A psychoneuroimmunologic examination of cumulative perinatal steroid exposures and preterm infant behavioral follow-up

Nearly 40 years have passed since Liggins and Howie (1972) identified the benefits that glucocorticoids offer for premature infant lung development. These initial findings led to further research and promotion of the use of antenatal steroids by the National Institutes of Health (2000). Clinicians administered repeated antenatal steroid treatments like dexamethasone (DEX) to women at risk of premature delivery prior to 32 weeks’ postconceptional age (PCA) and with the recurrence of premature labor. Initially, the recommended standard of care for single-course antenatal DEX was to administer four individual 6-mg doses intramuscularly (IM) 12 hr apart (National Institute of Health [NIH], 1994). At the same time, postnatal steroids were primarily administered in the neonatal intensive care unit (NICU) to reduce pulmonary inflammation leading to lung injury and to decrease the risk of bronchopulmonary dysplasia ([BPD] Jobe & Ikegami, 2000). Additionally, clinicians used long-term steroid-tapering regimens to aid in decreasing infant dependence on ventilators and oxygen (Halliday & Ehrenkranz, 2001a, 2001b). Glucocorticoids are essential for normal hypothalamic–pituitary–adrenal (HPA) axis activity; however, many researchers have warned that exposure to excess endogenous or synthetic glucocorticoids like DEX during a vulnerable period of fetal development, prior to 40 weeks’ PCA adversely affects the HPA axis, immunity, and behavioral outcomes (Ng et al., 1999). For example, Shoener, Baig, and Page (2006) found an association between late-gestation DEX exposure in rats and persistent changes in modulating HPA axis activity and mediated response to stress. Experts have also expressed concerns that increased steroid dosing may lead to neurologic problems, as additional animal studies have shown (Dunlap, Archer, Quinlivan, Beazley, & Newnham, 1997). Animal studies have also suggested that antenatal DEX might decrease immune responsiveness, resulting in prolonged effects post-birth (Coe & Lubach, 2005). While animal studies raise concerns, it is difficult to extrapolate their findings to humans because of the wide variations in drug dosage and duration, infant age, birth weights, and severity of illness. In fact, human infants exposed to higher cumulative perinatal steroid (PNS) may show no neurologic side effects until later in life. Clinical trials have associated steroid treatment with stunted growth, cerebral atrophy, neurobehavioral deficits, and endocrine disruption (Benesova & Pavlik, 1989). Due to these concerns, experts began to discourage the use of multiple-course antenatal steroids in 2000. In 2002, the American Academy of Pediatrics and the Canadian Paediatric Society Committees on Fetus and Newborn jointly advised against the routine use of systemic DEX for the prevention of chronic lung disease (CLD) in preterm infants. They based their recommendations on data-based evidence that antenatal or postnatal steroids were linked to increased risk of impaired growth and development and identified the need for long-term follow-up research (Barrington, 2001; Doyle & Davis, 2000; French, Hagan, Evans, Godfrey, & Newnham, 1999; Stark et al., 2001; Yeh et al., 2004). Even the minimal postnatal DEX treatment at 0.2 mg/kg was under scrutiny due to research identifying higher infant mortality rate, more intraventricular hemorrhage (IVH) Grades 3 and 4, and more necrotizing enterocolitis (NEC) in infants exposed to this dose compared to control infants (Kopelman, Moise, Holbert, & Hegemier, 1999; Peabody, 2000). Most basic science studies of steroid exposure conducted in the laboratory have examined the effects either on the body or on the brain but not both. Biophysiologic stress and immunity are more complex in the NICU than in the laboratory setting and both impact health outcomes. Psychoneuroimmunology (PNI) focuses on the interactions among the central nervous system, the endocrine system, and the immune system and is a useful framework for studying biophysiologic stress that may alter the HPA system (Adler, Felten, & Cohen, 2001; Daruna, 2004). Matthews (2001) described potential influences of steroids on the fetal brain that can lead to altered behavior and immunity beyond infancy. However, no human preterm infant studies to date have used a PNI approach to evaluate associations among DEX as a source of cumulative PNS exposure, early immunity, biophysiologic stress, and factors that could affect behavioral outcomes. Our primary aim in the present study was to examine relationships among preterm infant behavioral outcomes and maternal/infant DEX treatments while considering other potential factors such as immune markers at birth and neonatal sepsis. We asked the following research questions: (a) Do relationships exist between preterm infant cumulative PNS exposure and childhood behavioral problems? (b) Do maternal/infant characteristics (e.g., immune markers, sepsis, and biophysiologic stress) influence these relationships? We hypothesized that greater premature infant exposure to PNS and higher levels of biophysiologic stress at birth might underpin relationships with early immunity and life events associated with childhood behavioral problems.