The advent of neonatal intensive care led to a dramatic improvement in survival rates for children born preterm (Fig. 56.1), with subsequent concerns regarding the long-term outcomes of these new survivors. In the last 30 years, there have been multiple publications documenting their long-term neurodevelopmental and health outcomes. The spectrum of complications and morbidity is inversely related to gestational age (GA) (5). The early focus was on low-birthweight (LBW) infants (<2,500 g birth weight), very-low-birth-weight (VLBW) infants (<1,500 g), and extremely low-birth-weight (ELBW) infants (<1,000 g) and as GA assessments improved, on very preterm (<32 weeks’ GA) and extremely preterm (<29 weeks’ GA) infants. Late preterm (34 to 36 weeks’ GA) infants comprise 9% of all live births and 70% of all births less than 37 weeks’ gestation. Though the incidence of neurodevelopmental disability in late preterm infants is less than their more premature counterparts, they are more than 3 times as likely as term babies to be diagnosed with cerebral palsy (CP) and 1.25 times more likely to be diagnosed with developmental delay or a cognitive impairment (6).

The preterm infant is different from the term infant because of the vulnerability of the actively maturing brain, increased risk of brain injury, and the effect of injury on brain maturation. Preterm birth occurs at a time of peak brain growth, synaptogenesis, developmental regulation of specific receptor populations, and central nervous system organization and differentiation (7). The transient fetal subplate neurons that guide cortical neuron wiring and maturation are particularly vulnerable to hypoxia. The periventricular white matter is the zone most vulnerable to watershed injury from hypoxia in the preterm infant. Intraventricular hemorrhage and periventricular hemorrhage are injuries specific to prematurity because of the evolution of the germinal matrix. The risk of neurodevelopmental disability with intraventricular hemorrhage is 5% to 10% for grade 1, 15% to 20% for grade 2, 35% to 55% for grade 3, and over 90% for grade 4 (8). Concomitant ischemic parenchymal injury is likely a significant contributor to the disabilities seen with intraventricular hemorrhage (8). Other susceptible areas include the hippocampus, which is associated with working memory and numeracy problems. Corticostriatothalamic pathway alterations may affect attention and neurobehavior (9), and cerebellar volume reduction is associated with poorer cognitive function (10). Newer studies using diffusion tensor magnetic resonance imaging (MRI) techniques are showing widespread abnormal maturation in white (11) and gray matter (12), independent of destructive brain lesions (13). MRI performed at term equivalent age can provide important information about brain injury and development, is feasible, and is a useful tool to predict neurodevelopmental outcome (4). Routine MRI for preterm babies in neonatal intensive care units (NICUs) has been recommended by some (4). Risk factors during the period of neonatal intensive care may affect the brain in multiple ways.

Factors that affect outcome can be categorized as biologic factors, therapeutic interventions, and environmental factors. Biologic factors include central nervous system insults (periventricular-intraventricular hemorrhage, periventricular leukomalacia, hydrocephalus), degree of prematurity, male sex, multiple birth, chorioamnionitis, necrotizing enterocolitis or sepsis (7), chronic lung disease, severe growth restriction (14), and some congenital abnormalities. Prolonged postnatal steroid therapy is associated with adverse neurologic outcomes in humans (15). In animal models, reductions in cerebral blood flow and hippocampal volume, altered white matter protein metabolism, delayed myelination of the optic axon, altered hypothalamic-pituitary-adrenal axis, and changes in dopamine receptor responses (16) have been associated with steroids. The repeated painful procedures that very premature babies undergo during their neonatal intensive care admission have been associated with abnormal white matter microstructure and intelligence at 7 years of age (17). Opioids do not mitigate this effect. Animal models have shown that general anesthetics can cause neuronal apoptosis in developing brains. Though not conclusive, there is concern that in young children repeated exposures to general anesthetics may be associated with learning disabilities and attention deficit disorder (18). Protective therapeutic interventions include a single course of antenatal corticosteroids, caffeine for apnea of prematurity, and antenatal magnesium sulfate.

The child’s family characteristics are major determinants of neurodevelopmental outcome and increasingly so as the child grows older. Measures of socioeconomic status include family income, parental educational level, and socioeconomic status, which may
also interact with biologic factors. Mother-child interaction is a better predictor before 2 years of age (19). Maternal depression, substance use, and crowding in the home have a negative effect on outcome, and early intervention services are protective (14).