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BACKGROUND. Recent investigations have reported an influence of thrombophilic mutations and antithrombotic risk factors with development of intraventricular hemorrhage. It was our objective for this study to investigate the impact of genetic polymorphisms of hemostasis genes on the primary outcome measures of sepsis, bronchopulmonary dysplasia, intraventricular hemorrhage, and periventricular leukomalacia in a large cohort of very low birth weight infants. METHODS. There were 586 very low birth weight infants enrolled prospectively in a multicenter trial between September 2003 and July 2005, and an additional 595 very low birth weight infants, who had been recruited in a previous prospective trial, were studied. DNA samples were taken by buccal swab, and genotypes of factor V Leiden mutation, prothrombin G20210A mutation, the factor VII-323 del/ins polymorphism, and the factor XIII-Val34Leu polymorphisms were determined by polymerase chain reaction and restriction enzyme digestion. RESULTS. In contrast to data published previously, the frequency of intraventricular hemorrhage or periventricular leukomalacia was not significantly influenced by any of the genetic variants tested. Carriers of the factor XIII-Val34Leu polymorphism, however, had a higher sepsis rate and a longer period of hospital care compared with noncarriers. The factor VII-323 del/ins polymorphism was found to be a potential protective factor against bronchopulmonary dysplasia. CONCLUSIONS. We could not confirm previously reported associations of hemostasis gene variants and development of intraventricular hemorrhage in very low birth weight infants. To better understand gene-disease associations in very low birth weight infants, the prospective development of large-scale cohorts with well-defined phenotypes and corresponding DNA samples is essential. Key Words VLBW, outcome, hemostasis genes, polymorphism Abbreviations VLBW--very low birth weight IVH--intraventricular hemorrhage PVL--periventricular leukomalacia BPD--bronchopulmonary dysplasia ROP--retinopathy of prematurity, GENETIC ASSOCIATION STUDIES have been applied to a wide range of complex diseases to identify populations who are at an increased risk. For example, substantial progress has been made in [...]

The activity of neutrophil elastase may cause lung damage in newborns with severe respiratory distress syndrome (RDS). Neutrophils are cells of the immune system that release elastase. Samples of lung fluid were taken from 140 newborns with severe RDS after they had surfactant replacement therapy. The samples were analyzed for elastase activity and alpha-1-proteinase inhibitor activity. Forty-two of the infants (30%) had elevated levels of free elastase activity in their lungs and 98 (70%) had no elastase activity in their lungs. The infants with no elastase activity had protective levels of alpha-1-proteinase inhibitor, a substance that protects the lungs against the tissue-damaging activity of elastase. Infants with elevated free elastase activity had a higher risk of developing pulmonary interstitial emphysema.

There is now convincing evidence that the severity of neonatal respiratory distress syndrome can be reduced by surfactant replacement therapy; however, the optimal therapeutic regimen has not been defined. This randomized European multicenter trial was designed to determine whether the beneficial effects of a single large dose of Curosurf (200 mg/kg) in babies with severe respiratory distress syndrome (arterial to alveolar oxygen tension ratio 0.10) could be enhanced by using multiple doses of surfactant. Preterm neonates (birth weight 700 to 2000 g) with severe respiratory distress syndrome requiring artificial ventilation with fraction of inspired oxygen [is greater than or equal to] 0.6 were randomized into two groups at an age of 2 to 15 hours. Both groups received the usual dose of Curosurf (200 mg/kg) immediately after randomization. In neonates randomized to receive multiple-dose treatment, two additional doses of Curosurf (100 mg/kg each) were instilled into the airways (12 and 24 hours after the initial dose) provided that the patients still needed artificial ventilation with fraction of inspired oxygen > 0.21. In both groups (single dose: n = 176, multiple doses: n = 167) there was a rapid improvement in oxygenation as reflected by a threefold increase in arterial to alveolar oxygen tension ratio within 5 minutes after surfactant instillation (P < .001), and peak inspiratory pressure and mean airway pressure could be reduced significantly during the first 6 hours after surfactant treatment. In addition, ventilatory requirement (peak inspiratory pressure, ventilatory efficiency index) was reduced in the multiple-dose group 2 to 4 days after randomization (P < .05 to .01). Sixty-five percent of the patients randomized to the multiple-dose regimen and 68% of the single-dose group needed supplemental oxygen 12 hours after the first treatment. Analysis of 28-day outcome data showed a reduction of the incidence of pneumothorax in the multiple-dose group (9% vs 18%, P < .01). The primary end point, of combined incidence of mortality and bronchopulmonary dysplasia, was 33% in the single-dose group and 27% in the multiple-dose group (P = .08). Mortality at 28 days was reduced from 21% in the single-dose group to 13% in the multiple-dose group (P < .05 by logistic regression). It is concluded that treatment with multiple doses of surfactant is more effective than single-dose treatment in severe neonatal respiratory distress syndrome, further reducing pneumothorax and mortality.