How Pain in Newborns Can Have Lifelong Consequences

You probably don’t remember anything from when you were an infant. However, chances are that you experienced some pain immediately after you were born. You might have needed an IV or a chest tube, or you even might have undergone surgery. While it may seem comforting to think it’s all in the past now, it turns out that those painful procedures you experienced as an infant could affect your health today.

The sensation of pain normally has a protective function; however, this function is lost when people experience pain in the long-term. People who experience different types of chronic pain often face significant challenges to their quality of life because of how disabling the pain can be. Despite being a very common health problem, there is still a lot we do not know about pain, and many aspects about pain conditions are largely misunderstood.

One misconception is that neonates are not developed enough to feel or remember pain. Clinicians believed this until the late 1980s, and it was common for them to perform surgeries on newborn infants with no anesthetics or pain relief. Fortunately, we are more informed today. In fact, neonates are capable of sensing pain immediately after birth, and repeated painful events can produce long term changes in the developing nervous system, which can alter the response to future sensations such as touch, temperature, and pain.

“In fact, neonates are capable of sensing pain immediately after birth, and repeated painful events can produce long term changes in the developing nervous system…”

For example, the tactile (touch) sense is the first to develop in the third trimester of pregnancy. The newborn is almost continuously exposed to tactile skin stimulation, which plays an important role in the strengthening of connections within the nervous system. As the newborn grows up and contact with the environment increases, the pattern of tactile skin stimulation will change and increasingly include activity from receptors and nerve endings in the skin responsible for detecting painful stimuli. Signals from these receptors will be transmitted by nerve fibers to the spinal cord and then to the brain, and at the same time the signal will be modified by local excitatory neurons (which amplify the transmission of signals) or by inhibitory neurons (which reduce the transmission of signals). Depending on the stage of maturation, excitatory and inhibitory connections between neurons are strengthened or weakened according to the nature of the sensory stimuli that the infant experiences. However, the fine balance between excitation and inhibition established by these circuits can be damaged by excessive stimulation. We know that painful medically required procedures such as blood collection produce local changes in brain activity which resolve later in life. When these medical interventions are frequent or excessive during infancy, for example in babies born with medical problems which require surgery, long-term consequences can arise, such as persistent pain or abnormal skin sensations.

How is pain sensation processed in early life?

The division of the nervous system responsible for processing pain is called the somatosensory system. During brain development, this system uses the sensory stimuli the infant comes in contact with to organize itself and give rise to the pain sensation. The incoming sensory information first reaches the spinal cord where local inhibitory and excitatory neurons process the information they receive from nerve fibers. These local neuronal circuits are able to separate touch sensation from pain sensation and then send the appropriate signals to the brain.

Studies using functional magnetic resonance imaging (fMRI) revealed that, when in pain, the infant brain looks the same as an adult brain. This suggests that the system responsible for processing pain is functional at birth, and that the pain experienced by infants is very similar to the adult experience.

However, this system comes into place just before term-time birth. We know from studies of rat pups that the neural circuits for pain are immature in preterm infants. Rat pups are often used as animal models for human preterm life because the last stages of brain development (which in humans occur during the last trimester of pregnancy) actually take place during the first two weeks of postnatal life in rats. Such studies revealed that in rat pups, the body representation within the primary somatosensory cortex – one of the main brain regions responsible for processing touch and pain – differs extensively from the adult one.

Another important difference is that, while in adults there is a clear segregation between pain and touch, in early life, touch fibers from the periphery make many incorrect connections with the spinal cord neurons. One problem in particular is that touch fibers make connections which overlap with the ones from pain fibers. As a result, neurons responsible for the processing of painful stimuli are activated by touch fibers, which tricks the brain into perceiving light touch as painful. The touch fibers start pulling away from “pain areas” in the spinal cord in the weeks just before term time when the maturation of the somatosensory system is complete.

“…the brain’s response to a painful stimulus is increased in infants born preterm, suggesting that preterm infants indeed perceive pain more intensely.”

In the same critical period, the local inhibitory circuits in the spinal cord also start to mature and eventually become functional just before birth. However, in preterm infants this circuit is still immature. Because of this, the spinal cord circuit is not able to dampen the transmission of painful stimuli, and as a result the brain receives more pain signals. The reason for this is that certain receptors which respond to glycine, a mediator of neuronal inhibition, are immature and do not participate in the transmission of signals between neurons. Remarkably, another form of neuronal inhibition, mediated by a neurotransmitter called GABA, is actually excitatory in early life and amplifies the transmission of pain signals. Therefore, the circuit which is usually in place to minimize pain in adults actually functions to increase the perception of pain. While the system eventually matures just before birth, such that the infant no longer experiences pain in the presence of touch stimuli, it is not the case for infants born preterm.

In humans, researchers have studied the sense of pain in early life by taking advantage of clinically required painful procedures. Using electroencephalography (EEG), it is possible to record the brain’s response to a painful stimulus. A big advance in the field came from the Fitzgerald Lab at University College London, which developed a method to directly measure the activity of neurons responsible for the sensation of pain in the human infant. These researchers demonstrated that during their first weeks of life, the brain’s response to a painful stimulus is increased in infants born preterm, suggesting that preterm infants indeed perceive pain more intensely.

What are the consequences of pain in early life?

Painful stimulation in the first weeks of postnatal life can be detrimental to one’s health. For example, due to the misconception that infants do not feel pain, circumcision used to be carried out without analgesia. Clinicians observed that boys that have been circumcised without analgesia displayed more sensitivity when they experienced painful procedures, such as vaccination, later in life.

