The fetal pain paradox

Abstract

Controversy exists as to when conscious pain perception in the fetus may begin. According to the hypothesis of cortical necessity, thalamocortical connections, which do not form until after 24–28 weeks gestation, are necessary for conscious pain perception. However, anesthesiologists and neonatologists treat age-matched neonates as both conscious and pain-capable due to observable and measurable behavioral, hormonal, and physiologic indicators of pain. In preterm infants, these multimodal indicators of pain are uncontroversial, and their presence, despite occurring prior to functional thalamocortical connections, has guided the use of analgesics in neonatology and fetal surgery for decades. However, some medical groups state that below 24 weeks gestation, there is no pain capacity. Thus, a paradox exists in the disparate acknowledgment of pain capability in overlapping patient populations. Brain networks vary by age. During the first and second trimesters, the cortical subplate, a unique structure that is present only during fetal and early neonatal development, forms the first cortical network. In the third trimester, the cortical plate assumes this function. According to the subplate modulation hypothesis, a network of connections to the subplate and subcortical structures is sufficient to facilitate conscious pain perception in the fetus and the preterm neonate prior to 24 weeks gestation. Therefore, similar to other fetal and neonatal systems that have a transitional phase (i.e., circulatory system), there is now strong evidence for transitional developmental phases of fetal and neonatal pain circuitry.

Terminology matters: is the International Association for the Study of Pain definition of pain fully satisfactory for fetuses, neonates, and infants?

“…In light of this evidence, we believe that the International Association for the Study of Pain definition of pain appears to be limited and inadequate to explain fetal-neonatal nociception and pain because noxious stimuli may result in “immediate or long-term ramification” ( 3 ), that is, a more complex network of short term and long term resulting phenomena from the initial trigger of the nociceptive experience. Thus, pain should be quantified more appropriately, perhaps with more sophisticated scales of assessment, to select the most fitting perinatal and neonatal pediatric therapy ( 29 ) synergically with neonatology, perinatology, obstetrics, fetal surgery, fetal anesthesiology, fetal neurobehavior, neuroscience, legal medicine, and medical bioethics ( 13 ). This is a tedious task, however, pain is necessary to be analyzed sociologically, and ethically, besides theology and medicine.…”

“…But it was highlighted that fetuses can perceive and react to pain via the cortical subplate structures as early as 12 weeks of gestation ( 1 , 3 , 11 , 12 ). The “fetal pain paradox” described by Thill ( 13 ) states that even below <24-week fetuses and preterm babies born present the same pain items (immature cortex, active and functional subplate, facial expression of pain in response to noxious stimuli, fight-or-flight stress in response to noxious stimuli, and body movement in response to noxious stimuli), pain management in preterm babies is deemed as an important clinical task, while fetuses are still not sufficiently and universally considered capable of perceiving pain ( 13 ).…”

Narrative Review of the Complex Interaction between Pain and Trauma in Children: A Focus on Biological Memory, Preclinical Data, and Epigenetic Processes

“…Painful experiences are processed and modulated by several neuronal circuits, involving the brainstem, thalamus, cortical subplate, and cortex [31]. While the brain areas involved in pain perception are completely developed by 24 weeks of gestation, the descending inhibitory circuits that control pain are still immature at birth [31,32]. Therefore, neonates are likely to be more sensitive to pain than older children and adults [31,32].…”

“…While the brain areas involved in pain perception are completely developed by 24 weeks of gestation, the descending inhibitory circuits that control pain are still immature at birth [31,32]. Therefore, neonates are likely to be more sensitive to pain than older children and adults [31,32]. Although every child may experience pain from the earliest stages of life, childhood pain is one of the most misunderstood, underdiagnosed, and under-treated medical problems [33,34].…”

“…Traumaexposed individuals (regardless of clinical presentation) often tend to retrieve memories of events from their past in a generalized way, with a lack of event-specific details [67]. These impaired memories have been implicated in the development and maintenance of psychiatric disorders, such as post-traumatic stress disorder (PTSD) and major depressive disorder [30][31][32]. Furthermore, memory biases for previous pain experiences are known to be strong predictors of post-surgical pain outcomes in children [68].…”