Engaging Families in HIE Research: A Call to Action for Neonatal Care and Drug Development

With an incidence of 2–20 per 1,000 live born infants, moderate to severe hypoxic ischemic encephalopathy (搜索)搜索该疾病 (HIE) remains one of the most important causes of neonatal death and adverse motor and cognitive outcomes. Although therapeutic hypothermia (搜索)搜索该药品 (cooling) is the established standard of care in high-income countries, many children do not qualify for cooling or experience significant morbidity despite treatment. No neuroprotective pharmacological interventions are yet available, leaving affected families with immense multilayered burdens and lifelong challenges.

These findings emerge from a 2-day hybrid international multistakeholder meeting (MSM) held September 18–19, 2023 in Rome, Italy, organized by conect4children (搜索)搜索该词条 (c4c), a pan-European network that facilitates pediatric drug development. The meeting aimed to improve timely development and access to therapies by addressing unmet needs of neonates with HIE and introducing innovative development pathways in the regulatory environment.

The Family Experience in the NICU

From a family's perspective, the diagnosis and naming of the condition is the first challenge after birth. Members of the writing group reported that some affected families never receive a specific HIE diagnosis; without a named diagnosis, families cannot connect with the relevant patient community or engage in research or clinical trials. The authors noted a perception that "medico-legal" concerns led some clinicians to practice defensive medicine and avoid or downplay the possibility of HIE, which "breaks down trust in the medical team."

Wide variation in NICU experience was a recurring theme. Some parents reported being allowed in the NICU only 20 minutes twice daily, while others had unrestricted bedside access. "We had 2 times 20 minutes visiting time daily, had no psychological support and no involvement in daily care," one parent reported. "I could only watch my baby and had to ask for permission to touch him."

The writing group emphasized that wording matters: "it is important to educate parents/caregivers respectfully about their babies' health without scaring them but also without sugar coating; in order to make them feel seen, respected and included into medical decisions."

Post-Discharge Challenges and Fragmented Care

After NICU discharge, parents are often left alone and become the primary caretaker while also organizing all healthcare processes without support. Parents noted that caring for a child affected by HIE can be a full-time job, leading to exhaustion — a marked contrast to the disempowerment many experience on the neonatal unit.

Families described gaps including lack of coordinated follow-up planning, differences in clinical perspectives between neonatologists and pediatric neurologists, unclear responsibility for long-term management, and insufficient integration of services across disciplines. "There is no standardized patient roadmap," one parent stated. "We have NICU follow up programs — but not one master orchestrator — parents have to be the director of a huge team; it's a full-time job managing communication across many medical teams, therapists, school teams, early intervention teams."

Marked variation in follow-up across countries was also noted — some European countries have no follow-up at all, while others continue until age 6 or 8 — which the authors described as "inexplicable to parents."

Optimizing Research Through Family Engagement

The authors stressed that engaging families from the design phase of research can ensure relevance, prioritize critical research questions, and inform feasibility. Engaging families throughout recruitment and study completion decreases dropout and yields better data. However, parent members reported that parents of children affected by HIE "have been historically not included and marginalized in neonatal parental partnerships."

"Neuroprotective treatment options were not offered to us after birth," one parent reported. "We as parents had to research, present, and advocate for the execution of an existing clinical trial out of country. Difficult as a parent to later find out about available treatments that could have helped our child."

The authors noted that the main barrier to effective research participation appears to be "lack of researcher awareness of the importance and value of meaningful family involvement at all stages of the research process." They emphasized that skills promoting research participation "are not simple extensions of skills used for communication in clinical practice."

Research Priorities and Outcome Measures

The writing group argued that discussion about research should start by asking what families would like research to cover and what constitutes meaningful outcome measures. "Often, the current standard measures are not the outcomes that are most meaningful to families," they wrote. The COHESION core outcome set for neonatal encephalopathy — developed with parental involvement — includes seven outcomes: survival; brain injury on imaging; neurological status at discharge; cerebral palsy; general cognitive ability; quality of life of the child; and adverse events related to treatment. However, the authors noted that no HIE advocacy organization was involved in its development.

A Call to Action

Based on their lived experience and advocacy work, the writing group identified four key action points:

1. A pan-stakeholder coalition for HIE needs to be established to develop and promote an integrated approach to HIE care and research.
2. Clinical care needs to be optimized according to standardized, evidence-based guidelines with a focus on reducing unwarranted variation, including timely and accurate diagnosis, equitable access to therapeutic hypothermia and neuro-monitoring, consistent communication, and coordinated long-term follow-up.
3. Core content of communication with families during the acute phase needs to be standardized while delivery is tailored to each family's circumstances.
4. Research about HIE needs to be led by and include families with relevant lived experience, ensuring that research reflects the needs, priorities, and preferences of those affected.

"Rapid advances in basic science and the development of multiple new therapeutic approaches to HIE mean that we are on the threshold of a revolution in the management of this condition," the authors concluded. "Attention to the points raised in this paper is likely to improve the likelihood of successful development of new treatments and the implementation of effective interventions to the benefit of thousands of families each year."

The paper was prepared by an enthusiastic subgroup of attendees at the 2023 MSM, reflecting the experiences of six families with extensive experience of HIE care, research, and advocacy. The authors acknowledged that this sample of convenience led to incomplete representation and that a formal thematic analysis was not conducted, but maintained that the core messages are likely to be widely applicable given several authors' active roles in family advocacy groups.