NAEYE SHOWED IN a large autopsy series in 1980 that infants who succumbed to sudden infant death syndrome (SIDS) had morphological signs of antecedent hypoxia in several organs (1). Among the most important findings were brain stem gliosis, also described by Takashima et al. two years earlier (2), and confirmed by Kinney et al.(3), and Valdes-Dapena et al.(4). Since brainstem astrogliosis takes several days to develop, a search for biochemical hypoxia markers was initiated. The first biochemical evidence was demonstration of elevated hypoxanthine in vitreous humor in approximately 80% of SIDS cases (5, 6). However, a substantial overlap was found between victims of SIDS and infectious deaths (7), a possible reason why others were not able to confirm these results (8).

Jones et al.(9) recently found evidence that SIDS is preceded by prolonged hypoxia. These authors measured vascular endothelial growth factor (VEGF) in the cerebrospinal fluid, vitreous humor, and serum of SIDS infants. SIDS was verified according to well-established criteria. A control group consisted of cases whose cause of death was clearly established.

VEGF is an important factor for neovascularization, and is upregulated by hypoxia and down regulated by hyperoxia (10–12). Therefore, a high level may indicate preceding hypoxia. In CSF, mean VEGF was 3.6 fold higher in the SIDS group than in controls. With a VEGF cut off point of 200 pg/dL, 60% of the SIDS cases had elevated levels compared with 6.5% of controls. The study by Jones et al. is important, although it contains some well-known weaknesses in SIDS research including the establishment of a proper control group and the biochemical post mortem changes. The causes of death in the control group were heterogeneous and several of these including pneumonia, sepsis, suffocation, and congenital heart diseases might also be preceded by hypoxia. In spite of this, Jones et al.' s data indicate that hypoxic episodes precede SIDS, pointing out as suggested earlier, that SIDS may not be as sudden as previously believed (5). The paper was strengthened in that rat experiments were added showing that VEGF increases in CSF after a hypoxic challenge peaking at 12 hours and returning to baseline after 24 hours. VEGF increased slowly in rat CSF during the first 36 hours after death, indicating that samples obtained in human infants after a mean post mortem time of 22 hours reflect the levels at time of death. Repeated sampling during the post mortem time in at least a few dead infants could have disclosed important additional information.

The etiology of hypoxia in SIDS is poorly understood. Further, it is not known whether SIDS victims undergo single or multiple hypoxic events before death. But the authors underline that it takes several hours for genomic transcription and expression of VEGF protein after activation and nuclear binding of the hypoxic sensing elements mediating VEGF gene regulation.

This study should prompt us to intensify research identifying possible triggering factors inducing hypoxia and the cascade of events leading to SIDS. If such trigger factors are found, screening methods to identify infants at risk may be established representing a first step to reduce SIDS even further by prevention.