The Paediatric Pain Research Group at the UCL Great Ormond Street Institute of Child Health has been trying to understand pain processing in early life and develop better pain management strategies for infants, children, and adolescents. Based on results obtained in laboratory studies, Dr. Suellen Walker – one of the investigators in this group – began carrying out EPICure studies on young adults that were born extremely premature (prior to 28 weeks of pregnancy), some of whom underwent surgery during their early postnatal life. EPICure is a series of studies conducted on the long term health of children and young adults that were born preterm.

“If painful experience in early preterm life could indeed lead to chronic pain, it is important to understand the risk carried by different painful situations and try to limit painful medical procedures during the first few weeks of life.”

These studies showed that reports of long-term pain are much more common in young adults that were born premature compared to young adults born at term. The young adults born preterm were also less sensitive to stimuli such as heat, cold, touch, and pressure, but those that underwent surgery as infants were more sensitive in the skin areas close to their surgery scars, particularly to dynamic stimuli such as stroking the skin with a brush. The abnormal sensation may be due to abnormal modulation of the spinal cord circuits from the brain. This modulation is part of a feedback loop through which the brain receives pain signals from the spinal cord, processes the information and generates the sensation of pain, and then sends signals back to the spinal cord which can amplify or dampen the transmission of pain and touch signals. This system may be ‘hijacked’ by excessive painful experiences during the period when the circuits are maturing, such that the brain dampens down touch signals, resulting in a loss of sensation in some areas of the body, but at the same time also amplifies touch signals from the scar areas resulting in an increase of sensitivity.

However, what is most worrisome is the increase in the incidence of pain conditions amongst young adults born preterm, which was established by the EPICure studies. Chronic pain is one of the greatest challenges that clinicians and researchers are facing today. In a recent study, this condition was found to affect almost half of all adults in the UK. If painful experience in early preterm life could indeed lead to chronic pain, it is important to understand the risk carried by different painful situations and try to limit painful medical procedures during the first few weeks of life.

Despite the very compelling research, some clinicians working in Neonatal Intensive Care Units still do not always use pain medication for some potentially painful procedures. This is mostly because there are still very serious concerns about the safety of analgesia and pain medications, particularly in neonates. For this reason, research is absolutely necessary in order to improve the identification, diagnosis, and treatment of pain, as well as to understand the factors which may predispose us to chronic pain conditions. We have barely scratched the surface in understanding the complex experience of pain and the Pain Paediatric Research Group at UCL are at the forefront of our future insight.

Have you had any experiences, first-hand or otherwise, with neonatal pain having effects later in adulthood? Let us know in the comments below.

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Feature image depicting a fetus in the womb of a pregnant woman experiencing pain shortly after birth and having that pain show up later on in adulthood. Illustrated by McCall Sarrett.

— Written by Denis Duagi. Illustrated by McCall Sarrett.

References
  • Anand, K., & Hickey, P. (1987). Pain and Its Effects in the Human Neonate and Fetus. The New England Journal of Medicine, 317(21), 1321-1329.
  • Baccei, ML, & Fitzgerald, M. (2004). Development of GABAergic and glycinergic transmission in the neonatal rat dorsal horn. J NEUROSCI (2004), 24 (20) 4749 – 4757.
  • Fayaz, A., Croft, P., Langford, R., Donaldson, L., & Jones, G. (2016). Prevalence of chronic pain in the UK: A systematic review and meta-analysis of population studies. BMJ Open, 6(6), E010364.
  • Fitzgerald M. (2005). The development of nociceptive circuits. Nature Reviews Neuroscience, 6(7), 507-50720.
  • Granmo, M., Petersson, P., & Schouenborg, J. (2008). Action-based body maps in the spinal cord emerge from a transitory floating organization. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience, 28(21), 5494-503.
  • Sezgi, G., Hartley, C., Emery, F., Rogers, R., Campbell, J., Sanders, M., . . . Tracey, I. (2015). FMRI reveals neural activity overlap between adult and infant pain. ELife, 4, ELife, 2015, Vol.4.
  • Slater, Fabrizi, Worley, Meek, Boyd, & Fitzgerald. (2010). Premature infants display increased noxious-evoked neuronal activity in the brain compared to healthy age-matched term-born infants. Neuroimage, 52(2), 583-589.
  • Taddio, A., Stevens, B., Craig, K., Rastogi, P., Ben-David, S., Shennan, A., . . . Koren, G. (1997). Efficacy and Safety of Lidocaine–Prilocaine Cream for Pain during Circumcision. The New England Journal of Medicine, 336(17), 1197-1201.
  • Walker, S. (2019). Early life pain—effects in the adult. Current Opinion in Physiology, 11, 16-24.

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Denis Duagi

Denis is a final year student of an integrated master’s program in Neuroscience at University College London (UCL). She previously worked with a clinical research group at the UCL Institute of Child Health, investigating neuropathic pain in children and adolescents. Currently she is undertaking laboratory-based research, aiming to understand how neural circuits drive pain and protective behaviours. In the near future she hopes to pursue a PhD and work on understanding the neurobiology underlying the complex experience of pain. She is ultimately interested in translating laboratory research on animal models to effective treatments for chronic pain. Outside the lab, she enjoys writing articles about neuroscience research for the lay audience and is passionate about science advocacy and outreach.
Denis Duagi

Latest posts by Denis Duagi (see all)

Denis Duagi

Denis is a final year student of an integrated master’s program in Neuroscience at University College London (UCL). She previously worked with a clinical research group at the UCL Institute of Child Health, investigating neuropathic pain in children and adolescents. Currently she is undertaking laboratory-based research, aiming to understand how neural circuits drive pain and protective behaviours. In the near future she hopes to pursue a PhD and work on understanding the neurobiology underlying the complex experience of pain. She is ultimately interested in translating laboratory research on animal models to effective treatments for chronic pain. Outside the lab, she enjoys writing articles about neuroscience research for the lay audience and is passionate about science advocacy and outreach.

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