When a healthy baby experiences too little oxygen or too much carbon dioxide, Goldstein explains, their breathing stops (“pause apnea”) before they start gasping. “Those gasps, usually, in a healthy baby, will cause the heart rate to increase,” says Goldstein. “Those babies get excited, and the reflexes associated with excitement occur: they bend, yawn, turn, wake up and cry, and this relieves most babies of relatively modest obstacles and they survive.
“And babies with SID didn’t do that. They didn’t get excited and remained ‘untethered’ between these agonal breaths, which are triggered by certain brain centers, and the cardiac response.”
That means a “vicious cycle” in which the feedback system doesn’t work, ending in coma and death, Rognum says.
Why? In Norway, Rognum, together with pediatrician and neuroscientist Ol Diedrik Saugstad, came up with the theory of the “fatal triangle”, which they defined as “a vulnerable period after birth, some genetic predisposition and a trigger event”. In the US around the same time, a team led by Goldstein and Hannah Kinney of Boston Children’s Hospital came up with a similar idea: the “triple risk model”.
The latter designation has become popular, and it is this theory that is now the leading explanation among SIDS researchers. It gets to the heart of what scientists have suspected since at least the 1970s: SIDS is not caused by a single event, but by several factors coming together. “There’s not just one reason,” says Goldstein. “We put it more in the category of expressing a rare undiagnosed disease where at least part of the time, at initial presentation, it is incompatible with survival.”
Rognum noted that the period of greatest risk for dying from SIDS, between the second and fifth months after birth, is also a time when the immune system is developing rapidly. “When something develops very quickly, it’s also unstable,” he says. It is a vulnerable period after birth. The trigger can be a seasonal respiratory infection or a tendency to sleep, or both together—a pairing that increases the risk of SIDS by 29 times.
However, what the “predisposition” is may be the most enduring puzzle at the heart of SIDS. In recent years, however, this aspect has also become less of a mystery.
Researchers, including Kinney, thought it might be a problem with the serotonergic system — neurotransmitters centered in the brainstem that regulate a number of automatic processes, including sleep and breathing. Over the past 20 years, Kinney’s team has refined their hypothesis through multiple studies. In particular, elevation of serotonin (5-HT) in the blood is a biomarker for SIDS in about 30% of cases. And their findings were confirmed by other teams. One study of autopsies, for example, found that serotonin levels were 26% lower in SIDS cases than in healthy babies—a biomarker discovered before Harrington’s finding.
Similarly, Rognum thought the genetic element might be due to variants, or polymorphisms, in the genes that make interleukins — which can be either anti-inflammatory or pro-inflammatory molecules. They are usually produced in response to damage caused by infection or injury, so variants in these genes can make this part of the immune response weaker or stronger than it should be.
“We found in the cerebral spinal fluid that SIDS cases had significantly higher levels of interleukin-6.” It’s the interleukin that gives us a fever,” says Rognum. “Half of SIDS cases have levels in the same range as children who died of meningitis and septicemia without having those illnesses.