4, 105116. Bacterial communities found in placental tissues are associated with severe chorioamnionitis and adverse birth outcomes. Vasoconstriction is mediated through the -adrenergic receptors in liver, kidney, skin and gut, and vasodilation is mediated through adrenergic receptors in skeletal muscle. doi: 10.1016/0378-3782(86)90187-8, Shuffrey, L. C., Myers, M. M., Odendaal, H. J., Elliott, A. J., du Plessis, C., Groenewald, C., et al. Choline: exploring the growing science on its benefits for moms and babies. Paediatr. 1981 Dec 1; 141(7):797-806. 10:922. doi: 10.3389/fphys.2019.00922, Ouellet-Morin, I., Dionne, G., Lupien, S. J., Muckle, G., Ct, S., Prusse, D., et al. Front. doi: 10.1371/journal.pone.0068211, Stone, M. L., Tatum, P. M., Weitkamp, J.-H., Mukherjee, A. Hence, measuring HRV during different sleep states can help better assess ANS development (Yiallourou et al., 2012; Dereymaeker et al., 2017). 38, R61R88. Acad. Infant Child Dev. A preliminary report. doi: 10.1111/mono.v80.3, DiPietro, J. J Gynecol Obstet Hum Reprod. The mechanisms of homeostatic intrinsic plasticity depend on the abundance and spatial distribution of voltage-gated ion channels (Na+,K+ and Ca2+ channels) at the plasma membrane, and on their biophysical characteristics. Invest. Rochester, NY: Social Science Research Network. (2018). Biobehav. J. Obstet. Front. (2020). Obstet Gynecol. doi: 10.1080/14767058.2016.1249844, Verdurmen, K. M. J., Renckens, J., van Laar, J. O. E. H., and Oei, S. G. (2013). A. BaroreceptorB. A well-developed ANS responds efficiently to umbilical cord clamping by inducing the fetus to commence spontaneous breathing. The repetitive movements, with the consequent repetitive sensory afferents induced, produce habituation in the fetus, that is manifested also in fHR changes: the ANS trains to adapt the body systems' response to environmental stimuli, even through the movements (Lecanuet et al., 1992; Kisilevsky and Low, 1998). 12, 170177. Med. Available online at: https://embryology.med.unsw.edu.au/embryology/index.php/Neural_System_Development (Accessed April 23, 2021). There are many observed effects of this medication on fHRV and fetal breathing patterns, mostly transient and dose-/time-dependent (van Geijn et al., 1980; Kariniemi and Mml, 1981; Low et al., 1981; Viscomi et al., 1990; Capogna, 2001; Mattingly et al., 2003; Shekhawat et al., 2020). (2009). 9, 17641773. Cardiovasc. None of these guidelines specify what level of metabolic acidemia or degree of reliability they mean. doi: 10.1016/j.physio.2018.05.001, Cogan, R., and Spinnato, J. Heart rate variability analysis can give paramount hints about the fetus' or newborn's well-being and allow clinicians to predict the occurrence of even deadly complications (Table 1) (Stone et al., 2013; Al-Shargabi et al., 2017; Massaro et al., 2017; Chiera et al., 2020; Frasch, 2020). The basic anatomy and physiology of heart rate control are described in textbooks on physiology and fetal monitoring.1,2 The schematic diagram shown in Figure 1 summarizes the heart rate control pathways. 41, 197219. 16, 483488. (2010). Sleep and brain development: the critical role of sleep in fetal and early neonatal brain development. However, the long-term impact is currently under investigation. Gynecol. 86, 319325. Here, we show that hyperactivity-induced REST/NRSF activation, triggers a homeostatic rearrangement of GABAergic inhibition, with increased frequency of miniature inhibitory postsynaptic currents (IPSCs) and amplitude of evoked IPSCs in mouse cultured hippocampal neurons. Sleep disorders during pregnancy. Oncotarget 8, 100717100723. Contributions of the maternal oral and gut microbiome to placental microbial colonization in overweight and obese pregnant women. doi: 10.1371/journal.pone.0104193, Rodgers, S. K., Chang, C., DeBardeleben, J. T., and Horrow, M. M. (2015). doi: 10.1152/jn.90680.2008, Kamitomo, M., Sameshima, H., Ikenoue, T., and Nishibatake, M. (2000). Since the placental microbiome could also affect metabolic pathways, thus leading to a pro-inflammatory environment (Gomez-Arango et al., 2017; Fischer et al., 2019), it could also affect the ANS and vagus development of the fetus. Obstet. The transitional heart: from early embryonic and fetal development to neonatal life. Biol. 94, 693700. Effects of intrapartum oxytocin administration and epidural analgesia on the concentration of plasma oxytocin and prolactin, in response