ibis^® Technology - Athogen, Carlsbad, CA) [60 (link)–63 (link)]. Intra-amniotic inflammation was diagnosed when AF interleukin (IL)-6 concentration was ≥ 2.6 ng/mL [64 (link),65 (link)]. Based on the results of AF culture, PCR/ESI-MS and AF concentration of IL-6, patients were classified as: 1) no intra-amniotic inflammation/infection (either using AF culture or PCR/ESI-MS); 2) microbial invasion of the amniotic cavity (MIAC) (identification of microorganisms by either AF cultures or PCR/ESI-MS without intra-amniotic inflammation); 3) microbial-associated intra-amniotic inflammation (combination of MIAC and intra-amniotic inflammation); or 4) sterile intra-amniotic inflammation (an elevated AF IL-6 concentration without evidence of microorganisms using cultivation or molecular methods). Acute histologic chorioamnionitis was diagnosed based on the presence of inflammatory cells in the chorionic plate and/or chorioamniotic membranes [66 (link),67 (link)], and acute funisitis was diagnosed by the presence of neutrophils in the wall of the umbilical vessels and/or Wharton’s jelly, using criteria previously described [66 (link)–68 (link)]. For all newborns, data records regarding morbidity and mortality were reviewed. Neonatal outcome was assessed by measuring composite neonatal morbidity and mortality, defined as the presence of one or more of the following: bronchopulmonary dysplasia, respiratory distress syndrome, necrotizing enterocolitis, intraventricular hemorrhage ≥ grade III, and respiratory failure requiring mechanical ventilation. Perinatal mortality (stillbirth and neonatal death) were documented separately.