REVIEW ARTICLE

https://doi.org/10.5005/jp-journals-10009-1700
Donald School Journal of Ultrasound in Obstetrics and Gynecology
Volume 15 | Issue 2 | Year 2021

Fetal Awareness

Milan Stanojević¹, Asim Kurjak², Aida Salihagić Kadić³, Lara Spalldi Barišić⁴, Miro Jakovljević⁵

¹Department of Obstetrics and Gynecology, Clinical Hospital “Sveti Duh”, Medical School University of Zagreb, Zagreb, Croatia
²Department of Obstetrics and Gynecology, Clinical Hospital “Sveti Duh”, Medical School University of Zagreb, Zagreb, Croatia; Sarajevo School of Science and Technology, Sarajevo, Bosnia and Herzegovina
³Department of Physiology, Medical School University of Zagreb, Zagreb, Croatia
⁴Outpatient Department, Veritas, Zagreb, Croatia
⁵Department of Psychiatry, University Hospital Center Zagreb, Zagreb, Croatia

Corresponding Author: Milan Stanojević, Department of Obstetrics and Gynecology, Clinical Hospital “Sveti Duh”, Medical School University of Zagreb, Zagreb, Croatia, Phone: +385 91 3712110, e-mail: mstanoje29@yahoo.com

How to cite this article Stanojević M, Kurjak A, Salihagic Kadic A, et al. Fetal Awareness. Donald School J Ultrasound Obstet Gynecol 2021;15(2):188–194.

Source of support: Nil

Conflict of interest: None

ABSTRACT

Background: While studying fetal behavior using four-dimensional ultrasound (4D US), we have been speculating about the fetal awareness and fetal cognitive function, trying to become familiarized with fetal emotional life and its readiness to separate from the intrauterine environment and begin independent life as a new individual.

Aim and objective: The aim and objective to see whether by observing the fetus by 4D US we are able to enter fetal behavior, emotions, mental status, consciousness, awareness, and other states connected with fetal mind and ability of self-regulation.

Results: After 24–26 weeks, the fetus has the necessary connections to sense pain. Somatosensory evoked potentials can be registered from the cortex at 29 weeks, and they may provide evidence of pain processing in the somatosensory cortex. According to recent findings, the cortical pain response has been recorded by near-infrared spectroscopy from about 25 weeks. Fetal facial expressions like those of children sustaining pain have been noticed by 4D US. The fetus can alter the frequency, patterning, and coordination of movement in response to sensory challenges, while retention of information from motor experience and motor learning may contribute to normal prenatal motor development.

Conclusion: We have learned from the research by 4D US that the fetus is capable of action planning and learning, meaning that probably the capability of being aware and conscious should proceed. Fetal life in utero is dramatic and rich in different experiences, which probably would not be possible without development of fetal awareness and consciousness.

Keywords: Awareness, Consciousness, Fetal behavior, Fetal senses, Four-dimensional ultrasound..

INTRODUCTION

Introduction of ultrasound >70 years ago into medical diagnostics was an important diagnostic tool in clinical medicine.^1,2 When >60 years ago ultrasound was introduced to the field of obstetrics and gynecology, it has opened mysterious and unknown world of fetal life to the eyes of clinicians and the mothers.³ Advancement of ultrasound and computer technology almost 30 years ago enabled introduction of three- and four-dimensional ultrasound (3D and 4D US) which has made depiction of fetal anatomy more realistic with many details of normal and abnormal structures of many organs and organ systems.^4–6 Two-dimensional ultrasound (2D US) has been used as the tool not only to depict fetal anatomical structures but also its function by assessment of Prechtl’s fetal general movements (GMs), reflecting the development of fetal central nervous system.^7–9 Some 15 years ago, 4D US has been introduced in the field of fetal behavior with the development of Kurjak Antenatal Neurodevelopmental Test (KANET) aiming to detect fetuses at high neurodevelopmental risk by the assessment not only of fetal GMs and movements but also some other signs from prenatal neurological assessment like skull sutures, neurological thumb, and facial movements.^10–14 While studying fetal behavior, we have been speculating about the fetal awareness and fetal cognitive function, trying to become familiarized with fetal emotional life and its readiness to separate from the intrauterine environment and begin independent life as a new individual.^15,16 This concept of looking at the fetus as a complete person is very important, because only by putting together all aspects of one’s health even in utero is enabling better results of treatment. This means that at that time we have been thinking in the way of so-called personalized medicine, taking every fetus as a separate and unique individual.¹⁷ Problem with fetus is that not all postnatal diagnostic tools are available prenatally, and the influence of intrauterine environment which is quite different from one postnatally is also disturbing and complicating our diagnostic means and approach.^18,19

The aim of this paper is to see whether by observing the fetus by 4D US we are able to enter fetal behavior, emotions, mental status, consciousness, awareness, and other states connected with fetal mind and ability of self-regulation.

Definition of Human Awareness

Linguistic definitions of awareness are available on the Internet. Webster dictionary defines awareness the quality or state of being aware: knowledge and understanding that something is happening or exists,²⁰ while MacMillan dictionary provides with two aspects of awareness:²¹

Knowledge or understanding of a subject, issue, or situation.
The ability to notice things.

