Cot deaths, or sudden infant death syndrome (SIDS), are tragic and often lack a clear medical explanation.

Findings from the Safe Passage Study (SPS), recently published in the scientific journal PlosOne in the article ‘Abnormal serotonin receptor binding in SIDS in a high-risk population’, shed new light on this syndrome by highlighting the key role of abnormalities in brainstem serotonin in SIDS cases, with a strong link to maternal and prenatal stress in high-risk populations.

The SPS also revealed that high-risk factors for SIDS, such as premature birth, poverty and severe maternal stress, are closely linked to socioeconomically disadvantaged environments. The findings suggest that stress is universal, but social deprivation more often leads to prolonged and/or more severe stress.

This international study has spanned two decades, was conducted in low-income communities in South Africa and the USA by researchers from several universities, and follow-up research is ongoing.

According to Prof Hein Odendaal, leader of the South African arm of the study and professor emeritus in the Department of Obstetrics and Gynaecology of the Faculty of Medicine and Health Sciences at Stellenbosch University (SU), this prospective and multi-centre study indicates the close link between serotonin (a neurotransmitter used by nerve cells to communicate with each other and which plays an important role in the life-supporting brainstem) and the reflex of normal breathing when babies sleep.

Odendaal says the brainstem serotonin hypothesis is currently the most accepted school of thought about the causes of SIDS. It suggests a malfunction in the neuronal networks of the pons and medulla, areas of the brainstem that are associated with respiratory regulation and vital functions and that play an important role in the mechanism of SIDS.

“If babies’ reflexes are compromised, they are not able to respond to stressful situations on their own, such as when they experience a temporary cessation of breathing, or if their noses hit a pillow, blanket or soft toy. Unlike ‘normal’ children, they cannot recover from the stressful situation on their own, because a critical reflex is damaged.

“To get closer to determine the exact cause of SIDS, it was necessary to examine these networks in the pons and medulla of SIDS infants and compare them with deaths from another cause. Therefore, samples of the central nervous system of SIDS infants of the SafePassage Study were taken after permission had been obtained, stored at -80 °C, and flown to the pathology laboratory at Harvard University.

“There, Prof Hannah Kinney, one of the world’s most well known researchers on SIDS, and her staff further examined the brain tissue for defects in the serotonin network of the brainstem,” says Odendaal.

In earlier research in San Diego (a middle- and high-income area in California), Kinney and her colleagues had found that lower serotonin receptor binding occurred in the brainstems of SIDS infants compared to deaths from other causes. Neurotransmitters need a receptor (binding site) to work, and lower serotonin receptor binding was found in the brainstems of SIDS babies.

Although SIDS is a leading cause of post-neonatal mortality worldwide, it occurs disproportionately in socioeconomically disadvantaged populations. The SPS followed approximately 12 000 pregnancies in the Cape Town suburbs of Bishop Lavis and Belhar and in North and South Dakota in the USA, where risk factors for premature birth such as poverty, stress, and nicotine and alcohol use are high.

In their latest research, Kinney and her colleagues compared the brainstem tissue of 14 of these babies who died from SIDS with a control group of 22. Of the 36 babies, 21 (58%) were born prematurely.

Many women in the SIDS group were anxious and depressed during pregnancy and lived in poverty. This maternal stress likely ultimately leads to reprogramming of serotonin networks that increase babies’ vulnerability to SIDS in critical circumstances, says Odendaal.

In their earlier work, Kinney and her colleagues found that brain receptor binding increased with age after birth. Receptor binding was similar after birth for SIDS and controls, but it didn’t increase in SIDS cases as it did in the controls. SIDS infants therefore had less receptor binding in the months after birth than control infants who died of other causes. Receptor binding was highest among the most premature infants and decreased closer to full term. The results indicate a disruption in the development of the serotonin network. 

With this new information from the SPS, Kinney and colleagues modified the Triple Risk Hypothesis (dating back to 1994), to add a significant influence of maternal and/or prenatal stressors on brain development, making prematurely born infants more vulnerable to serotonin abnormalities and therefore to SIDS. Differences in the findings of the research at two locations (lower receptor binding in San Diego and higher receptor binding in Bishop Lavis and Belhar) are likely attributable to more premature births among the local population.

The Triple Risk Hypothesis attributes SIDS to an interaction of: (1) a critical age of around 6 months, when cardiorespiratory control in the brainstem changes rapidly, making babies more vulnerable, (2) intrinsic vulnerability (something about the baby that makes them likely to respond to environmental hazards), and (3) extrinsic environmental hazards (such as sleeping on the stomach, bed sharing, and toys or blankets in the crib that can cause suffocation. 

The researchers postulate that the SafePassage Study highlights the possible interplay between biological and social causes of SIDS. Significant chronic maternal stress and early life stress – often a by-product of socioeconomic deprivation – can affect fetal brain development and serotonin receptor binding, increasing vulnerability to SIDS.

The altered serotonin receptor binding observed in SIDS infants, especially those from high-risk populations, provides a valuable framework for understanding the biological vulnerabilities that contribute to SIDS, Odendaal says. The SPS highlights the need for a multidisciplinary approach to tackle SIDS that combines biological insights with a clear focus on social determinants of health.

“By addressing both the neurochemical and behavioural or environmental risk factors, we can make significant progress in preventing SIDS, especially in the most vulnerable communities,” Odendaal emphasises.