When a healthy baby experiences either too little oxygen or too much carbon dioxide, explains Goldstein, their breathing halts (an “apneic pause”) before they start to gasp. “Those gasps, usually, in a healthy baby, will cause the heart rate to come up,” Goldstein says. “Those babies arouse, and arousal-related reflexes occur: they arch, they yawn, they turn, they wake up and cry, and that frees most babies from relatively modest obstructions and they survive.
“And the SIDs babies didn’t do that. They didn’t arouse and they stayed ‘uncoupled’ between these agonal gasps, which are driven by certain centres of the brain, and the cardiac response.”
That means a “vicious circle” where the feedback system doesn’t function, ending in a coma and death, says Rognum.
Why? In Norway, Rognum, together with paediatrician and neuroscientist Ola Didrik 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 at 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”.
It’s the latter label that caught on, and it’s 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 several factors coming together. “There’s not just a single reason,” says Goldstein. “We put it more in the category of an expression of a rare undiagnosed disease where at least some of the time, at its initial presentation, it is incompatible with survival.”
Rognum had noticed that the highest-risk period for dying of SIDS, between the second and the fifth month after birth, is also a period where the immune system rapidly develops. “When something develops very rapidly, it’s also unstable,” he says. That’s the vulnerable period after birth. A trigger event could be a seasonal respiratory infection or sleeping prone, or both together – a pairing which increases the risk of SIDS 29-fold.
It is what the “predisposition” is, though, that may be the most enduring puzzle at the heart of SIDS. In recent years, however, this aspect too is becoming less of a mystery.
Researchers including Kinney have thought it might be an issue with the serotonergic system – the neurotransmitters centred in the brainstem that regulate a number of automatic processes, including sleep and breathing. Over the last 20 years, Kinney’s team have honed their hypothesis through multiple studies. An elevation of serotonin (5-HT) in the blood, in particular, is a biomarker for SIDS in around 30% of cases. And their findings have been corroborated by other teams. One study of autopsies, for example, found that serotonin levels were 26% lower in SIDS cases than in healthy infants – a biomarker discovered before Harrington’s finding.
Similarly, Rognum thought the genetic element could be due to varients, 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 infections or injuries, so variants in these genes can make this part of the immune response weaker or stronger than they should be.
“We found in the cerebral spinal fluid that the SIDS cases had significantly higher levels of interleukin-6. That’s the interleukin that gives us fever,” Rognum says. “Half of the SIDS cases have levels in the same range as children that died from meningitis and septicaemia, without having those diseases.”