Awareness is the ability to directly know and identify, to feel, or to be aware of events, meaning that one is conscious of something, informing environment about it through specific behavioral process.²² Weather awareness is synonymous with consciousness itself is not quite clear, although some investigators think about awareness in that way.²³ Many investigators believe that consciousness consists of two components: awareness which is a content of consciousness, and arousal describing the level of consciousness.^24,25 Awareness and arousal are mostly positively correlated meaning that with decreased arousal awareness is decreasing as well.²⁴ Concept of awareness has at least two aspects: the first focused on internal state which could be described as the intuitive feeling of something, and the second directed toward the external events by means of sensory perception, when the brain is activated in certain ways enabling sensing something, which is process distinguished from observation and perceiving.¹⁶ While thinking about awareness, there can be at least two aspects of the state of awareness depending on the subject to which awareness is directed: one is self-awareness meaning that one is aware of one’s own awareness state, and the other component is external awareness implicating how external world is perceived.^16,24 The organization of self-awareness denotes the inner experience of the subject which has a central role in the self-regulation.²⁶ One’s awareness of internal and external world is defined as basic awareness and is dependent on the brain stem, while higher forms of awareness like self-awareness require cortical contribution. Primary consciousness means ability to integrate sensations from the environment which are transposed to certain behavior. This primary consciousness or basic awareness consists of the capacity to generate emotions and awareness of surrounding without ability to talk, label, or describe this experience. There are interconnected regions down the brain stem regulating the direction of the gaze and organize the decisions about one’s next activity.^25,26

Development of Consciousness and Awareness

As it was pointed out before, consciousness has two main components: arousal which involves the activity of subcortical structures encompassing brain-stem reticular formation, hypothalamus, and basal forebrain, and awareness which is related to the activity of frontoparietal associative areas.²⁴ While self-awareness networks include the posterior cingulate/precuneal cortices, medial frontal cortex, and bilateral temporoparietal junctions, the external awareness network encompasses lateral frontal and parietal cortices.^24,27

The brain stem is formed around 7 weeks of gestation, while cerebral hemispheres and diencephalon develop by the end of 8 gestational weeks.²⁸ Production of 250,000 neurons per minute starts at 7 weeks of gestation.²⁹ Early in gestation neurons differentiate and migrate through the forming cortical layers. Migration of neurons to the cortical plate peaks around 12–20 weeks and is complete around 26–29 weeks.^30–32 Approximately between 24 weeks and 34 weeks, cortical area differentiation begins and continues until the end of gestation.³³ The peak period of synaptogenesis begins at 34 weeks and continues well into early postnatal life.³⁴ Thalamocortical and corticocortical connections are fundamental for cortical processing of sensory information and mental processes. The first such connections grow at 24–26 weeks of gestation.^35,36 Between 26 weeks and 28 weeks, evoked potentials can be registered from the cortex, indicating that the functional connection between periphery and cortex operates from that time onward.^37,38

Diagnostic Tools Demonstrating Brain Function

As it was pointed out earlier not many diagnostic methods are available for prenatal use due to technical and ethical constraints. Depicting fetal structural brain anatomy is much easier than the assessment of fetal brain function. Methods like functional magnetic resonance imaging (fMRI), diffuse correlation spectroscopy and near-infrared spectroscopy, positron emission tomography (PET), magnetoencephalography, or electroencephalography (EEG) can be used postnatally in premature infants and these data can be transposed to the fetuses of the same gestational age, but this comparison is not quite plausible at least because fetus and neonate are living in quite different environments, which may have a substantial influence on the findings.^39–41 Most methods rely on the idea to make assumptions about the timing or location of some activity pattern of the activated brain system.^24,42–46

The EEG is more and more routinely recorded alongside fMRI to study spontaneous brain activity.^43,47 The EEG data provide access to very useful information regarding the timing of spontaneous brain activity. There are some differences between neonatal and adult brain activity shown by fMRI detecting the highest activity in the somatosensory, auditory, and visual cortex, whereas less activity is revealed in the association area and the prefrontal cortex of the newborn brain as compared with adults.⁴⁸

As we can see from the data of sophisticated neuroimaging and neurophysiological data used postnatally, neither of them has been routinely used in fetuses due to different technical and ethical constraints.^49,50 At the moment, one of the available methods for functional assessment of fetal brain is 4D US for assessment of fetal behavior.

