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.

Keywords: fetal analgesia; fetal anesthesia; fetal awareness; fetal nociception; fetal pain; subplate.

Figure 1

The fetal pain paradox. Both the fetus and preterm infant <24 weeks gestation have an immature cerebral cortex (12) and an active, functional cortical sublate (13, 14). Both mount hormonal and hemodynamic stress responses (6, 15) and demonstrate pain-related facial expressions (6, 16) and body movements (6, 15) following noxious stimuli. The standard of care for preterm infants, according to the American Academy of Pediatrics, is pain management utilizing validated pain assessment tools. However, the American College of Obstetricians and Gynecologists (11), the Society for Maternal Fetal Medicine (1), and the Royal College of Obstetricians and Gynaecologists (2) state that pain perception is not possible until after 24–28 weeks gestation.

Figure 2

The multidisciplinary dimensions of fetal pain research.

Figure 3

An evolving understanding of pain. Scientific understanding and recognition of pain capacity in the neonate and fetus have evolved over time. In the 1980s and 1990s, medical consensus held that neonates (32, 38) and fetuses (15) lacked the capacity to perceive pain. In the 200s (12), 2010s (34), and 2020s (4, 35, 36), the understanding of fetal pain capacity has shifted.

Figure 4

Development of nociceptive pathways. Peripheral pain receptors develop in most areas of the fetus between 7.5–15 weeks gestation (48). Afferents reach the spinal cord (49), the brainstem, and thalamus by 7–8 weeks (50, 51). Thalamic projections to the cortical subplate emerge at 12–15 weeks (14, 34, 52) and to the cortical plate after 23–24 weeks gestation (53).

Figure 5

3D analysis of the sensory innervation of the developing human hand (67). Time series illustrating the developing innervation of sensory nerves of the right hand from GW7–GW11, labeled for the neuron-specific intermediate filament protein peripherin (Prph). Individual segmentation of the radial (blue), median (magenta), and ulnar (green) nerves are shown. The musculocutaneous nerve (arrows) transiently extends into the hand. Prph, neuron-specific intermediate filament protein peripherin; 3D, three-dimensional; GW, gestational week.

Figure 6

Normal multilayered magnetic resonance imaging (MRI) appearance of fetal brain early in gestation (72). (A) A diagram representing the fetal brain at 19 weeks of gestation shows smooth surface and multilayered appearance of the parenchyma with an inner germinal matrix (G), intermediate layer (I), and a developing cortex (C). The small arrows point to the direction of the migrating neurons from germinal matrix to the developing cortex. (B) Axial balanced fast field echo MR image of a normal brain at 19 weeks of gestation shows a smooth surface and multilayered parenchyma with an inner hypointense germinal matrix (white arrow), an intermediate layer, and an outer hypointense developing cortex (black arrow). Two additional sublayers can be identified: subventricular zone (white arrowhead) and subplate (black arrowhead). Subventricular zone is thick in the frontal region and shows slightly hypointense signal as it contains germinal matrix with increased cell production. The subplate zone appears slightly hyperintense as it has high water content because of extracellular matrix.

Figure 7

Pain assessment tool for third trimester fetuses during anesthetic injection into the thigh during fetal surgery (58). (A) Initial items from neonatal facial coding system and 2 supplementary items. 1. Brow lowering. 2. Eyes squeezed shut. 3. Deepening of the nasolabial furrow. 4. Open lips. 5. Horizontal mouth stretch. 6. Vertical mouth stretch. 7. Lip purse. 8. Taut tongue. 9. Tongue protrusion. 10. Chin quiver. 11. Neck deflection 12. Yawning. (B) Final items from the Fetal-5 Scale. 1. Brow lowering. 2. Eyes squeezed shut. 3. Deepening of the nasolabial furrow. 4. Open lips. 5. Horizontal mouth stretch. 6. Vertical mouth stretch. 7. Neck deflection.

Figure 8

Pain-related facial expressions in 23-week fetus in response to intramuscular injection of fetal thigh, analyzed by blinded investigators (16). Four-dimenstional ultrasound images of fetal facial expressions analyzed before (upper row) and after (lower row) anesthetic puncture, demonstrating the lack of pain-related facial response before and the presence of pain-related facial expressions after the painful stimulus. Seven criteria were considered to be indicative of fetal pain response: 1, brow lowering; 2, eyes tightly shut; 3, deepening of the nasolabial furrow; 4, open lips; 5, vertical mouth stretch; 6, horizontal mouth stretch; and 7, neck extension.

Figure 9

The emergence of consciousness. Consciousness has been likened to a dimmer switch beginning with a minimum basic level of consciousness mediated by the brainstem (100), thalamus (99), and possibly the cortical subplate (4) increasing to higher-order consciousness mediated by the cortex (100). Basic consciousness requires responsiveness to the environment (101), demonstrated by action planning, purposeful movements, and leaming (100), while higher-order consciousness involves memory, self-reflection, and imagining the future (98).

Figure 10

Schematic presentation of the processes underlying the subplate and cortical plate modulation hypothesis (5). The bottom line denotes age, first in weeks PMA, after term (40 weeks) in months (corrected age). Above the age line the developmental changes in the human cortex are depicted. SVZ/VZ represents the subventricular and ventricular zones where the neurons and glial cells are generated; IM/PWM denotes the intermediate zone that gradually develops into the periventricular white matter; MZ is the marginal zone. The following three timelines represent from bottom to top: the hyperexcitability of the nervous system, in which the intensity of the grey shading represents the degree of hyperexcitability; the cortical network activity that emerges across the brain from 9 to 10 weeks PMA, this gradually increases (indicated by increasing shading) to be full-blown present (in the subplate) at mid-fetal age, before moving from global and widespread activity to local and limited activity to local and limited activity (“sparsification”, indicated by the diminution of the dots); on top the developmental changes in general movements. GM, general movements; PMA, postmenstrual age; CA, corrected age; pt, preterm.