Thousands of infants each year die in their cribs from sudden infant death syndrome (SIDS) for reasons that have remained largely a mystery. A study published May 25 provides strong evidence that oxygen deprivation plays a big role.

One reason the cause of SIDS has been so difficult to study is the sheer number of variables researchers have had to account for: whether the infant sleeps face down, breathes secondhand smoke or has an illness as well as whether the child has an unidentified underlying susceptibility.

To isolate the effects of oxygen concentration, researchers from the University of Colorado compared the rate of SIDS in infants living at high altitudes, where the air is thin, to those living closer to sea level. Infants at high altitudes, they found, were more than twice as likely to die from SIDS. It was “very clever of the authors,” says Michael Goodstein, a pediatrician and member of the 2010–2011 Task Force on Sudden Infant Death Syndrome who was not involved in the study. “The authors did a good job controlling for other variables,” he adds.

Beyond the risk of living at high altitudes, the study suggests a common link among different risk factors about the causes of SIDS. For example, the authors note that sleeping on the stomach and exposure to tobacco smoke can also contribute to hypoxia—insufficient oxygen reaching the tissues. Similarly, past research has suggested that sleeping on soft surfaces may shift the chin down, partly obstructing the airway, which might cause an infant to breathe in less oxygen. It’s unclear how hypoxia might contribute to SIDS but it could have to do with a buildup of carbon dioxide in the tissues when a child does not wake up.

About 3,500 infants die each year from SIDS, accidental suffocation or strangulation and unknown causes. Although researchers do not fully understand what causes SIDS, the leading hypothesis describes it as a combination of environmental stressors occurring at a critical development period of an infant who has some underlying vulnerability, such as genetic condition or brain dysfunction. The risk of SIDS peaks between two and four months old, when babies undergo rapid development. Researchers have already established that stomach sleeping, soft sleeping surfaces, blankets and other soft items in the crib, bed sharing and cigarette smoke are environmental risk factors. Previous research has shown that infants at high altitudes may experience hypoxia. Thin air at high altitudes, the study suggests, is another risk factor.

This study in Pediatrics is the largest to look for a link between altitude and SIDS and the first since doctors began recommending that babies sleep on their backs in the mid-1990s. Death rates from accidental suffocation and unknown causes were similar across all altitudes in this study.

The researchers, led by cardiologist David Katz at the University of Colorado School Anschutz Medical Campus in Aurora, combed the infant birth and death registries of more than 390,000 babies from 2007 to 2012 and used mothers' addresses to determine altitude. Eight in 10 infants lived below 1,800 meters and 2 percent lived above 2,400 meters. After accounting for other factors, such as socioeconomic status, breast-feeding, birth weight and maternal smoking, infants living above 2,400 meters were 2.3 times more likely to die from SIDS than those below 1,800 meters. The absolute risk of SIDS, however, remains low at all altitudes: 79 deaths per 100,000 infants above 2,400 meters; 40 per 100,000 infants below 1,800 meters.

Parents at high altitudes should not panic, however, both Goodstein and Katz advise. "We hope this study will make families residing at altitude, and the physicians counseling them, increasingly vigilant about the known risk factors for SIDS in order to minimize risk," Katz says.