Developmental assessment of prematurely born children exposed to antenatal corticosteroids.

The beneficial effect of antenatal steroid administration on fetal lung maturation and on premature infant survival was first reported by Liggins and Howie in 1972 [1] and was subsequently confirmed by others [2±4]. Several studies have demonstrated a significant reduction in the incidence of intraventricular hemorrhage and periventricular leukomalacia in premature infants following antenatal exposure to exogenous steroids [5±7], and some authors have also observed a reduction in the incidence of bronchopulmonary dysplasia [8], necrotizing enterocolitis [9] and retinopathy of prematurity [10]. The National Institutes of Health Consensus Developmental Panel on the effect of corticosteroids for fetal maturation on perinatal outcome concluded in 1994 that the use of a single course of corticosteroids for fetal maturation is a rare sample of a technology that yields substantial cost savings in addition to improving health [11]. The presence of steroids is essential for the normal growth and development of the central nervous system [12]. In vitro studies have suggested that corticosteroids may promote resilient neuronal activity through their effect on various mediators, such as ciliary neurotrophic factor and basic fibroblast growth factor, and also on the availability of insulin-like growth factor-1 binding protein [13]. Being anti-inflammatory agents, steroids may also block the action of pro-inflammatory cytokines implicated in the evolvement of white matter cerebral lesions [14,15]. On the other hand, under normal circumstances, the brain is protected from a potentially harmful excess of steroids, and access of maternal cortisol and corticosterone to the fetus is low due to placental 11 b-hydroxysteroid dehydrogenase activity [12]. This enzyme, however, has a low affinity for synthetic glucocorticoids, which pass rapidly from mother to fetus [12]. Despite the improved neonatal outcome, concern has been raised regarding the long-term implications of exposure to antenatal steroids [16,17]. Animal studies have demonstrated that antenatal exogenous steroids administered at critical stages of development may alter later neuro-endocrine function and behavior pattern [12]. Ample evidence has accumulated regarding the inhibitory effect of antenatal exogenous steroids on fetal body growth and on the growth and development of the fetal brain [18± 22]. The magnitude of the effect differed according to the animal species studied and the number of doses given [12]. However, most animal studies demonstrated a larger inhibitory effect following multiple antenatal exposures than that following a single exposure [23]. During the last decade it became common practice to administer repetitive courses of steroids to women who remain at risk for premature delivery 7 days after the initial course [21,24]. The trend was consequent to the widely held belief, based on unsubstantiated initial results, that there is a decreased benefit from antenatal steroids 7 days after treatment [24]. While a few human studies have provided evidence that exposure to repetitive courses of steroids results in improved neonatal pulmonary function, others failed to observe similar beneficial effects and documented an inhibitory effect on birth weight and head circumference and an increased incidence of neonatal sepsis and mortality [21±23,25,26]. In view of the above data, recent publications have cautioned against the antenatal administration of multiple courses of corticosteroids, advocating the use of only one or two courses [17,24]. Consideration of the appropriate timing and dosage of exogenous steroid administration is incomplete without evaluating the long-term effect on human outcome. While quite abundant data have accumulated over the years regarding the long-term effect of a single course of antenatal steroids, follow-up studies of multiple course treatment are limited in number.