Possibilities of 4D US in Assessment of Fetal Behavior

Fetal Sensory Perception

The fetus can process tactile, vestibular, taste, olfactory, auditory, and visual sensations.^51–54 After establishing the thalamocortical connections, tactile experiences can be processed at a cortical level. It has been shown that body awareness develops after 25 weeks of gestation, which can be associated with the emergence of a minimum level of consciousness.⁵⁵

The fetus responds to painful stimuli with a wide spectrum of reactions.^{28,52,56–58} The first responses, motor reflexes appear at 7.5 weeks of gestation. Some of the physiological reactions, such as activation of the hypothalamohypophysial axis and autonomic nervous system, do not reach the cerebral cortex. Sensing pain requires a developed neural pain system, from nociceptors to sensory areas in the cerebral cortex. After 24–26 weeks, the fetus has the necessary connections to sense pain. Somatosensory evoked potentials can be registered from the cortex at 29 weeks, and they may provide evidence of pain processing in the somatosensory cortex.⁵⁹ According to recent findings, the cortical pain response has been recorded by near-infrared spectroscopy for about 25 weeks.^25,55 Facial expressions similar to those of adults sustaining pain have been observed in preterm infants after 25 weeks of gestation and these infants are probably conscious of pain. On the other hand, there is an opinion that the fetus may not be conscious of pain even after 25 weeks due to high endogenous sedatory and analgesic substances.⁵⁵ However, fetal facial expressions similar to those of children sustaining pain have been noticed by 4D sonography.⁶⁰

Fetal Motoric Activity

There is a growing pool of evidence that fetal motoric activity is fundamental for the development of most parts of the nervous system as well as the muscles.²⁸ Our investigations, performed by 4D ultrasound, have shown that GMs, the earliest complex, well-organized movement pattern which includes the head, trunk, and limb movements, appear at the 8th gestational week⁶¹ and these movements are the most frequent movement pattern in the first trimester of pregnancy.⁶² At 10 weeks of gestation, the fetus begins to show the earliest signs of right- or left-handed behavior. Stimulation of the brain influences its organization and fetal motor activity induces the brain to develop “handedness” and subsequent lateralization of the function.²⁸ From 13 gestational weeks onward, the fetus performs goal-oriented hand movements, and a target point can be recognized for each hand movement.¹⁰ Early in the second trimester, at 15 weeks of gestation, 16 different types of movement can be observed, including retroflection, anteflexion, and rotation of the head as well as facial movements such as mouthing, yawning, hiccups, sucking, and swallowing.²⁸ The earliest eye movements appear between 16 and 18 weeks of gestation. The second half of pregnancy is characterized by the gradual organization of fetal movement patterns. The periods of fetal quiescence begin to increase, and the rest–activity cycles become recognizable. According to our results, the most frequent facial movement patterns in the second trimester were isolated eye blinking patterns, grimacing, sucking, and swallowing.⁶¹ The fetus can alter the frequency, patterning, and coordination of movement in response to sensory challenges, while retention of information from motor experience and motor learning may contribute to normal prenatal motor development.⁶³ Based on evaluation of fetal spontaneous motor activity by 4D US, a prenatal neurologic scoring test named KANET, was created.¹² This test has been used to assess almost 2,000 fetuses and our results have indicated that KANET can recognize normal, borderline, and abnormal behavior in fetuses from normal and pathological pregnancies.^64–75

Emotional Development of the Fetus

One of the important external signs of emotion is facial expressions. The existence of a full range of facial expressions, including grimacing, smiling, crying, similar to emotional expressions in adults, has been revealed by 4D sonography in the second and third trimesters of pregnancy (Figs 1 to 5).^76–78 As the fetus matures, the complexity of facial expressions increases with the appearance of “cry-face gestalt” or “laughter-face gestalt” in the third trimester.^56,78 It might be beneficial for fetal and maternal communication and bonding in postnatal life, as well as for the regulation of parental care.⁷⁹ Pain or distress facial expression becomes also more complete as gestational age increases and this may be considered an adaptive process that is useful to the fetus postnatally.^60,80 Do the facial expressions represent a part of the reflexive behavior of the fetus? Smiling, as well as screaming and crying can be induced from the brainstem stimulation even with complete forebrain transection or destruction.^60,80 However, according to the observations obtained by the 4D US, the facial expressions and emotion-like behaviors may represent some kind of fetal emotion and awareness.⁸¹ Moreover, recent data indicate that fetal movements serve not only to express different orientations but also emotional states and manifestations of intentions. The limbic forebrain is responsible for the expression and experience of emotions.⁸² One of the very important structures, the amygdala, mediates emotional memory, attention, arousal, and the experience of love, fear, pleasure, and joy. It contains facial recognition neurons which discern the emotional significance of different facial expressions.^76,77 The evaluation of faces in social processing is an area of cognition specific to the amygdala.⁸²

Fig. 1: 3D surface rendering mode of the same fetal face, semi-profile at 34 gestational weeks. In the first image, the fetus is relaxed at sleep, in the second one, the fetus is frowning with a sad expression on his face, and in the third image, the fetus is awake with open eyes exploring the environment

Fig. 2: 3D HDlive surface rendering of the fetal face, profile. Fetus at 29 gestational weeks. A sequence of images where the fetus is awake, with open eyes, opening the mouth, and licking his own hand

Fig. 3: 3D surface rendering imaging of the fetal face, semi-profile at 32 gestational weeks. The fetus is swallowing amniotic fluid, tasting it, expelling the tongue, and making grimaces

Fig. 4: 3D HDlive surface rendering of the fetal semi-profile. A sequence of images showing the fetus and grimacing

Fig. 5: 3D surface rendering of the fetal profile at 32 gestational weeks. The fetus is awake with open eyes. A sequence of images captured fetal reaction on the mother’s voice; notice the wide smile on the fetal face

