Study design and patient population

In this retrospective cohort study, CR events were compared between preterm neonates with and without exposure to anteMg born at 18 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network (NRN). All infants born between 23 0/7 and 28 6/7 weeks’ gestation and enrolled in the Generic Database (GDB) registry from April 1, 2011, through March 31, 2012, were included in the study. Trained research personnel prospectively collected sociodemographic and clinical data from birth until death, discharge, or 120 days of age as part of the GDB registry. Each center’s institutional review board approved the study and data collection procedures. The decision to use anteMg was made by the clinician and recorded in the database; the indication for use was not collected. In addition, we do not have information on the protocols for magnesium use in our data registry. Exposure to anteMg was defined by maternal therapy with MgSO ₄ during the admission that resulted in the delivery of the infant. Gestational age was determined by best obstetric estimate. CR events include DR intubation, use of any respiratory support, and treatment of hypotension in the first 24 hours of life. The primary outcome was defined as the need for DR intubation or the use of any respiratory support at birth or in the first 24 hours of life. Only infants who were intubated (even if transiently) to allow positive pressure ventilation for breathing were included and coded as “yes” for DR intubation. If intubation was done for suctioning or to give surfactant and immediately removed, it is not included. Modes of respiratory support included high-frequency ventilation, oscillator, and jet; conventional ventilation, intermittent mandatory ventilation, synchronized intermittent mandatory ventilation, and/or assist control; and nasal synchronized intermittent mandatory ventilation or continuous positive airway pressure (CPAP) via nasal prongs. Use of high-frequency ventilation and conventional ventilation was defined as invasive mechanical ventilation (MV). Secondary outcomes were the following: continued need for any modes of respiratory support on the third day of life; hypotension in the first 24 hours of life defined by treatment with volume expansion, vasopressors, and/or corticosteroid; and presence of a PDA requiring either medical or surgical treatment. The decision to treat hypotension and treatments used were at the discretion of the clinical team. Other neonatal data included age at first and full enteral feeds; duration of ventilation and oxygen support; morbidities including bronchopulmonary dysplasia, retinopathy of prematurity, sepsis, and necrotizing enterocolitis; length of hospitalization; and mortality.

Sample size calculation and statistical analysis

Our study cohort included all infants who met the gestational age criteria and who were part of the GDB registry. Infants were grouped into those exposed and unexposed to anteMg. Based on the NRN’s SUPPORT trial with inborn infants of the same gestational age category, 34% of infants randomized to nasal CPAP needed intubation in the DR. Thus, we assumed a 30% rate of DR intubation in the group not exposed to anteMg and a 45% rate of DR intubation in the anteMg group. A total sample size of 326 (163 in each group) was needed to demonstrate statistical significance with α = 0.05, power = 0.80 in a 2-tailed test. Since MgSO ₄ is being increasingly used for fetal neuroprotection, it is possible that more infants may be exposed to anteMg than not. In that case, assuming a 2:1 ratio of anteMg exposed vs nonexposed infants, we calculated a sample size of 122 and 244 in the 2 groups, respectively. Based on the above sample size calculations, patients in the GDB registry were sufficient to detect even smaller differences in CR outcomes than estimated.

Data were analyzed using SAS statistical software (version 9.3; SAS Institute Inc., Cary, NC). Baseline maternal and neonatal clinical characteristics were compared using χ ² test and Fisher exact test for categorical variables and t test for continuous variables. Medians were tested using Wilcoxon test. A P value of < .05 was considered significant. Multivariate logistic regression models were used to determine the association between anteMg exposure and the primary outcome and other CR events such as hypotension and the risk of PDA. Covariates adjusted in the models included center, gestational age, ANS, and pregnancy-induced hypertension (PIH). Results were presented as odds ratio and 95% confidence interval.