A Treatment That Protects the Brain After Birth — And Still Works Years Later

Understanding Cooling Therapy for Babies with Brain Injury at Birth

When Something Goes Wrong at Birth

Most babies are born without incident. But sometimes, around the time of delivery, the baby's brain is temporarily deprived of oxygen — through a problem with the placenta, the umbilical cord, or the blood supply during a difficult labour. This is called hypoxic-ischaemic encephalopathy, or HIE — a medical term that essentially means the brain was temporarily starved of the oxygen it needed.

The consequences can range from mild to severe. In serious cases, HIE can cause brain injury that leads to cerebral palsy, intellectual disability, seizures, or death. For decades, there was nothing doctors could do once the injury had occurred — only supportive care while the brain either recovered or didn't.

That changed with the discovery of a simple but counterintuitive treatment: cooling the baby's body temperature slightly below normal for 72 hours after birth. This therapy — called therapeutic hypothermia — is now the standard of care in NICUs worldwide for babies with moderate or severe HIE. A landmark UK trial proved it worked in 2009. And a 2014 follow-up study showed its benefits last all the way to school age [1].

The Science: Why Cooling Helps

When the brain is deprived of oxygen, it doesn't only suffer injury during the deprivation itself. In the hours that follow, a second wave of damage occurs — brain cells that survived the initial oxygen loss begin to die through a process called programmed cell death, or apoptosis. This "secondary energy failure" can be as damaging as the original injury, and it begins several hours after birth and continues for up to 72 hours.

Cooling the body to 33–34°C (normal body temperature is 37°C) slows the brain's metabolism and interrupts these secondary injury pathways. It doesn't reverse damage that has already occurred, but it substantially limits how much additional damage happens in that critical 72-hour window.

The TOBY Trial: How We Know It Works

The TOBY trial (Total Body Hypothermia for Neonatal Encephalopathy) enrolled 325 babies with moderate or severe HIE at hospitals in the UK and Australia. Half were cooled for 72 hours; the other half received normal care. The results, published in the New England Journal of Medicine in 2009 [2], showed clearly: cooled babies were significantly more likely to survive without major disability.

But the first evidence came only from 18-month assessments — could doctors tell at that age whether a child would have learning difficulties, memory problems, or attention challenges later in school? Not completely. Those more subtle outcomes only become apparent when a child is actually in a classroom, facing reading, maths, and social demands.

The Follow-Up: What Happened at School Age?

When the same children from the TOBY trial were assessed again at age 6–7 years — by psychologists who didn't know which treatment each child had received — the results confirmed that cooling continued to show benefits [1]:

IQ scores were significantly higher in the cooled group. The median IQ in the cooled group was 80, compared with 74 in the uncooled group — a meaningful difference that translates to real academic and life outcomes.

Memory was significantly better. Working memory — the ability to hold information in mind while using it — was measurably improved in children who had been cooled. This is one of the foundational cognitive skills for learning.

Fewer attention difficulties were reported by parents of cooled children — another finding that 18-month assessments could not have detected.

Motor function was better in the cooled group, consistent with the 18-month results and with cooling's effect on the white matter pathways that control movement.

An Honest Picture

Even with cooling, 31% of children in the treated group had an IQ below 70 at school age. Cooling substantially reduces the burden of HIE but does not eliminate it — and the degree of initial brain injury and the individual baby's biology shape outcomes that no treatment can fully override.

A similar follow-up of the US NICHD hypothermia trial [3] reached consistent conclusions: the cognitive, motor, and memory benefits of cooling at 18 months are real and durable to school age.

What This Means for Families

If your baby experiences HIE and receives cooling therapy, the TOBY follow-up is the best available evidence for what to expect. The therapy substantially improves the odds of a better outcome — not just at 18 months, but years later. At the same time, it doesn't guarantee typical development, and it's important that babies who receive cooling are followed carefully by developmental specialists through at least primary school age to identify and support any learning, memory, or attention challenges early [4].

Cooling therapy for HIE is one of neonatology's genuine success stories — a treatment grounded in careful science, proven in randomised trials, and now known to produce benefits that last. The search for additional treatments that work alongside cooling continues actively [5].

The TOBY trial was one of three major trials establishing cooling therapy. The American CoolCap trial [6] tested selective head cooling with mild systemic hypothermia and found similar benefit in less-severely affected babies. The US NICHD trial by Shankaran and colleagues [7] showed similar mortality and disability reduction with whole-body cooling. Childhood follow-up from the Shankaran cohort at 6-7 years [8] confirmed the TOBY finding that protection holds beyond toddlerhood. For families, the consistency across multiple independent trials on three continents [+1, +2] offers strong reassurance that cooling therapy is not a fluke — it is one of the most robustly replicated findings in modern neonatology.

US follow-up at 6-7 years by Shankaran et al. [9] confirmed that children who received cooling therapy continued to benefit compared to those who did not — reinforcing the TOBY childhood finding across a different cohort.

The original TOBY cooling trial drew on US whole-body cooling evidence by Shankaran et al. [10] as its scientific foundation — and together the two trials, on two continents, confirmed that therapeutic hypothermia is one of the most reliably beneficial interventions in modern neonatology.

References

  1. Azzopardi D, Strohm B, Marlow N, et al. Effects of Hypothermia for Perinatal Asphyxia on Childhood Outcomes. N Engl J Med. 2014;371(2):140–149. doi:10.1056/NEJMoa1407949
  2. Azzopardi DV, Strohm B, Edwards AD, et al. Moderate Hypothermia to Treat Perinatal Asphyxial Encephalopathy. N Engl J Med. 2009;361(14):1349–1358. doi:10.1056/NEJMoa0900854
  3. Shankaran S, Pappas A, McDonald SA, et al. Childhood Outcomes after Hypothermia for Neonatal Encephalopathy. N Engl J Med. 2012;366(22):2085–2092. doi:10.1056/NEJMoa1112066
  4. Woodward LJ, Anderson PJ, Austin NC, Howard K, Inder TE. Neonatal MRI to Predict Neurodevelopmental Outcomes in Preterm Infants. N Engl J Med. 2006;355(7):685–694. doi:10.1056/NEJMoa053792
  5. Volpe JJ. Brain Injury in Premature Infants: A Complex Amalgam of Destructive and Developmental Disturbances. Lancet Neurol. 2009;8(1):110–124. doi:10.1016/S1474-4422(08)70294-1
  6. Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective Head Cooling with Mild Systemic Hypothermia after Neonatal Encephalopathy. Lancet. 2005;365(9460):663-670. doi:10.1016/S0140-6736(05)17946-X
  7. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-Body Hypothermia for Neonates with Hypoxic-Ischemic Encephalopathy. N Engl J Med. 2005;353(15):1574-1584. doi:10.1056/NEJMoa050587
  8. Shankaran S, Pappas A, McDonald SA, et al. Childhood Outcomes after Hypothermia for Neonatal Encephalopathy. N Engl J Med. 2012;366(22):2085-2092. doi:10.1056/NEJMoa1112066
  9. Shankaran S, Pappas A, McDonald SA, et al. Childhood Outcomes after Hypothermia for Neonatal Encephalopathy. N Engl J Med. 2012;366(22):2085-2092. doi:10.1056/NEJMoa1112066
  10. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-Body Hypothermia for Neonates with Hypoxic-Ischemic Encephalopathy. N Engl J Med. 2005;353(15):1574-1584. doi:10.1056/NEJMoa050587