Learning and Memory in Fetal Life

Fetal learning and memory have been investigated extensively employing habituation methods, classical conditioning, and exposure learning.⁸³ Habituation, the decrement in response following repeated presentation of the same stimulus, was demonstrated from 22 weeks of gestation onward.⁸⁴ Some investigators have registered developmental trends in habituation to vibroacoustic stimuli, with younger fetuses requiring more presentations of the stimulus than older fetuses.⁸⁵

Importance of the Investigation of Fetal Self-awareness

The entire human life is marked with the process of the separation from the mother to begin the independent life and fulfill one’s role during a lifetime.^86,87 The crucial question is when this process of separation begins and is it possible to investigate and detect this period of human life. This issue is very important from the philosophical and ethical point of view of the beginning of human life, which is fascinating to many generations of investigators of different scientific disciplines. At the moment of conception, a new unique form of life is created and it is questionable when it begins to be called a life.^88,89 Development of human beings is very complicated and with the onset of development probably the process of separation from the mother begins. The entire intrauterine development is marked with the preparation to be born and being born means the physical moment of the separation. This separation can be successful and unsuccessful, and all components of this process should be orchestrated in the way to be successful, but very gradual and cautious. Some investigators claim that the human product of conception is just a product of conception till the moment when it gains self-awareness, while the others consider embryo and the fetus as being a person from conception.^90,91

CONCLUSION

The fetus is living in a protective intrauterine environment with plenty of stimulating matrix of motion as well as tactile, chemical, auditory, vestibular, and possibly other sensory information enabling all kinds of development but provided in a manner to protect the fetus from overstimulation.⁵¹ The fetus should be and is exposed to hundreds of specific and patterned stimuli each day, shaping the structure and function of the brain.^16,28 The fetus is capable of detecting, responding, and even memorizing for long-time stimuli experienced during the prenatal and postnatal period, which may shape its behavior, development, and health postnatally.^92–94 It is proved that higher-order sensory perception begins in fetal life because functionally and structurally the fetus is ready to exert such behavior which is best studied by fetal awareness of noxious stimuli after the development of functional thalamocortical connections.⁵² Evidence for conscious sentience of pain during intrauterine life is indirect, but it is obvious that reaction on pain can be detected during fetal life and can impact reaction on pain postnatally when analgesia is considered as a standard of care.^52,58 On the other hand, we have learned from the research that the fetus is capable of action planning and learning, meaning that probably the capability of being aware and conscious should proceed.⁸³ Fetal movements are reflecting the development of the brain, but at the same time, they are stimulating the brain to develop, which can be applied to fetal senses and development of awareness as well. Progression in behavioral complexity begins with spontaneous fetal movements and culminates with presumed preferences for the sound of the mother’s voice, reflecting maturational events that take place in the brain stem, followed by the forebrain structures.⁸³ As we have learned from the 4D US study of fetal behavior, fetal motor function undoubtedly reflects the development of diverse cognitive, sensory, and motor systems.^16,25,28 The face is the mirror of the brain, many expressions can be depicted during fetal life, which are proving that fetal life in utero is very dramatic and rich in different experiences.^16,28,56,57 Would it be possible without the development of fetal awareness and consciousness?

This paper will be published in Kurjak A. Fetal Brain Function (in preparation). New Delhi: Jaypee Brothers Medical Publishers, 2021.

REFERENCES

1. Newman PG, Rozycki GS. The history of ultrasound. Surg Clin North Am 1998;78:179–195 McNay MB, Fleming EE. Forty years of obstetric ultrasound 1957-1997: from A-scope to three dimensions. Ultrasound Med Biol 1999;25(1):3–56. DOI: 10.1016/s0301-5629(98)00129-x.

2. Kurjak A, Stanojević M, Salihagić-Kadić A, et al. Is four-dimensional ultrasound (4D US) entering a new field of fetal psychiatry? Psychiatria Danubina 2019;31(2):133–140. DOI: 10.24869/psyd.2019.133.

3. McNay MB, Fleming EE. Forty years of obstetric ultrasound 1957-1997: from A-scope to three dimensions. Ultrasound Med Biol 1999;25(1):3–56. DOI: 10.1016/s0301-5629(98)00129-x.

4. Baba K, Satoh K, Sakamoto S, et al. Development of an ultrasonic system for three-dimensional reconstruction of the fetus. J Perinat Med 1989;17(1):19–24. DOI: 10.1515/jpme.1989.17.1.19.

5. Merz E. Einsatz der 3D-Ultraschalltechnik in der pränatalen Diagnostik. Ultraschall in Med 1995;16(4):154–161. DOI: 10.1055/s-2007-1003931.

6. Kurjak A, Hafner T, Kos M, et al. Three-dimensional sonography in prenatal diagnosis: a luxury or necessity. J Perinat Med 2000;28(3):194–209. DOI: 10.1515/JPM.2000.027.

7. Prechtl HFR. Qualitative changes of spontaneous movements in fetus and preterm infant are a marker of neurological dysfunction. Early Hum Dev 1990;23(3):151–158. DOI: 10.1016/0378-3782(90)90011-7.

