Necrotizing Enterocolitis Is Not Associated With Sequence Variants in Antioxidant Response Genes in Premature Infants.

Reactive oxygen species mediate intestinal injury in necrotizing enterocolitis (NEC), and yet the contribution of antioxidant response (ARE) gene polymorphisms to NEC risk remains unknown. Premature infants recruited in a multicenter study were genotyped for 6 ARE variants. Among 637 infants, 52 had NEC, and 22 developed surgical NEC. Gestational age <28 weeks (P < 0.02) and African American race (P = 0.03) were associated with NEC. The NFE2L2 (rs6721961), SOD2 (rs4880), GSTP1 (rs1695), NQO1 (rs1800566), GCLC (rs17883901), and HMOX1 (rs2071747) variants were not associated with medical or surgical NEC. This study does not support a role for common deleterious ARE variants in NEC.

Antioxidant response genes sequence variants and BPD susceptibility in VLBW infants.

BACKGROUND: Lung injury resulting from oxidative stress contributes to bronchopulmonary dysplasia (BPD) pathogenesis. Nuclear factor erythroid-2 related factor-2 (NFE2L2) regulates cytoprotective responses to oxidative stress by inducing enzymes containing antioxidant response elements (ARE). We hypothesized that ARE genetic variants will modulate susceptibility or severity of BPD in very-low-birth-weight (VLBW) infants. METHODS: Blood samples obtained from VLBW infants were used for genotyping variants in the SOD2, NFE2L2, GCLC, GSTP1, HMOX1, and NQO1 genes. SNPs were genotyped utilizing TaqMan probes (Applied Biosystems (ABI), Grand Island, NY), and data were analyzed using the ABI HT7900. Genetic dominance and recessive models were tested to determine associations between SNPs and BPD. RESULTS: In our cohort (n = 659), 284 infants had BPD; 135 of whom developed severe BPD. Presence of the hypomorphic NQO1 SNP (rs1800566) in a homozygous state was associated with increased BPD, while presence of the NFE2L2 SNP (rs6721961) was associated with decreased severe BPD in the entire cohort and in Caucasian infants. In regression models that adjusted for epidemiological confounders, the NQO1 and the NFE2L2 SNPs were associated with BPD and severe BPD, respectively. CONCLUSION: Genetic variants in NFE2L2-ARE axis may contribute to the variance in liability to BPD observed in preterm infants. These results require confirmation in independent cohorts.

A TLR5 (g.1174C > T) variant that encodes a stop codon (R392X) is associated with bronchopulmonary dysplasia.

Current evidence supports a major role for inherited factors in determining bronchopulmonary dysplasia (BPD) susceptibility. The Toll-like receptor (TLR) family of proteins maintain pulmonary homeostasis in the developing lung by aiding pathogen recognition and clearance, regulating inflammation, and facilitating reparative tissue growth. We hypothesized that sequence variation in the TLR pathway genes would alter the susceptibility/severity of BPD in preterm infants. Very low birth-weight infants were recruited prospectively in a multi-center study involving collection of blood samples and clinical information. Nine TLR pathway single-nucleotide polymorphisms were genotyped using a multiplexed single-base extension assay. BPD outcomes were compared among infants with and without the variant allele using Chi-square or Fisher's exact tests. In our cohort (n = 289), 66 (23.6%) infants developed BPD, out of which 32 (11.2%) developed severe BPD. The TLR5 (g.1174C > T) variant was associated with BPD (P = 0.03) and severe BPD (P = 0.004). The TIRAP (g.2054C > T) variant was associated with BPD (P = 0.04). Infants heterozygous for the X-linked IRAK1 (g.6435T > C) variant had a lower incidence of BPD compared to infants homozygous for either the reference or variant allele (P = 0.03). In regression models that controlled for potential epidemiological confounders, the TIRAP variant was associated with BPD, and the TLR5 variant was associated with severe BPD. Our data support the hypothesis that aberrant pathogen recognition in premature infants arising from TLR pathway genetic variation can contribute to BPD pathogenesis.

