Perinatal asphyxia biomarkers and neurodevelopment

Perinatal asphyxia occurs when oxygen delivery or blood flow is inadequate around birth. Its effects may emerge hours later as seizures or encephalopathy, and years later as cerebral palsy, epilepsy, learning difficulty or impaired social development. Biomarkers for predicting neurodevelopmental outcomes can estimate risk, yet no single measurement determines an individual child’s outcome.

In Australian practice, the value of prediction is practical. A reliable signal can support timely therapeutic hypothermia, neurological assessment, rehabilitation and developmental follow-up. Evidence must be interpreted alongside the examination, clinical course, gestation and family priorities; research markers should not trigger unproven treatment. A practical comparison separates current clinical signals from emerging tests:

Why prediction matters in Australian care

An infant can look reasonably well after a difficult birth, yet deteriorate over the next hours. The Apgar score, cord blood gas and early neurological examination answer different questions. At neonatal units in Melbourne, Sydney, Brisbane, Perth and regional hospitals, even a modest improvement in risk estimation can shape observation, escalation and family counselling.

Follow-up cannot be reduced to a single MRI appointment. In a country where many families in regional and remote areas drive long distances to tertiary hospitals, developmental review often combines telehealth, local paediatric services and occasional travel to a major city. Prediction becomes useful when it shapes practical support, including seizure surveillance, early allied-health referral and a clear plan for school-age review.

Multidisciplinary review is essential because no laboratory result interprets itself. The exchange model seen at the VTEC 2018 meeting illustrates how international meetings can connect laboratory evidence with clinical questions. Perinatal teams similarly need obstetricians, neonatologists, neurologists, psychologists, data scientists and families working from shared definitions and outcomes.

Reading the clinical signal at birth

At birth, the most informative accessible measures remain umbilical artery pH, base excess and lactate. A low cord pH can identify fetal acidemia, while elevated lactate reflects anaerobic metabolism and impaired perfusion. Neither is infallible: sampling technique, the time after birth, sepsis, maternal events and prematurity can alter results, so trends and the newborn examination remain essential.

During the next 12 to 24 hours, clinicians watch for altered alertness, abnormal muscle tone, seizures, feeding difficulty and multi-organ dysfunction. Repeated neurological examination, bedside aEEG and selected laboratory testing help distinguish transient illness from evolving neonatal encephalopathy. In Australia, therapeutic hypothermia is used under established criteria and local neonatal protocols; early reliable risk assessment supports timely transfer and treatment.

The FAOPS 2020 program set out the scientific agenda for the 21st Congress of the Federation of Asian and Oceania Perinatal Societies, planned for Tokyo alongside PREBIC AA 2020. The congress was cancelled in April 2020 because of COVID-19 and international travel difficulties. That history reinforces a practical lesson: shared definitions, quality specimens and follow-up are needed even when face-to-face exchange is interrupted.

Cellular and molecular biomarkers

Blood-based markers extend beyond acid–base status. Cytokines such as IL-6, IL-8 and TNF-alpha reflect inflammation; GFAP, UCH-L1 and S100B reflect neuronal or axonal injury. Cell-free DNA, microRNAs and metabolomic profiles may capture tissue stress, while placental pathology adds another view of the birth process.

Their value depends on timing and context. A marker drawn soon after resuscitation may differ from one collected during cooling or several days later. Age, infection, anaesthesia, renal function and treatment can also alter concentrations. Proteomic and metabolomic panels are promising because they capture multiple pathways, but complex models require calibration, external validation and clinically usable thresholds before they can support decisions.

Research coverage of cell and gene therapies shows how new interventions may eventually depend on biological selection and safety monitoring. For neonatal brain injury, experimental regenerative approaches are not standard care, and biomarkers must not be used to imply eligibility. Their strongest near-term role is trial design: identifying participants, measuring response and detecting treatment-related effects.