8. Einspieler C, Prechtl HFR, Bos AF, et al. Prechtl’s method on the qualitative assessment of general movements in preterm, term and young infants. Cambridge: Mac Keith Press; 2004.

9. Hadders-Algra M. General movements: a window for early identification of children at high risk for developmental disorders. J Pediatr 2004;145(2 Suppl):S12–S18. DOI: 10.1016/j.jpeds.2004.05.017.

10. Kurjak A, Azumendi G, Veček N, et al. Fetal hand and facial expression in normal pregnancy studied by four-dimensional sonography. J Perinat Med 2003;31(6):496–508. DOI: 10.1515/JPM.2003.076.

11. Kurjak A, Stanojevic M, Andonotopo W, et al. Behavioral pattern continuity from prenatal to postnatal life – a study by four-dimensional (4D) ultrasonography. J Perinat Med 2004;32(4):346–353. DOI: 10.1515/JPM.2004.065.

12. Kurjak A, Miskovic B, Stanojevic M, et al. New scoring system for fetal neurobehavior assessed by three- and four-dimensional sonography. J Perinat Med 2008;36(1):73–81. DOI: 10.1515/JPM.2008.007.

13. Kurjak A, Abo-Yaqoub S, Stanojevic M, et al. The potential of 4D sonography in the assessment of fetal neurobehavior – multicentric study in high-risk pregnancies. J Perinat Med 2010;38(1):77–82. DOI: 10.1515/jpm.2010.012.

14. Amiel Tison C, Gosselin J, Kurjak A. Neurosonography in the second half of fetal life: a neonatologist point of view. J Perinat Med 2006;34(6):437–446. DOI: 10.1515/JPM.2006.088.

15. Kurjak A, Stanojevic M, Azumendi G, et al. The potential of four-dimensional ultrasonography in the assessment of fetal awareness. J Perinat Med 2005;33(1):46–53. DOI: 10.1515/JPM.2005.008.

16. Salihagic Kadic A, Kurjak A. Cognitive functions of the fetus. Ultraschall in Med 2018;39(02):181–189. DOI: 10.1055/s-0043-123469.

17. Ingerslev HJ, Kesmodel US, Jacobsson B, et al. Personalized medicine for the embryo and the fetus - Options in modern genetics influence preconception and prenatal choices. Acta Obstet Gynecol Scand 2020;99(6):689–691. DOI: 10.1111/aogs.13882.

18. Sekulic SR, Lukac DD, Naumovic NM. The fetus cannot exercise like an astronaut: gravity loading is necessary for the physiological development during second half of pregnancy. Med Hypotheses 2005;64(2):221–228. DOI: 10.1016/j.mehy.2004.08.012.

19. Meigal AY. Synergistic action of gravity and temperature on the motor system within the lifespan: a “Baby Astronaut” hypothesis. Med Hypotheses 2013;80(3):275–283. DOI: 10.1016/j.mehy.2012.12.004.

20. Merriam-Webster Dictionary. Awareness. https://www.merriam-webster.com/dictionary/awareness (Accessed 21.12.2020.

21. MacMillan Dictionary. Awareness. https://www.macmillandictionary.com/dictionary/british/awareness(Accessed 21.12.2020).

22. Wikipedia. Awareness. https://en.wikipedia.org/wiki/Awareness(Accessed 21.12.2020.).

23. Hussain A, Aleksander I, Smith L, et al. ed. Brain Inspired Cognitive Systems. 2008.New York: Springer Science Business Media; 2010. pp.221–256. DOI: 10.1007/978-0-387-79100-5.

24. Boly M, Phillips C, Tshibanda L, et al. Intrinsic brain activity in altered states of consciousness: how conscious is the default mode of brain function? Ann N Y Acad Sci 2008;1129(1):119–129. DOI: 10.1196/annals.1417.015.

25. Hata T, Kanenishi K, AboEllail MAM, et al. Fetal consciousness: four-dimensional ultrasound study. Donald School J Ultrasound Obstet Gynecol 2015;9(4):471–474. DOI: 10.5005/jp-journals-10009-1434.

26. Amadei G, Bianchi I. Living systems, evolving consciousness, and the emerging person: a selection of papers from the life work of Louis Sander.New York: Taylor and Francis; 2012. pp.157–166.

27. Droit-Volet S, Dambrun M. Awareness of the passage of time and self-consciousness: what do meditators report? Psych J 2019;8(1):51–65. DOI: 10.1002/pchj.270.

28. Salihagić Kadić A, Predojević M. Fetal neurophysiology according to gestational age. Semin Fetal Neonatal Med 2012;17(5):256–260. DOI: 10.1016/j.siny.2012.05.007.

29. Budday S, Steinmann P, Kuhl E. Physical biology of human brain development. Front Cell Neurosci 2015;9:257. DOI: 10.3389/fncel.2015.00257.

30. Anderson AL, Thomason ME. Functional plasticity before the cradle: a review of neural functional imaging in the human fetus. Neurosci Biobehav Rev 2013;37(9 Pt B):2220–2232. DOI: 10.1016/j.neubiorev.2013.03.013.

