OBJECTIVE Periventricular hemorrhagic infarction (PVHI) is a major contributing factor to poor neurodevelopmental outcomes in preterm infants. We hypothesized that surviving infants with unilateral PVHI would have more favorable outcomes than those with bilateral PVHI. METHODS This was a multicenter, retrospective study of infants who were admitted to 3 NICUs in North Carolina from 1998 to 2004. The clinical course and late neuroimaging studies and neurodevelopmental outcomes of 69 infants who weighed <1500 g and had confirmed PVHI on early cranial ultrasonography were reviewed. A predictive model for Bayley Scales of Infant Development, Second Edition, Mental Developmental Index (MDI) <70 was constructed by using radiologic and clinical variables. RESULTS Infants with unilateral PVHI had higher median MDI (82 vs 49) and Psychomotor Developmental Index (53 vs 49) than infants with bilateral PVHI. Infants with unilateral PVHI were less likely to have severe cerebral palsy (adjusted odds ratio: 0.15 [95% confidence interval (CI): 0.05–0.45]) than infants with bilateral PVHI. Infants who had unilateral PVHI and developed periventricular leukomalacia and retinopathy of prematurity that required surgery had an increased probability of having MDI <70 compared with those without these complications (probability of MDI <70: 89% [95% CI: 0.64–1.00] vs 11% [95% CI: 0.01–0.28]). CONCLUSIONS Infants with unilateral PVHI had better motor and cognitive outcomes than infants with bilateral PVHI. By combining laterality of PVHI, periventricular leukomalacia, and retinopathy of prematurity it is possible to estimate the probability of having an MDI <70, which will assist clinicians when counseling families.

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Altered gene expression and/or actions of the insulin-like growth factors (IGFs) have been implicated in the mediation of both pre- and postnatal growth retardation secondary to glucocorticoid excess. To investigate this possibility, we assessed the gene expression of the IGFs, the type I IGF receptor, and IGF-binding proteins (IGFBPs) in 20-day gestation liver and lung of growth-retarded fetuses whose mothers were treated with dexamethasone (DXM; 100 micrograms, ip, daily) on gestation days 15-19 (gestation = 21-22 days). DXM treatment in dams produced fetal growth retardation without decreasing litter size (32% decrease in fetal body weight). Both fetal liver and lung demonstrated decreased wet weight (48% and 47%, respectively) and DNA content (65% and 51%, respectively) compared to control animals. Our results suggest that increased expression of IGFBP-1, and possibly IGFBP-2, is involved in mediating the marked growth retardation. As assessed by solution hybridization assays and Northern blot analysis, there was an 8.5-fold increase in IGFBP-1 mRNA expression in the livers of DXM-treated fetal animals compared to that in sham-injected controls (P less than 0.002). IGFBP-2 mRNA expression was also increased (60%) in fetal liver, whereas IGFBP-3 was decreased (57%). In fetal lung, IGFBP-1 transcript abundance was also higher in DXM-treated fetal animals. Serum concentrations of IGFBP-1, but not those of IGFBP-2, were increased (approximately 4-fold) in the DXM-treated fetuses, as quantified by [125I]IGF-I ligand blotting and IGFBP-2 immunoblotting. Because hypoinsulinemia increases the expression of IGFBP-1 and -2, serum insulin concentrations were measured and found to be decreased in the DXM-treated fetuses (24 microU/ml) compared to control values (72 microU/ml). Analysis of mRNA expression for IGF-I, IGF-II, and the type 1 receptor transcripts did not support a role for decreased IGF or IGF receptor expression in the etiology of DXM-mediated growth retardation. IGF-I was unchanged in both liver and lung, and IGF-II transcripts were increased by 31% in liver and unchanged in lung of DXM-treated fetal animals. Northern analysis of hepatic and lung poly(A) RNA demonstrated no evidence for independent regulation of specific-sized IGF transcripts. Further, type 1 IGF receptor RNA abundance increased 42% in fetal liver and was unchanged in lung. Because IGFBPs may modulate IGF action, these results suggest that increased IGFBP-1, and possibly IGFBP-2, expression may be of importance in the etiology of DXM-induced fetal growth retardation.

