When a child is born with hypoxic-ischaemic encephalopathy, commonly called birth asphyxia – poor consciousness, not crying, not sucking, not breathing on their own – doctors have limited options. And a treatment that many had anticipated would be effective turns out not to be.
In fact, newborns with the condition who were treated with the hormone erythropoietin were more likely to have serious adverse events, potentially including death, reports STAT News.
Hypoxic-ischaemic encephalopathy is the second largest cause of neonatal deaths, behind premature birth, and is relatively common, afflicting 1.5 babies out of 1,000 live births.
A study published in the New England Journal of Medicine found that erythropoietin did not improve survival and other outcomes in newborns with the condition.
The clinical trial of 500 infants was the culmination of decades of study, including prior work that suggested erythropoietin was safe and had promise in mice, macaques and, in a smaller study, humans. Another clinical trial of erythropoietin is ongoing in Australia.
“There is a robust body of literature showing erythropoietin provides neuroprotection in newborn brains,” said Hannah Glass, a paediatric neurologist at the University of California, San Francisco, founding co-director of its Neuro-Intensive Care Nursery, and author of the new paper. “So it was a big disappointment that this trial was negative.”
Erythropoietin, which some athletes have used illicitly to boost performance, tells your body to make red blood cells. But it can also do more than that. In 1993, an influential publication reported that the erythropoietin receptor was found on mouse neurons.
“That was totally out of the box,” said Sandra Juul, senior author of the study, clinical trialist, and professor of paediatrics in the Division of Neonatology at the University of Washington and Seattle Children’s Hospital. “People at the time thought erythropoietin had one job, and that was to increase red blood cell production.”
“But actually, no, it has direct effects on brain cells,” said Yvonne Wu, a paediatric neurologist at UCSF, and first author of the new study. The erythropoietin receptor is expressed in the brain and in mice, erythropoietin has been shown to improve neurological function after neonatal stroke and spinal cord trauma.
Based on previous positive results, some physicians were already prescribing erythropoietin to newborns with hypoxic-ischaemic encephalopathy. “We heard that some practitioners in the US and in other countries decided to just go ahead and start doing this treatment,” said Adam Hartman, from the National Institute of Neurological Disorders and Stroke who helped oversee the implementation of this study.
The exact reason that erythropoietin failed is unclear. Researchers believe one possible factor relates to a change in the standard of care for hypoxic-ischaemic encephalopathy.
Therapeutic hypothermia, a technical term for cooling the baby to 33.5 degrees Celsius for 72 hours, initiated within the first 24 hours of life, has become widespread in the past decade. In preclinical studies, hypothermia was not yet common and most animal models did not include cooling.
A more recent study performed in sheep did not find erythropoietin to provide an additional benefit on top of hypothermia. The study authors said, though, that they had finished enrolling the babies before that result came out.
Juul said a different, earlier study she was involved in found that erythropoietin did not help pre-term babies. Despite that, the data that team collected allowed them to publish 20 papers, she said.
The researchers have a wealth of data to further examine, including histological sections of placentas, brain MRI scans from newborns, and records on adverse events. This could help answer questions about biomarkers of the condition, how to predict outcomes, and the timing of symptoms.
“It shows the importance of doing phase three studies. It’s important to do these large trials to see what the real answer is,” she added.
“It was a negative trial, and so people always ask, ‘Was it adequately designed, was it adequately executed?’” said Hartman. “People need to know that this was well-executed and, in this case, no really means no.”
Though meaningful, the result was still a disappointment for a field that has had few advances in the past decades.
Sometimes there is an indication that physicians should be concerned a newborn could develop hypoxic-ischaemic encephalopathy. In about a quarter of cases, there is something known as a “sentinel event”.
Sometimes, the umbilical cord is wrapped around the baby’s neck, or the baby’s shoulder gets stuck while coming out, or the placenta separates from the uterus prematurely. “But even then, it’s just right before delivery,” said Fernando Gonzalez, a neonatologist at UCSF, the other co-director of its Neuro-Intensive Care Nursery, and author of the study.