Imaging and neurophysiology

MRI remains the strongest imaging method for describing established brain injury after hypoxic–ischaemic encephalopathy. Diffusion-weighted imaging can show acute restriction, while spectroscopy and conventional sequences reveal later changes in basal ganglia, thalami and white matter. Interpretation differs between term and preterm infants, so timing, technique and specialist reporting are integral to prognosis.

aEEG provides a bedside view of cortical function over hours or days. Background slowing, discontinuity and electrographic seizures help identify dysfunction that may be missed clinically. Full EEG adds detail for difficult or equivocal cases. Neither test forecasts development in isolation, however, and signals must be reconciled with examination and other physiological data.

A stronger model combines cord gases, lactate, neurological course, aEEG and MRI rather than relying on one impressive number. Such models can estimate probabilities for death, severe disability or later cognitive impairment, but they should communicate uncertainty and possible modifiability. Serial review is often more informative than a single prediction generated during the first day of life.

Building a clinically useful pathway

A clinically useful pathway starts with standardised sampling and documentation: time-stamped cord blood, arterial or venous lactate, serial neurological observations and, where appropriate, aEEG and MRI. The same definitions should be used for hypoxic–ischaemic encephalopathy, other causes of neonatal encephalopathy and no encephalopathy. Placental pathology and clinical covariates belong in the dataset rather than being added later.

Prediction models need transparent development, internal validation and testing in independent Australian cohorts. Performance should be reported beyond discrimination, including calibration, missing data, subgroup performance and the consequences of false positives and false negatives. A model imported from another country may perform differently because of population mix, care pathways and outcome definitions.

The FAOPS account of prenatal surgical planning for placenta accreta spectrum offers a useful operational lesson. Coordinating imaging, pathology, referral timing and theatre planning improved a complex care pathway; an asphyxia pathway can apply the same discipline to cord sampling, therapeutic decisions, imaging and developmental follow-up. The key is a named team and a schedule that survives shift changes and transfers between hospitals.

Equity, regulation and data stewardship

Prediction models can widen disparities when they rely on variables that reflect access rather than biology. Aboriginal and Torres Strait Islander families, remote communities, families with limited English and households facing financial or transport barriers may begin with different pathways into specialist care. Co-design with communities, appropriate interpreters and transparent reporting of subgroup performance are essential; race should never act as a biological proxy.

Australian maternity care combines Medicare-funded public hospitals with private obstetric services, while neonatal intensive care, pathology, point-of-care blood-gas analysers, MRI and laboratory testing form interconnected markets. The Therapeutic Goods Administration regulates medical devices and in-vitro diagnostics, so a marker’s analytical performance must be separated from its clinical usefulness. Procurement should consider interoperability, maintenance, staff training and equitable access, not price alone.

Linkage across hospitals, laboratories and community services also creates legal and ethical duties. The Privacy Act 1988 and Australian Privacy Principles govern many personal health records, while state health-records legislation, tissue laws and retention requirements vary. NHMRC guidance, consent that respects future use, secure storage and documented data-governance plans should precede any multicentre biobank or algorithm deployment.

Turning evidence into action

Until larger studies validate newer panels, clinical teams can act on established evidence: document cord gases and lactate, perform serial neurological examinations, use aEEG when indicated and obtain MRI where clinically appropriate. Families should receive plain-language information about uncertainty, what is known and how follow-up will be organised. Nothing in a research panel should justify an unproven therapy.

Research networks can build the evidence needed for safer decisions by standardising specimen collection, linking time-resolved clinical data and measuring neurodevelopment at two years and again at school age. Consumer involvement, rural and remote representation, transparent code and independent replication should be built into the study from the outset.

The immediate call to action is to unite clinicians, laboratories, hospitals, universities, professional colleges and families around one family-centred pathway. Use validated markers now, test promising ones rigorously, and make timely developmental support the destination of every prediction. Support the shared pathway, contribute to validation and ensure that each child receives follow-up matched to need rather than to the severity of a single laboratory value.