Protective versus Risk Factors for 18-month Outcomes in a multi-decade sample of preterm infants age 23-30 weeks

This paper summarizes risk and protective factors modulating cognitive, language and motor outcomes in a cohort of preterm infants from Connecticut Children's Medical Center and University of Connecticut Health Center. Infants were born at 23-30 weeks gestational age and admitted to the neonatal unit (1991 – 2017). Extracted and de-identified patient data included sex, gestational age (GA), birthweight, maternal health conditions (pre-eclampsia, diabetes, etc.), presence of necrotizing enterocolitis, intra-ventricular hemorrhage and grade, maternal magnesium sulfate (MGS) treatment, and administration of the methylxanthine (MX) adenosine antagonists (caffeine or theophylline) and timing (< 48 hrs from birth (early) or > 48 hrs (late)). Outcome measures were obtained at 18-month follow-up evaluations (Bayley Scale and/or Cognitive Adaptive Test/Clinical Linguistic and Auditory Milestone Scale). Scores on different components of the tests were z-scored and averaged into 3 categories for each infant as Language, Cognitive, and Motor indices.

Significant risk factors for poor outcomes were found to include: (1) being male, (2) extremely low birthweight (a better predictor of poor outcome than low GA), (3) positive inflammatory perinatal profile; and (4) MGS exposure in males, particularly when followed by early MX treatment. Factors leading to significantly better outcomes included: (1) MX exposure within 48 hours of birth, particularly in infants with inflammation (but excluding males with prior MGS exposure); and (2) perinatal MGS exposure, particularly in lower birthweight females (but excluding early MX-treated males). This novel evidence of sub-group specific therapeutic benefits and harms emphasizes a serious need for additional research on individualized therapeutic interventions for at-risk preterm infants and reveals a novel deleterious interaction between magnesium sulfate exposure and subsequent treatment with methyxanthines (e.g., caffeine) within 48 hours of birth for preterm boys.