Liveborn infants enrolled in the Generic Database registry of the NICHD Neonatal Research Network were eligible for inclusion in the study if they met the following three criteria: they were born between January 1, 2000, and December 31, 2011, their gestational age at birth was 22 0/7 to 28 6/7 weeks, and they were born in a Neonatal Research Network center. The inclusion criteria were chosen to ensure a consistent selection of infants throughout the study period, because the registry selection criteria were revised in 2008 to exclude infants not born in Neonatal Research Network centers and those with a gestational age at birth of 29 weeks or older. The registry was reviewed and approved by the institutional review board at each participating center. In 3 centers, written or oral informed consent was obtained from the parent or guardian, and in the other 22 centers, a waiver of the requirement for consent was approved by the institutional review board.
Data were collected prospectively by trained research coordinators for all liveborn infants, including those never admitted to an intensive care unit. Gestational age was determined with the use of the best obstetrical estimate based on the date of the last menstrual period, obstetrical variables, prenatal ultrasonography, or all three. If the best obstetrical estimate was unavailable or uncertain, gestational age was determined on the basis of the neonatologist’s estimate with the use of physical examination criteria, including the Ballard9 (link) or Dubowitz10 (link) examination. Enrolled infants were actively followed from birth to a postnatal age of 120 days, death, hospital discharge, or transfer to another center (whichever occurred first); infants who remained hospitalized for more than 120 days were evaluated for death until 1 year of age. The primary cause of death was prospectively identified and defined as the single underlying, proximate disease that initiated the series of events leading to the final cause of death. The definitions of the specific causes of death are listed in Table S1 in the Supplementary Appendix (available with the full text of this article at NEJM.org) and were included in the manual of operations for the registry. The primary cause of death had to be causally specific to the underlying disease and antecedent to all other causes with respect to time and pathologic relationship. Primary causes of death with infection or central nervous system (CNS) injury as complicating factors were identified from prespecified subcauses. If autopsy findings were available, the cause of death was based on both clinical and autopsy findings. In situations in which the cause of death was not certain, the single cause of death was selected after consultation with the principal investigator (or appointee) from each center. However, interobserver reliability was not assessed. Causes of death that could not be classified as one of the prespecified causes were classified as “other.” Causes that were investigated but could not be established were classified as “unknown.”