The journey of a newborn, especially one born prematurely, is often marked by life-saving medical care that involves numerous painful procedures. While essential for survival, a growing body of scientific evidence reveals that these early painful experiences leave a profound and lasting imprint on the body.
For decades, the prevailing assumption was that newborns, particularly preterms, did not feel or remember pain in a significant way. Modern science has completely overturned this notion. The nervous system of a newborn is not simply a smaller version of an adult's. Instead, it is a work in progress, with key pathways for pain perception developing at a startling pace in the final weeks of gestation 1 .
The maturation of the pain connectome—the network of brain regions that process pain—happens in distinct stages:
This is the first system to mature, allowing infants to sense the intensity and location of a painful stimulus by around 34–36 weeks after conception 7 .
This network, which allows the baby to identify pain as unpleasant and threatening, matures around 36–38 weeks 7 .
The ability to appraise and interpret pain does not fully develop until after a full-term birth, at more than 42 weeks after conception 7 .
In the Neonatal Intensive Care Unit (NICU), preterm infants can endure a staggering 7 to 17 painful procedures daily, from simple heel lances to more complex interventions 2 . The challenge for clinicians is monumental: how do you assess pain in a patient who cannot speak?
Healthcare providers rely on behavioral and physiological cues, using a variety of pain assessment scales. These tools, however, have limitations. A systematic review found that no single scale excels in all areas, and many struggle to distinguish between pain and general stress 3 . Preterm infants show more subtle signs of pain, such as simple grimacing or reduced movement, making their pain easy to overlook .
This leads to a significant problem: undertreatment. A 2025 Swedish study of over 3,686 babies found that while 90% of the most extremely preterm infants underwent painful procedures, clinicians documented pain in only 45% of them . The study also revealed that the smallest, most vulnerable babies received the least morphine, likely due to fears of side effects like low blood pressure . This suggests a widespread "undertreatment" of neonatal pain .
| Scale Name | Parameters Measured | Reported Strengths | Reported Limitations |
|---|---|---|---|
| ALPS-Neo 3 | Behavioral (facial expression, breathing, tone, etc.) | High inter-rater reliability, good for continuous pain | Lacks physiological parameters |
| BPSN (Bernese Pain Scale for Neonates) 3 | Behavioral & Physiological (heart rate, oxygen saturation) | Can distinguish distress from pain in some cases | Low inter-rater reliability |
| CHIPPS 3 | Behavioral | Good for acute pain, high inter-rater reliability | No physiological parameters, limited training materials |
| PIPP-R 3 | Behavioral, Physiological, & Contextual | Includes gestational age context | Complex, can be time-consuming |
The consequences of unmanaged neonatal pain extend far beyond the immediate moment. Repeated pain-related stress in the NICU is linked to alterations in brain development, including reduced white matter integrity, smaller thalamic and cerebellar volumes, and poorer cognitive and motor outcomes later in life 2 .
Groundbreaking research is now uncovering the biological basis for this "memory." A pivotal 2024 study from Cincinnati Children's Hospital pinpointed a specific cellular mechanism.
Researchers discovered that an early-life injury in mice causes a long-lasting "memory" within the immune system, specifically in macrophage cells 4 6 .
The team made a small incision in the paws of newborn mice, mimicking a routine surgical injury. They then tracked the mice's pain responses and analyzed their immune cells over time, for more than 100 days (equivalent to 10-15 human years).
The study found that the initial injury caused epigenetic changes in the stem cells within the bone marrow. These stem cells subsequently produced macrophages that were "primed" or hypersensitive. When the mice experienced another injury later in life, these primed macrophages mounted an exaggerated response, leading to more intense and prolonged pain 4 6 .
| Aspect | Finding | Implication |
|---|---|---|
| Primary Cell Type | Macrophages (immune cells) | Pain memory is linked to the immune system, not just nerves. |
| Mechanism | Epigenetic reprogramming of bone marrow stem cells | A single injury causes systemic, long-lasting changes in cell function. |
| Key Gene | p75NTR | A potential future target for therapies to block pain memory. |
| Duration | >100 days in mice (~10-15 human years) | Early pain can affect pain sensitivity throughout adolescence. |
| Sex Effect | Effects stronger and longer-lasting in females | Pain management strategies may need to be sex-specific. |
To unravel the mysteries of neonatal pain memory, scientists rely on sophisticated tools and models. The following table details some of the essential "research reagents" used in the featured experiment and this field of study.
| Tool/Model | Function in Research |
|---|---|
| Translational Rodent Models 2 | Mice and rats are born with neurologically immature systems; their first week of life models the third trimester in humans, allowing controlled study of early-life pain. |
| p75NTR Receptor Blockers 6 | Experimental compounds used to block a specific receptor on macrophages. In mice, this partially prevented prolonged pain, suggesting a therapeutic target. |
| Epigenetic Assays | Laboratory techniques to identify chemical modifications (e.g., to DNA or histone proteins) that change gene activity without altering the DNA sequence itself. |
| Flow Cytometry 6 | A technology used to analyze the physical and chemical characteristics of cells, such as macrophages, isolated from tissue or bone marrow. |
| EEG/fMRI 2 7 | Electroencephalography (EEG) and functional Magnetic Resonance Imaging (fMRI) allow researchers to measure brain activity and connectivity in response to pain in human infants. |
The evidence is clear: neonatal pain leaves a lasting biological imprint. The old paradigm of dismissing or undertreating infant pain is no longer tenable. The new science of pain memory calls for a fundamental shift in how we care for infants in the NICU:
We must move from asking "Does the baby feel pain?" to "How can we best protect the developing brain and nervous system from the harmful effects of pain?"
Relying solely on sucrose is insufficient. Care must integrate non-pharmacological interventions like skin-to-skin contact with parents as a powerful analgesic 9 . Pharmacological pain relief must be optimized to balance efficacy with safety.
The ultimate vision for neonatal care is to be as pain-free as possible . This involves not only better treatments but also reducing the total number of painful procedures performed.
Research into blocking specific targets, like the p75NTR receptor in macrophages, offers hope for future interventions that could prevent pain memory from forming in the first place 6 .
The cry of a newborn in the NICU is more than a momentary discomfort; it is a signal that echoes through the developing architecture of the brain and immune system. By listening closely and responding with the most compassionate and science-driven care, we can help ensure that a child's difficult beginning does not predetermine their future relationship with pain.