31. Faghiri A, Stephen JM, Wang YP, et al. Brain development includes linear and multiple nonlinear trajectories: a cross-sectional resting-state functional magnetic resonance imaging study. Brain Connect 2019;9(10):777–788. DOI: 10.1089/brain.2018.0641.

32. Jena A, Montoya CA, Mullaney JA, et al. Gut-brain axis in the early postnatal years of life: a developmental perspective. Front Integr Neurosci 2020;14:44. DOI: 10.3389/fnint.2020.00044.

33. Kostović I, Judas M, Petanjek Z, et al. Ontogenesis of goal-directed behavior: anatomo-functional considerations. Int J Psychophysiol 1995;19(2):85–102. DOI: 10.1016/0167-8760(94)00081-o.

34. Tau GZ, Peterson BS. Normal development of brain circuits. Neuropsychopharmacology 2010;35(1):147–168. DOI: 10.1038/npp.2009.115.

35. Kostović I, Judas M. The development of the subplate and thalamocortical connections in the human foetal brain. Acta Paediatr 2010;99(8):1119–1127. DOI: 10.1111/j.1651-2227.2010.01811.x.

36. Thomason ME. Development of brain networks in utero: relevance for common neural disorders. Biol Psychiatry 2020;88(1):40–50. DOI: 10.1016/j.biopsych.2020.02.007.

37. Klimach VJ, Cooke RW. Maturation of the neonatal somatosensory evoked response in preterm infants. Dev Med Child Neurol 1988;30(2):208–214. DOI: 10.1111/j.1469-8749.1988.tb04752.x.

38. Nevalainen P, Lauronen L, Pihko E. Development of human somatosensory cortical functions - what have we learned from magnetoencephalography: a review. Front Hum Neurosci 2014;8:158. DOI: 10.3389/fnhum.2014.00158.

39. Laureys S, Goldman S, Phillips C, et al. Impaired effective cortical connectivity in vegetative state: preliminary investigation using PET. Neuroimage 1999;9(4):377–382. DOI: 10.1006/nimg.1998.0414.

40. Wintermark P, Hansen A, Warfield SK, et al. Near-infrared spectroscopy versus magnetic resonance imaging to study brain perfusion in newborns with hypoxic-ischemic encephalopathy treated with hypothermia. Neuroimage 2014;85(Pt 1(0 1):)287–293. DOI: 10.1016/j.neuroimage.2013.04.072.

41. Counsell SJ, Arichi T, Arulkumaran S, et al. Fetal and neonatal neuroimaging. Handb Clin Neurol 2019;162:67–103. DOI: 10.1016/B978-0-444-64029-1.00004-7.

42. Heiss WD. PET in coma and in vegetative state. Eur J Neurol 2012;19(2):207–211. DOI: 10.1111/j.1468-1331.2011.03489.x.

43. Arichi T, Whitehead K, Barone G, et al. Localization of spontaneous bursting neuronal activity in the preterm human brain with simultaneous EEG-fMRI. Elife 2017.6. pii:e27814 10.7554/eLife.27814.

44. Andersen JB, Lindberg U, Olesen OV, et al. Hybrid PET/MRI imaging in healthy unsedated newborn infants with quantitative rCBF measurements using 15O-water PET. J Cereb Blood Flow Metab 2019;39(5):782–793. DOI: 10.1177/0271678X17751835.

45. Giovannella M, Contini D, Pagliazzi M, et al. BabyLux device: a diffuse optical system integrating diffuse correlation spectroscopy and time-resolved near-infrared spectroscopy for the neuromonitoring of the premature newborn brain. Neurophotonics 2019;6(2):025007. DOI: 10.1117/1.NPh.6.2.025007.

46. O’Sullivan M, Temko A, Bocchino A, et al. Analysis of a low-cost EEG monitoring system and dry electrodes toward clinical use in the neonatal ICU. Sensors (Basel) 2019;19(11): pii:E2637 10.3390/s19112637.

47. Salek-Haddadi A, Friston KJ, Lemieux L, et al. Studying spontaneous EEG activity with fMRI. Brain Res Brain Res Rev 2003;43(1):110–133. DOI: 10.1016/s0165-0173(03)00193-0.

48. Lagercrantz H. The emergence of consciousness: science and ethics. Semin Fetal Neonatal Med 2014;19(5):300–305. DOI: 10.1016/j.siny.2014.08.003.

49. Di Mascio D, Sileo FG, Khalil A, et al. Role of magnetic resonance imaging in fetuses with mild or moderate ventriculomegaly in the era of fetal neurosonography: systematic review and meta-analysis. Ultrasound Obstet Gynecol 2019;54(2):164–171. DOI: 10.1002/uog.20197.

50. Hart AR, Embleton ND, Bradburn M, et al. Accuracy of in-utero MRI to detect fetal brain abnormalities and prognosticate developmental outcome: postnatal follow-up of the MERIDIAN cohort. Lancet Child Adolesc Health 2020;4(2):131–140. DOI: 10.1016/S2352-4642(19)30349-9.