“It’s almost always a surprise when they’re born with concern for HIE.”
Ultrasounds and electronic foetal monitoring are commonly normal, too, he added. Gonzalez leads a team that treats between 35 to 50 cases of hypoxic-ischaemic encephalopathy every year.
Outcome notwithstanding, researchers said, the fact that this study has been done is in itself a positive, given how little study there is of potentially helpful treatments for newborns. “There are so many things that we do off-label with babies, because there just isn’t any evidence,” said Gonzalez. “It makes sense to use it, it just hasn’t been studied.”
Experts said the new results highlight the importance of running larger trials, which study enough people to minimise unintentional mistakes. The phase two study found erythropoietin was beneficial.
However, two babies in that trial had genetic disorders that were associated with abnormal neurological development; they were both assigned to the placebo group, dragging down the overall outcomes among newborns who did not receive erythropoietin. After re-analysing the data without those two infants, “the difference that we saw at age 12 months went away”, said Wu. “It was no longer significant statistically.”
Some experts said the new result was not as surprising, given that diseases often have many pathways. Perhaps too frequently, scientists pin their hopes on a single magical pill or silver bullet, expecting it to work.
The current treatment, hypothermia, has its own drawbacks. To cool the baby, physicians place them on a cooling blanket away from their parents. This may lead to bonding issues, Wu said, as the baby cannot interact with their mother in the first few days of life. And in other, more measurable outcomes, hypothermia is not a cure-all either.
Of the babies who did not receive erythropoietin, 11.5% died. “The adverse outcomes, if you look at the placebo arm, is still over 40%,” said Floris Groenendaal, a neonatologist at Wilhelmina Children’s Hospital in the Netherlands who did not participate in the trial. “There is definitely a need for additional therapies on top of therapeutic hypothermia.”
In low- and middle-income countries, hypothermia is not used because a large-scale trial found it to be ineffective. Experts suggest the effectiveness varies by geography because of differences in the underlying risk factors of hypoxic-ischaemic encephalopathy, which potentially include infection, hypertension, and type 2 diabetes.
And Gonzalez said that because of quirks in how different cooling systems measure body temperature – UCSF uses rectal probes, others use oesophageal ones – the babies may have been kept at too low a temperature. “It was a surprising finding,” said Gonzalez. “But that’s why we study things like EPO and other things, to see, maybe if there are other medications or strategies that would hopefully benefit low- to middle-income countries.”
Notwithstanding the conclusion that erythropoietin did not provide a benefit and may actually have caused harms, Hartman, of the National Institute of Neurological Disorders and Stroke, sees an important message that connects with other government-funded studies.
“This is why we do clinical trials. Because there are some good ideas out there, and until you test them, you don’t know how the result’s going to turn out,” he said. “In this case, there is enough equipoise, that you really needed to ask the question.” There are trials that have an inconclusive result, and he is glad this is not one of them.
Study details
Trial of erythropoietin for hypoxic–ischaemic encephalopathy in newborns
Yvonne W. Wu, Bryan A. Comstock, Fernando F. Gonzalez, Dennis Mayock, Amy Goodman, Nathalie Maitre, Taeun Chang, Krisa Van Meurs, Andrea Lampland, Ellen Bendel-Stenzel, Amit. Mathur, Tai-Wei Wu et al., for the HEAL Consortium*
Published in New England Journal of Medicine on 14 July 2022
Abstract
Background
Neonatal hypoxic–ischaemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesised to have neuroprotective effects in infants with hypoxic–ischaemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown.
Methods
In a multicentre, double-blind, randomised, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic–ischaemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.
Results
Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P=0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57).
Conclusions
The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic–ischaemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events.
NEJM article – Trial of erythropoietin for hypoxic–ischemic encephalopathy in newborns (Open access)
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