A New Way to Predict Neurodevelopment in Infants Serum Copeptin and Neuron-Specific Enolase Are Markers of Neonatal Distress and Long-Term Neurodevelopmental Outcome

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Three out of every two thousand infants born in developed countries suffer from hypoxic-ischemic encephalopathy (HIE). HIE is brain damage that occurs due to a lack of oxygen. Hypothermia therapy (also known as cooling therapy) has proven to be a reliable method for preventing neurological damage in infants.

Several methods are available to evaluate HIE and predict its neurological outcomes, including magnetic resonance imaging (MRI), amplitude-integrated EEG, cerebrospinal fluid samples, and urine and saliva samples. However, many of these methods are not feasible for routine use, and some are not widely studied. Therefore, there is a pressing need to develop a method for evaluating HIE that is easy enough for routine use.

Serum samples remain the most useful source of HIE biomarkers in newborns. Specifically, serum samples contain two molecules—neuron-specific enolase (NSE) and copeptin—that provide information about HIE and its effects on the neurodevelopment of newborns.  Both NSE and copeptin are biomarkers of brain injury. Infants with birth asphyxia have higher levels of these molecules.

An HIE Research Study

Researchers conducted a study titled “Serum Copeptin and Neuron-Specific Enolase Are Markers of Neonatal Distress and Long-Term Neurodevelopmental Outcome,” in which they studied the relationship between NSE, copeptin, and HIE treated with therapeutic hypothermia. In the study, they assessed the neurodevelopmental outcomes in children at two years of age.

Seventy-five babies were recruited for the study. These babies either needed continuous ventilation for ten minutes after birth or were born with an altered level of consciousness, seizures, hypotonia, or abnormal reflexes. All the babies underwent cooling therapy within six hours after birth. Serum samples for analysis were collected at 6, 12, 24, 48, 72, and 168 hours after birth.

When the babies reached two years of age, the researchers used the Bayley Scales of Infant and Toddler Development TM II, which include various parameters for analyzing the developmental functions of toddlers and infants, to perform neurodevelopmental assessments of all the children.


Copeptin concentrations were highest at six hours after birth and decreased progressively thereafter. NSE levels remained relatively stable for twenty-four hours but had decreased significantly by 168 hours after birth. The cooling therapy did not seem to have any effect on serum NSE levels, but copeptin levels were significantly lower in hypothermic newborns compared to newborns with normal body temperatures.

The mode of delivery also seemed to affect NSE levels. NSE levels six hours after birth were significantly higher in infants born via emergency cesarean section than in those born via vaginal delivery. The mode of delivery did not affect NSE levels at any other time after birth. The mode of delivery also had no effect on copepetin levels.

The seventy-five infants who took part in the study were divided into two groups based on the results: infants with a favorable outcome (who survived without any severe disability) and infants with a poor outcome (who experienced a severe disability or death).

Of the seventy-five newborns, fifty had favorable outcomes while twenty-five had poor outcomes. Fourteen of the poor-outcome newborns died within a month after birth. Both copeptin and NSE levels were significantly higher in the poor-outcome group compared to the favorable-outcome group.

The copeptin levels of the poor-outcome group were higher than the favorable-outcome group at six, twelve, and forty-eight hours, and NSE levels were higher at all time points. The researchers were able to predict whether an infant would have a favorable or a poor outcome simply by looking at the levels of NSE and copeptin at different time intervals.


The study identified both NSE and copeptin as biomarkers of neurodevelopmental outcomes. However, the prognostic value of these biomarkers needs to be studied further in a larger, multicenter study. These serum biomarkers may help predict the long-term consequences of hypoxic ischemia, thus influencing clinical decision making, parent counseling, patient selection for other neuroprotective trials, and methods for monitoring the progress of the disease.


Kelen, Dorottya, Csilla Andorka, Miklós Szabó, Aleksander Alafuzoff, Kai Kaila, and Milla Summanen. “Serum Copeptin and Neuron Specific Enolase Are Markers of Neonatal Distress and Long-Term Neurodevelopmental Outcome.” PLOS One 12, no. 9 (2017): e0184593. Retrieved from: http://journals.plos.org/plosone

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