51. Clark-Gambelunghe MB, Clark DA. Sensory development. Pediatr Clin North Am 2015;62(2):367–384. DOI: 10.1016/j.pcl.2014.11.003.

52. Bellieni CV. New insights into fetal pain. Semin Fetal Neonatal Med 2019;24(4):101001. DOI: 10.1016/j.siny.2019.04.001.

53. Podzimek Š, Dušková M, Broukal Z, et al. The evolution of taste and perinatal programming of taste preferences. Physiol Res 2018;67(Suppl 3):S421–S429. DOI: 10.33549/physiolres.934026.

54. Donovan T, Dunn K, Penman A, et al. Fetal eye movements in response to a visual stimulus. Brain Behav 2020;10(8):e01676. DOI: 10.1002/brb3.1676.

55. Lagercrantz H. The emergence of the mind - a borderline of human viability? Acta Pediatrica 2007;96(3):327–328. DOI: 10.1111/j.1651-2227.2007.00232.x.

56. Kurjak A, Azumendi G, Andonotopo W, et al. Three- and four-dimensional ultrasonography for the structural and functional evaluation of the fetal face. Am J Obstet Gynecol 2007;196(1):16–28. DOI: 10.1016/j.ajog.2006.06.090.

57. Reissland N, Francis B, Mason J. Can healthy fetuses show facial expressions of “pain” or “distress”? PLoS One 2013;8(6):e65530. DOI: 10.1371/journal.pone.0065530.

58. Pierucci R. Fetal pain: the science behind why it is the medical standard of care. Linacre Q 2020;87(3):311–316. DOI: 10.1177/0024363920924877.

59. Bellieni CV, Vannuccini S, Petraglia F. Is fetal analgesia necessary during prenatal surgery? J Matern Fetal Neonatal Med 2018;31(9):1241–1245. DOI: 10.1080/14767058.2017.1311860.

60. Bernardes LS, Ottolia JF, Cecchini M, et al. Grupo de estudo da dor fetal (fetal pain study group). On the feasibility of accessing acute pain-related facial expressions in the human fetus and its potential implications: a case report. Pain Rep. 2018;3(5):e673. DOI: 10.1097/PR9.0000000000000673.

61. Kurjak A, Andonotopo W, Hafner T, et al. Normal standards for fetal neurobehavioral developments—longitudinal quantification by four-dimensional sonography. J Perinat Med 2006;34(1):56–65. DOI: 10.1515/JPM.2006.007.

62. Andonotopo W, Medic M, Salihagic-Kadic A, et al. The assessment of fetal behavior in early pregnancy: comparison between 2D and 4D sonographic scanning. J Perinat Med 2005;33(5):406–414. DOI: 10.1515/JPM.2005.073.

63. Robinson SR. Spinal mediation of motor learning and memory in the rat fetus. Dev Psychobiol 2015;57(4):421–434. DOI: 10.1002/dev.21277.

64. Kurjak A, Stanojević M, Predojević M, et al. Neurobehavior in fetal life. Semin Fetal Neonatal Med 2012;17(6):319–323. DOI: 10.1016/j.siny.2012.06.005.

65. Salihagić Kadić A, Stanojević M, Predojević M, et al. Assessment of the fetal neuromotor development with the new KANET test. In: Reissland N, Kisilevsky BS, ed. Fetal Development Research on Brain and Behavior, Environmental Influences, and Emerging Technologies. Heidelberg, New York, Dordrecht, London: Springer International Publishing Switzerland; 2016. pp.177–189.

66. Kurjak A, Antsaklis P, Stanojevic M, et al. Multicentric studies of the fetal neurobehavior by KANET test. J Perinat Med 2017;45(6):717–727. DOI: 10.1515/jpm-2016-0409.

67. Kurjak A, Antsaklis P, Stanojevic M, et al. Fetal behavior assessed by four-dimensional ultrasound. Donald School J Ultrasound Obstet Gynecol 2017;11(2):169–173. DOI: 10.5005/jp-journals-10009-1516.

68. Moreira R, Kurjak A, Porovic S, et al. Clinical study of fetal neurobehavior by the Kurjak Antenatal developmental test. Donald School J Ultrasound Obstet Gynecol 2017;11(4):355–361. DOI: 10.5005/jp-journals-10009-1543.

69. Kurjak A, Stanojević M, Spalldi Barišić L, et al. A critical appraisal of Kurjak Antenatal neurodevelopmental test: five years of wide clinical use. Donald School J Ultrasound Obstet Gynecol 2020;14(4):304–310. DOI: 10.5005/jp-journals-10009-1669.

70. Stanojevic M, Perlman M, Andonotopo W, et al. From fetal to neonatal behavioral status. Ultrasound Rev Obstet Gynecol 2004;4(1):459–471. DOI: 10.3109/14722240410001713939.

71. Stanojevic M, Kurjak A. Continuity between fetal and neonatal neurobehavior. Donald School J Ultrasound Obstet Gynecol 2008;2(3):64–75. DOI: 10.5005/jp-journals-10009-1066.

