Frontiers glial fibrillary acidic protein is not an early marker of injury in perinatal asphyxia and hypoxic–ischemic encephalopathy neurology anoxia vs hypoxia

Ann-marie looney*,

Caroline ahearne,

Geraldine B. Boylan and deirdre M. Murray

• neonatal brain research group, department of paediatrics and child health, irish centre for fetal and neonatal translational research, cork university maternity hospital, cork, ireland

Brain-specific glial fibrillary acidic protein (GFAP) has been suggested as a potential biomarker for hypoxic ischemic encephalopathy (HIE) in newborns ( 1, 2). Previous studies have shown increased levels in post-natal blood samples. However, its ability to guide therapeutic intervention in HIE is unknown. Therapeutic hypothermia for HIE must be initiated within 6 h of birth, therefore a clinically useful marker of injury would have to be available immediately following delivery.Anoxia vs hypoxia

the goal of our study was to examine the ability of GFAP to predict grade of encephalopathy and neurological outcome when measured in umbilical cord blood (UCB). Infants with suspected perinatal asphyxia (PA) and HIE were enrolled in a single, tertiary maternity hospital, where UCB was drawn, processed, and bio-banked at birth. Expression levels of GFAP were measured by ELISA. In total, 169 infants (83 controls, 56 PA, 30 HIE) were included in the study. GFAP levels were not increased in UCB of case infants (PA/HIE) when compared to healthy controls or when divided into specific grades of HIE. Additionally, no correlation was found between UCB levels of GFAP and outcome at 36 months.


anoxia vs hypoxia

Perinatal asphyxia (PA) occurs when there is a disruption of oxygen delivery or blood supply to the fetus around time of birth. PA, when severe, leads to hypoxic–ischemic encephalopathy (HIE) in the neonatal period. HIE remains one of the leading clinical challenges faced in the neonatal period and the greatest cause of acquired brain injury in term infants. To optimize outcomes in neonatal HIE, early and accurate prediction of the degree of encephalopathy is vital. Neuroprotective therapies must be commenced prior to the development of secondary brain injury, giving a narrow therapeutic window of 36 weeks gestational age were identified under strict enrollment criteria: cord ph 2 SD below the standardized mean, was advised in more than one area.Anoxia vs hypoxia statistical analysis

Statistical analysis was performed using IBM SPSS statistics 22 (SPSS inc., USA). Results were calculated using student t-tests, mann–whitney, and kruskal–wallis tests, as appropriate. Results study population

In total, 169 infants were included in this study; 83 controls and 86 HIE cases. Of the 86 cases, 56 were classified as perinatal asphyxia without HIE, 21 with mild HIE, 5 with moderate HIE, and 4 with severe HIE, according to both the modified sarnat assessment and EEG classification. Population demographics for the entire cohort are shown in table 1.


Increased levels of GFAP have been shown to be useful biomarkers of adult brain pathology ( 6, 10– 15). In spite of this, investigations into its use in the neonatal field have been somewhat limited, with only a small number of publications suggesting GFAP as a biomarker in HIE with the ability to distinguish between grades of HIE ( 1, 2, 16– 18).Anoxia vs hypoxia while these studies provided promising results, they also cited major limitations with regard to sample size and sample availability throughout. Post-natal blood samples were predominately used, with few studies determining levels in UCB, which is arguably the earliest possible source for a biomarker of HIE. However, as HIE is known to encompass a two stage evolving mechanism of injury, the time at which GFAP levels most represent degree of injury must be established.

In this study, our goal was to add to the current knowledge available for this promising biomarker specifically in relation to HIE. We aimed to validate the use of GFAP as a marker of HIE severity specifically and to overcome the previously cited limitations, mainly through the use of a larger, carefully defined population cohort and through the use of UCB as our sample source.Anoxia vs hypoxia all our samples are collected and processed in an operational biobank following strict sops. Additionally, UCB represents the earliest possible blood sample available after delivery. Although it is not taken directly from the infant, it provides a snapshot of an infant’s circulation at the time of delivery and can therefore offer a unique insight into the neonatal condition. This sample is relatively easy to obtain, does not involve an invasive procedure to an already stressed newborn and could potentially classify infants depending on degree of injury, contributing to rapid and reliable therapeutic decision-making.

A large collection of previously published research focused on GFAP and CNS damage in general is available; however, a recent review of neonatal biomarkers by bersani et al. ( 19) called for further work to investigate the validity of this protein with a particular focus on outcome.Anoxia vs hypoxia we discovered no significant alterations in GFAP expression between our case and control groups or between different grades of HIE. Additionally, we found no correlation of GFAP levels with outcome at 36 months of age.

Our findings initially seem to contradict previously published research regarding the potential use of GFAP as an early biomarker of moderate/severe HIE. However, most studies to date have focused on post-natal samples, with significant elevation seen after 6–12 h ( 1, 18). More recently, a study focused on mixed cord samples in a historical cohort has shown no difference in serum GFAP levels between controls and infants with moderate-severe HIE ( 20). This is in keeping with previous work in adult TBI where peak levels occur at 12 h post-injury.Anoxia vs hypoxia

While there is good evidence that GFAP may be a useful marker of HIE severity in samples taken after six post-natal hours, we have not shown altered levels in UCB samples. This is the first prospective, carefully defined cohort study to focus on GFAP in UCB. This may limit the usefulness of GFAP as a biomarker to guide therapeutic intervention. Conclusion

Serum GFAP is not altered in the UCB samples of infants with perinatal asphyxia, with or without clinical and electrographic HIE, compared to normal controls. GFAP therefore may not be the ideal early biomarker to predict eligibility for therapeutic intervention. Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Anoxia vs hypoxia funding

A-ML, dr. CA, dr. DM, and the bihive study are funded by the health research board (HRB) (CSA/2012/40). This research was also supported by a science foundation ireland (SFI) research centre award (INFANT – 12/RC/2272). References