It’s every parent’s worst nightmare: You put your healthy infant to bed, but your child never wakes up.
Dr. Richard Goldstein, M.D., a pediatric palliative care specialist at Boston Children’s Hospital, has watched this tragedy unfold hundreds of times; and according to Dr. Goldstein, it never gets easier. “These parents have such profound suffering,” he said. “It’s a peculiar and sad little corner of medicine.”
In 2017, 3,600 infants died suddenly and unexpectedly, according to the latest data from the Centers for Disease Control and Prevention. Of those, about 1,400 were believed to have died from Sudden Infant Death Syndrome, or SIDS — a catchall term for when an infant under 1 year of age dies, often while sleeping, with no specific environmental or medical cause.
Despite the fact that SIDS is the third leading cause of infant death, however — behind birth defects and prematurity — experts are still puzzled as to exactly how it kills, said Dr. Michael Ackerman, M.D., Ph.D., a genetic cardiologist at the Mayo Clinic.
But Dr. Goldstein, Dr. Ackerman and a small cadre of other researchers are hoping to chip away at that uncertainty by studying the biological underpinnings of this puzzling syndrome. Their work promises both to give parents much-needed explanations for why their children died, and to prevent additional SIDS deaths from occurring in the first place.
“We’ve been making big progress by looking at how a cloud of factors come together in a perfect storm,” said Dr. Nino Ramirez, Ph.D., a neuroscientist at the University of Washington. “Every SIDS child has a unique history, but we can identify common risks by letting the data speak.”
What Causes SIDS? A SIDS Diagnosis
Before the 1960s, healthy infants who had died seemingly suddenly or inexplicably were said to have died from “asphyxiation” or “unexplained causes.” But it wasn’t until the late ’60s and ’70s that experts formally defined and recognized the diagnosis of “SIDS.”
What put infants most at risk, however, was a mystery. Babies born into poorer families or to mothers who smoked during pregnancy and after the birth, for instance, seemed to be more likely to die from SIDS than their more affluent counterparts who lived in smoke-free environments. But as scientists teased apart its potential risk factors, one seemed to outweigh the others: Babies who had died from SIDS were much more likely to have been put to sleep on their stomachs.
Infants who sleep facedown rebreathe the same air over and over again, researchers hypothesized, depleting it of vital oxygen and leaving it with higher levels of carbon dioxide. If newborns can’t rouse themselves when this happens (as babies younger than 6 months can struggle to do), the thinking went, they could suffocate.
In 1994, the National Institute of Child Health and Human Development began the “Back to Sleep” campaign, which encouraged parents to place their infants to sleep on their backs at nap- and bedtimes. Within 10 years, SIDS deaths in infants plummeted from more than 5,000 per year in the 1990s to between 2,000 to 3,000 deaths each year in the early 2000s.
But by the mid-2000s, that decline in SIDS deaths stalled, and a small but persistent number of babies continued to die in their sleep. While scientists were successful in identifying certain factors that might increase an infant’s risk of dying of SIDS, said Dr. Peter Blair, Ph.D., an epidemiologist at the University of Bristol in the United Kingdom, “we don’t really know the ultimate causes of these deaths.”
SIDS remained distressingly, and perplexingly, random; and its causes much harder to pinpoint.
Is The Brain To Blame?
In her work as a neuropathologist at Boston Children’s Hospital in Massachusetts, Dr. Hannah Kinney, M.D., saw many unexplained infant deaths. If she could understand what caused them, Dr. Kinney reasoned, she might be able to prevent them.
In the 1980s, Dr. Kinney found that infants who had died of SIDS had shown cellular signs of damage in the part of the brain that controls breathing. As she homed in on the thick, stemlike structure in the brainstem called the medulla oblongata, she noticed that about 40 percent of the brains of babies who had died from SIDS had produced unusually low levels of the neurotransmitter serotonin.
Serotonin is famous for its links to mood, but it also plays a role in controlling breathing, heart rate, blood pressure, temperature regulation and arousal from sleep. When Dr. Kinney and Dr. Susan Dymecki, M.D., Ph.D., a neuroscientist from Harvard University, engineered mice with the same serotonin deficiencies as seen in the brains of babies who had died of SIDS, these mice didn’t gasp and resuscitate themselves in low-oxygen, high-carbon dioxide environments. Instead, “they just lied there and died,” said Dr. Goldstein.