72. Stanojevic M, Kurjak A, Salihagić-Kadić A, et al. Neurobehavioral continuity from fetus to neonate. J Perinat Med 2011;39(2):171–177. DOI: 10.1515/jpm.2011.004.

73. Stanojevic M. Neonatal aspects: is there continuity?. Donald School Jultrasound Obstet Gynecol 2012;6(2):189–196. DOI: 10.5005/jp-journals-10009-1242.

74. Stanojevic M, Zaputovic S, Pavicic Bosnjak A. Continuity between fetal and neonatal neurobehavior. Semin Fetal Neonat Med 2012;17(6):324–329. DOI: 10.1016/j.siny.2012.06.006.

75. Stanojevic M. Antenatal and postanatal assessment of neurobehavior: which one should be used? Donald School J Obstet Gynecol 2015;9(1):67–74. DOI: 10.5005/jp-journals-10009-1391.

76. AboEllail MAM, Hata T. Fetal face as important indicator of fetal brain function. J Perinat Med 2017;45(6):729–736. DOI: 10.1515/jpm-2016-0377.

77. Nitta E, Kanenishi K, Mori N, et al. Twin fetal facial expressions at 30-33+6 weeks of gestation. J Perinat Med 2019;47(9):963–968. DOI: 10.1515/jpm-2019-0127.

78. Mori N, AboEllail MAM, Tenkumo C, et al. Fetal facial expressions in small-for-gestational-age and growth-restricted fetuses. J Matern Fetal Neonatal Med 2019;32(9):1426–1432. DOI: 10.1080/14767058.2017.1410788.

79. de Jong-Pleij EA, Ribbert LS, Pistorius LR, et al. Three-dimensional ultrasound and maternal bonding, a third trimester study and a review. Prenat Diagn 2013;33(1):81–88. DOI: 10.1002/pd.4013.

80. Borg Cunen N, Jomeen J, Borg Xuereb R, et al. A narrative review of interventions addressing the parental-fetal relationship. Women Birth 2017;30(4):e141–e151. DOI: 10.1016/j.wombi.2016.11.005.

81. van Manen MA. Towards the womb of neonatal intensive care. J Med Humanit 2019;40(2):225–237. DOI: 10.1007/s10912-017-9494-9.

82. Rolls ET. The cingulate cortex and limbic systems for action, emotion, and memory. Handb Clin Neurol 2019;166:23–37. DOI: 10.1016/B978-0-444-64196-0.00002-9.

83. Borsani E, Della Vedova AM, Rezzani R, et al. Correlation between human nervous system development and acquisition of fetal skills: an overview. Brain Dev 2019;41(3):225–233. DOI: 10.1016/j.braindev.2018.10.009.

84. Dirix CE, Nijhuis JG, Jongsma HW, et al. Aspects of fetal learning and memory. Child Dev 2009;80(4):1251–1258. DOI: 10.1111/j.1467-8624.2009.01329.x.

85. Hepper PG, Dornan JC, Lynch C. Sex differences in fetal habituation. Dev Sci 2012;15(3):373–383. DOI: 10.1111/j.1467-7687.2011.01132.x.

86. Kossowsky J, Wilhelm FH, Roth WT, et al. Separation anxiety disorder in children: disorder-specific responses to experimental separation from the mother. J Child Psychol Psychiatry 2012;53(2):178–187. DOI: 10.1111/j.1469-7610.2011.02465.x.

87. Bergman NJ. Birth practices: maternal-neonate separation as a source of toxic stress. Birth Defects Res 2019;111(15):1087–1109. DOI: 10.1002/bdr2.1530.

88. Kurjak A. Controversies on the beginning of human life - science and religions closer and closer. Psychiatr Danub 2017;29(Suppl 1):89–91.

89. Kurjak A, Carrera JM, McCullough LB, et al. Scientific and religious controversies about the beginning of human life: the relevance of the ethical concept of the fetus as a patient. J Perinat Med 2007;35(5):376–383. DOI: 10.1515/JPM.2007.088.

90. Watt H, McCarthy A. Targeting the fetal body and/or mother-child connection: vital conflicts and abortion. Linacre Q 2020;87(2):147–160. DOI: 10.1177/0024363919887613.

91. Peterfy A. Fetal viability as a threshold to personhood. A legal analysis. J Leg Med 1995;16(4):607–636. DOI: 10.1080/01947649509510995.

92. Marx V, Nagy E. Fetal behavioral responses to the touch of the mother’s abdomen: a frame-by-frame analysis. Infant Behav Dev 2017;47:83–91. DOI: 10.1016/j.infbeh.2017.03.005.

93. Miranda-Morales RS, D’Aloisio G, Anunziata F, et al. Fetal alcohol programming of subsequent alcohol affinity: a review based on preclinical, clinical and epidemiological studies. Front Behav Neurosci 2020;14:33. DOI: 10.3389/fnbeh.2020.00033.

94. Amiel-Tison C, Gosselin J. From neonatal to fetal neurology: some clues for interpreting fetal findings. In: Pooh RK, Kurjak A, ed. Fetal neurology. New Delhi: Jaypee Brothers Medical Publishers; 2009. pp.373–404.

________________________
© The Author(s). 2021 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.