Effect of dose on response to adrenocorticotropin in extremely low birth weight infants.

CONTEXT: Various cosyntropin doses are used to test adrenal function in premature infants, without consensus on appropriate dose or adequate response. OBJECTIVE: The objective of this study was to test the cortisol response of extremely low birth weight infants to different cosyntropin doses and evaluate whether these doses differentiate between groups of infants with clinical conditions previously associated with differential response to cosyntropin. DESIGN: The design was a prospective, nested study conducted within a randomized clinical trial of low-dose hydrocortisone from November 1, 2001, to April 30, 2003. SETTING: The setting was nine newborn intensive care units. PATIENTS: The patients included infants with 500-999 g birth weight. INTERVENTION: The drug used was cosyntropin, at 1.0 or 0.1 microg/kg, given between 18 and 28 d of birth. MAIN OUTCOME MEASURE: We measured the cortisol response to cosyntropin. RESULTS: Two hundred seventy-six infants were tested. Previous hydrocortisone treatment did not suppress basal or stimulated cortisol values. Cosyntropin, at 1.0 vs. 0.1 microg/kg, yielded higher cortisol values (P < 0.001) and fewer negative responses (2 vs. 21%). The higher dose, but not the lower dose, showed different responses for girls vs. boys (P = 0.02), infants receiving enteral nutrition vs. not (P < 0.001), infants exposed to chorioamnionitis vs. not (P = 0.04), and those receiving mechanical ventilation vs. not (P = 0.02), as well as a positive correlation with fetal growth (P = 0.03). A response curve for the 1.0-microg/kg dose for infants receiving enteral nutrition (proxy for clinically well infants) showed a 10th percentile of 16.96 microg/dl. Infants with responses less than the 10th percentile had more bronchopulmonary dysplasia and longer length of stay. CONCLUSIONS: A cosyntropin dose of 0.1 microg/kg did not differentiate between groups of infants with clinical conditions that affect response. We recommend 1.0 microg/kg cosyntropin to test adrenal function in these infants.

Prophylaxis of early adrenal insufficiency to prevent bronchopulmonary dysplasia: a multicenter trial.

BACKGROUND: Infants developing bronchopulmonary dysplasia (BPD) show decreased cortisol response to adrenocorticotropic hormone. A pilot study of low-dose hydrocortisone therapy for prophylaxis of early adrenal insufficiency showed improved survival without BPD at 36 weeks' postmenstrual age, particularly in infants exposed to histologic chorioamnionitis. METHODS: Mechanically ventilated infants with birth weights of 500 to 999 g were enrolled into this multicenter, randomized, masked trial between 12 and 48 hours of life. Patients received placebo or hydrocortisone, 1 mg/kg per day for 12 days, then 0.5 mg/kg per day for 3 days. BPD at 36 weeks' postmenstrual age was defined clinically (receiving supplemental oxygen) and physiologically (supplemental oxygen required for O2 saturation > or =90%). RESULTS: Patient enrollment was stopped at 360 patients because of an increase in spontaneous gastrointestinal perforation in the hydrocortisone-treated group. Survival without BPD was similar, defined clinically or physiologically, as were mortality, head circumference, and weight at 36 weeks. For patients exposed to histologic chorioamnionitis (n = 149), hydrocortisone treatment significantly decreased mortality and increased survival without BPD, defined clinically or physiologically. After treatment, cortisol values and response to adrenocorticotropic hormone were similar between groups. Hydrocortisone-treated infants receiving indomethacin had more gastrointestinal perforations than placebo-treated infants receiving indomethacin, suggesting an interactive effect. CONCLUSIONS: Prophylaxis of early adrenal insufficiency did not improve survival without BPD in the overall study population; however, treatment of chorioamnionitis-exposed infants significantly decreased mortality and improved survival without BPD. Low-dose hydrocortisone therapy did not suppress adrenal function or compromise short-term growth. The combination of indomethacin and hydrocortisone should be avoided.