In 2018, Dr. Dymecki and her colleagues published a follow-up study in the journal eLIFE, which demonstrated that blocking the activity of serotonin neurons in the brainstems of mice prevented them from returning to a normal breathing pattern after they temporarily stopped during sleep.
In other words, Dr. Dymecki’s mice behaved exactly like babies who had died from SIDS, bolstering the idea that serotonin deficiencies are at least partly to blame for some SIDS deaths.
Halfway around the world in Australia in 2017, a team of researchers including Dr. Fiona Bright, Ph.D., then a neuroscience doctoral student at the University of Adelaide, began finding other neurotransmitter abnormalities in the brainstems of SIDS babies. Specifically, she found defects in the brain pathways that regulated breathing and recognition and response to low oxygen levels (which relied on the neurotransmitters serotonin and substance P). These abnormalities, Dr. Bright found, significantly impacted babies’ abilities to rescue themselves when struggling to breathe during sleep, and were especially pronounced in premature and male infants — two of the highest risk groups for sudden unexpected infant death.
Between Dr. Bright’s work in Australia, ongoing work in Boston and other global research efforts into the causes of SIDS, it became clear that certain babies had an innate biological risk for the syndrome. “During sleep, most infants can wake themselves up,” said Dr. Bright. “SIDS babies don’t have this ability.” Combine that underlying biology with a 6-month-old (whose other arousal brain circuits have yet to fully mature) and an environmental stressor such as soft bedding or secondhand smoke, and this triple risk can coalesce into the perfect storm.
A Defect In The DNA?
Other scientists began finding that babies who’d died of SIDS had specific mutations in their DNA. In fact, recent studies suggest that upward of 20 percent of SIDS deaths may have been due to inherited or genetic conditions.
In 2018, Dr. Ackerman of the Mayo Clinic published a study in the Journal of the American College of Cardiology which analyzed the genomes of 419 babies who had died from SIDS. He found that 5 percent carried mutations in a set of genes involved in sudden cardiac death. (Five percent might seem like a relatively low number, but according to Dr. Ackerman, the results are significant.)
Others have found links between SIDS and mutations in genes that play roles in metabolism, inflammation, development and epilepsy, underscoring the syndrome’s complexity.
An Undiagnosed Disease
Despite emerging research, Dr. Goldstein and Dr. Kinney still hadn’t been able to provide grieving parents with suitable explanations for how their children died. In 2014, the pair launched a clinical program and research study at Boston Children’s Hospital, which performs genetic testing and detailed clinical case reviews for children in Massachusetts who died of uncertain causes before age 3. In essence, the duo decided to treat SIDS like an undiagnosed disease.
In 2017, they found explanations for 16 of the first 17 deaths in the program, which had initially been blamed on SIDS or Sudden Unexplained Death in Childhood (unexplained death in children older than 1 year). These results — which included undetected infections, unusual birth defects and rare genetic mutations — not only provided answers for bereft parents but may have also prevented additional deaths. In one case, an epilepsy-causing mutation that was identified in a SIDS baby was also found in the child’s sibling, who was then placed on anti-seizure medications. A March 2019 paper in Trends in Neurosciences also highlighted the close links between SIDS, S.U.D.C. and epilepsy, suggesting that the conditions may share similar neurobiology.
Other studies have also begun to pinpoint potential SIDS causes. A study published in April 2019 in the journal Pediatrics, for instance, found that mothers who smoked during their pregnancies were twice as likely to have babies who died of SIDS as nonsmokers were.
Although scientists have generally abandoned the idea that they will identify a singular cause for SIDS, Dr Ackerman said that by slowly chiselling away at the multitude of SIDS causes, scientists can at least give parents a small piece of clarity and comfort that they might otherwise be missing.
"What Causes SIDS?" by Carrie Arnold © 2020 The New York Times Company
Carrie Arnold is an award-winning health and environment reporter based in Virginia.
This story was originally published on 17 April 2020 in NYT Parenting.