When a healthy baby has too little oxygen or too much carbon dioxide, Goldstein explains, his breathing stops (an “apneic pause”) before he begins to gasp. “These gasps, usually in a healthy baby, cause the heart to beat faster,” says Goldstein. “These babies are waking up and arousal-related reflexes are happening: arching, yawning, rolling over, waking up and crying, and that releases most babies from relatively modest obstructions and they survive.
“And the SID babies didn’t do that. They didn’t wake up and they remained ‘uncoupled’ between those agonal gasps, which are triggered by certain centers in the brain, and the cardiac response.”
It means a “vicious cycle” where the feedback system doesn’t work, ending in coma and death, Rognum says.
Why? In Norway, Rognum, together with pediatrician and neuroscientist Ola Didrik Saugstad, proposed the “fatal triangle” theory, which they defined as “a vulnerable period after birth, a certain genetic predisposition and a triggering event”. In the United States, around the same time, a team led by Goldstein and Hannah Kinney from Boston Children’s Hospital came up with a similar idea: the “triple risk model”.
It was this latter label that caught on, and it is this theory that is now the leading explanation among SIDS researchers. This goes 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 that come together. “There’s not just one reason,” Goldstein says. “We put it more in the category of an expression of an undiagnosed rare disease where at least some of the time, when initially presented, it is incompatible with survival.”
Rognum had noticed that the period most at risk of dying from SIDS, between the second and fifth month after birth, is also a period when the immune system is developing rapidly. “When something develops very quickly, it’s also unstable,” he says. This is the vulnerable period after birth. A triggering event could be a seasonal respiratory infection or a tendency to sleep, or both together – a pairing that increases the risk of SIDS by 29 times.
It is what “predisposition” is, however, that may be the most persistent puzzle at the heart of SIDS. In recent years, however, this aspect is also becoming less mysterious.
Researchers including Kinney thought it might be a problem with the serotonin system – the 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. Elevated serotonin (5-HT) in the blood, in particular, is a biomarker of SIDS in about 30% of cases. And their findings have been corroborated by other teams. A study of autopsies, for example, found that serotonin levels were 26% lower in SIDS cases compared to healthy infants – a biomarker discovered before Harrington’s discovery.
Similarly, Rognum thought the genetic element could be due to variants, or polymorphisms, in the genes that make interleukins – which can be anti-inflammatory or pro-inflammatory molecules. They are usually produced in response to damage from infection or injury, so variants of these genes can make this part of the immune response weaker or stronger than it should be.
“We found in cerebrospinal fluid that SIDS cases had significantly higher levels of interleukin-6. It’s interleukin that gives us fever,” Rognum said. “Half of SIDS cases have levels in the same range as children who died of meningitis and sepsis, without having those illnesses.”