Developmental and neuropathological consequences of ductal ligation in the preterm baboon

Abstract

A patent ductus arteriosus (PDA) alters pulmonary mechanics and regional blood flow in the preterm infant. Its significance with respect to brain injury and brain development are unclear. We evaluated the effects of surgical ductal ligation on the preterm baboon brain. Baboons were delivered at 125 d of gestation (dg, term approximately 185 dg) and ventilated for 14 d (n = 12). The PDA was ligated 6 d after delivery (n = 7) or left untreated (n = 5). Animals were euthanized at 139 dg and brains compared histologically with gestational control fetuses (n = 7) at 140 dg. Brain and body weights were reduced (p < 0.05) in both groups of ventilated preterm animals; however, the brain to body weight ratio was increased (p < 0.01) in ligated, but not unligated newborns compared with gestational controls. No overt lesions were observed in either premature newborn group. Astrocyte density in the neocortex and hippocampus were greatest in the unligated newborns (p < 0.01). Myelination and oligodendrocytes were reduced (p < 0.05) in both premature newborn groups. The brain growth and development index was reduced, and the damage index was increased in prematurely delivered baboons. Surgical ligation of the PDA does not increase the incidence of brain injury and may be beneficial if the PDA is contributing to persistent pulmonary and hemodynamic instability.

Figure 1

The growth and development index scores were decreased (†, p<0.001) in both unligated and ligated groups compared to gestational controls but there was no difference between prematurely delivered groups.

Figure 2

A-C: GFAP-IR in the neocortex; Astrocyte density was increased in unligated (B) compared to ligated (C) and control animals (A). D-F: GFAP-IR in the hippocampus; Astrocyte density within the stratum radiatum of the hippocampus was increased in unligated (E, p<0.001) and ligated (F, p<0.05) compared to control animals (D) and in unligated animals (p<0.01) compared to ligated animals; arrows indicating astrocytes. G-L: There was a reduction (p<0.05) in the density of myelin basic protein-immunoreactive (MBP-IR) oligodendrocytes in unligated (H, K) and ligated (I, L) animals compared to controls (G, J); arrows indicate MBP-IR oligodendrocytes. A-C=70μm; D-I=1.7mm; J-L=160μm.

Figure 3

Regression analysis included both groups of prematurely delivered animals (unligated and ligated). A positive correlation was observed between the mean flux in FiO₂ and the brain damage index score (r²=0.33; p<0.05).