Glucocorticoid exposure accelerates the maturation of small bowel mucosa. We hypothesized that IGF-I, a mitogen and differentiating peptide expressed in small bowel, mediates steroid-induced change within the developing ileum. To investigate this possibility, we intraperitoneally administered 1 g/gm/d of dexamethasone (DEX) or equal volumes of saline to litter-mate newborn mice. The animals were killed on d 1-3 of life and their ileums were harvested and prepared for microscopy. Tissue sections of ileum were examined for morphologic analyses, mucin staining, immunolocalization of IGF-I and -II, proliferating cell nuclear antigen (PCNA), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and in situ hybridization for IGF-I transcripts. Morphologic comparisons showed increases in goblet cell number, total cell number, and TUNEL-positive cells within the mucosa of DEX-treated animals. In contrast, the number of smooth muscle nuclei per cross-section was unchanged with DEX treatment despite a reduction in the number of PCNA-positive nuclei and an increased bowel circumference. These findings suggest the muscularis stretches to accommodate increasing bowel diameter. IGF-I peptide was localized to the mesenchyme of all control animals. After 48 h of DEX treatment, IGF-I was detected in the epithelia whereas mesenchymal IGF-I localization appeared diminished. In situ hybridization analyses for IGF-I transcripts showed no differences in localization between the groups. We conclude that DEX administration differentially affects adjacent tissues in the newborn ileum and that the associated changes in IGF-I localization are consistent with its participation in this process. The fetal small bowel undergoes rapid maturation during the latter third of gestation by increasing villus length, mucosal thickness, goblet cell number, lumen diameter, and smooth muscle thickness. Cell proliferation, differentiation, and turnover must be coordinated by local growth factors for these changes to occur. The IGFs, with their known actions on cell proliferation, cell differentiation, cell motility, matrix production, and cell survival are logical candidates for participation in this process.There are two forms of IGF. IGF-II is abundant in fetal tissue but rapidly wanes around the time of birth and is increasingly difficult to detect thereafter. IGF-I has been shown to be important for both growth and repair within developing and mature bowel models (1-3). For example, transgenic mice that overexpress IGF-I have longer small bowel length and increased mucosal mass when compared with controls. Likewise, i.v. IGF-I has been shown to rescue mucosal and villus atrophy in mature rodents receiving prolonged parental nutrition. Finally, IGF-I has been demonstrated to be a potent promoter of mucosal growth after bowel resection. Collectively, these findings suggest a central role for IGF-I in growthrelated phenomena of the bowel mucosa.Glucocorticoids also affect the growth and differentiation of the bowel mucosa. Examp...

Altered gene expression and/or actions of the insulin-like growth factors (IGFs) have been implicated in the mediation of both pre- and postnatal growth retardation secondary to glucocorticoid excess. To investigate this possibility, we assessed the gene expression of the IGFs, the type I IGF receptor, and IGF-binding proteins (IGFBPs) in 20-day gestation liver and lung of growth-retarded fetuses whose mothers were treated with dexamethasone (DXM; 100 micrograms, ip, daily) on gestation days 15-19 (gestation = 21-22 days). DXM treatment in dams produced fetal growth retardation without decreasing litter size (32% decrease in fetal body weight). Both fetal liver and lung demonstrated decreased wet weight (48% and 47%, respectively) and DNA content (65% and 51%, respectively) compared to control animals. Our results suggest that increased expression of IGFBP-1, and possibly IGFBP-2, is involved in mediating the marked growth retardation. As assessed by solution hybridization assays and Northern blot analysis, there was an 8.5-fold increase in IGFBP-1 mRNA expression in the livers of DXM-treated fetal animals compared to that in sham-injected controls (P less than 0.002). IGFBP-2 mRNA expression was also increased (60%) in fetal liver, whereas IGFBP-3 was decreased (57%). In fetal lung, IGFBP-1 transcript abundance was also higher in DXM-treated fetal animals. Serum concentrations of IGFBP-1, but not those of IGFBP-2, were increased (approximately 4-fold) in the DXM-treated fetuses, as quantified by [125I]IGF-I ligand blotting and IGFBP-2 immunoblotting. Because hypoinsulinemia increases the expression of IGFBP-1 and -2, serum insulin concentrations were measured and found to be decreased in the DXM-treated fetuses (24 microU/ml) compared to control values (72 microU/ml). Analysis of mRNA expression for IGF-I, IGF-II, and the type 1 receptor transcripts did not support a role for decreased IGF or IGF receptor expression in the etiology of DXM-mediated growth retardation. IGF-I was unchanged in both liver and lung, and IGF-II transcripts were increased by 31% in liver and unchanged in lung of DXM-treated fetal animals. Northern analysis of hepatic and lung poly(A) RNA demonstrated no evidence for independent regulation of specific-sized IGF transcripts. Further, type 1 IGF receptor RNA abundance increased 42% in fetal liver and was unchanged in lung. Because IGFBPs may modulate IGF action, these results suggest that increased IGFBP-1, and possibly IGFBP-2, expression may be of importance in the etiology of DXM-induced fetal growth retardation.