to suckling during the second day postpartum. Maternal heart rate variability during the first stage of labor. doi: 10.1016/j.wombi.2018.12.001, Fox, G. P. P., and Matthews, T. G. (1989). Meas. Res. J. Obstet. Dev. Patterns preceding fetal death, further observations. Crit. (2019). doi: 10.1073/pnas.1012911107, Seckl, J. R., and Meaney, M. J. The dysregulation of placental functions can induce an insufficient intake of nutrients for the fetus, thus, especially during mid and late gestation, impairing the development of various brain areas, including the hypothalamus that seems to be particularly sensitive to the nutrient deficiency (Nugent and Bale, 2015). (2009). The 2nd stage of labor begins with complete cervical dilation and ends with the delivery of the fetus. The preclinical studies analyzed in this review were selected from among those carried out on the ovine species. In turn, the stretch-sensitive baroreceptors were activated, stimulating the cardioinhibitory center and causing rapid slowing of the heart rate mediated via the vagus nerve. (2009). 7, 54. doi: 10.3390/jcdd7040054, Fischer, L. A., Demerath, E., Bittner-Eddy, P., and Costalonga, M. (2019). The emergence of fetal behaviour. These critical windows could help clinicians know when to monitor fetuses to effectively assess the developmental status of both ANS and specifically the vagus nerve. 66, 201209. Med. J. Comp. O. Walusinski (Basel: KARGER), 3241. (2016). doi: 10.2147/JIR.S248382, Haraldsdottir, K., Watson, A. M., Goss, K. N., Beshish, A. G., Pegelow, D. F., Palta, M., et al. Gynecol. Everything You Need to Know, 2023 Flo Health Inc., Flo Health UK Limited, Maternal low blood pressure (or hypotension). Neonatology 112, 187192. doi: 10.1097/AOG.0b013e3181c4f8ec, Fagard, J., Esseily, R., Jacquey, L., O'Regan, K., and Somogyi, E. (2018). The emergence of fetal behaviour. C Embryo Today Rev. Therefore, it would be worth it to improve fetal cardiac monitoring technology in order to detect ECG and fHRV even in the first weeks of pregnancy. Fetal heart rate variability after epidural fentanyl during labor. doi: 10.1146/annurev-cellbio-021120-033518, Lutterodt, M. C., Khler, P., Kragstrup, J., Nicolaisdottir, D. R., Siersma, V., and Ertmann, R. K. (2019). As newborns spend most of their time sleeping, ANS development correlates also with sleep development, with quiet sleep (absence of movements and slow rhythmic breathing) characterized by PNS predominance and active sleep (myoclonic twitching, facial, eye, and head movements, and irregular heart and breath rates) characterized by SNS predominance. Since fetal movements (FMs) tend to synchronize with fetal heart rate variability (fHRV), their detection can give important insights on ANS development, even in the 1st trimester (DiPietro et al., 2007; Zizzo et al., 2020). The above-mentioned studies show us what impact labor can have on the ANS and the vagus nerve. Behavioral responses to pain are heightened after clustered care in preterm infants born between 30 and 32 weeks gestational age. (2014). doi: 10.1111/aogs.12681, Haley, D. W., Handmaker, N. S., and Lowe, J. Coregulated approach to feeding preterm infants with lung disease: effects during feeding. Goldstein, D. S. (2006). 25, 236247. Gynecol. One way to approach this question is to confront a simple neural system with conflicting perturbations and determine whether the outcome reflects a coordinated, homeostatic response. Indeed, several studies have shown the vagus nerve is involved in many vital processes during fetal, perinatal, and postnatal life: from the regulation of inflammation through the CAP, which may affect each organ (Herry et al., 2019; Frasch, 2020), to the production of hormones involved in bioenergetic metabolism (Bystrova, 2009). doi: 10.1113/JP278773, Frasch, M. G., Keen, A. E., Gagnon, R., Ross, M. G., and Richardson, B. S. (2011). (2005). Here, environmental factors such as temperature, light, noise, procedures could induce a high amount of stress, which could become toxic, that is, induce severe alterations in the brain and organic development, with long-lasting complications (De Jonckheere and Storme, 2019; Weber and Harrison, 2019). J. Calif. Perinat. J. Afr. Diet and lifestyle before and during pregnancy practical recommendations of the germany-wide healthy start young family network. The heart is a muscle with its own pacemaker, conducting system, numerous types of receptors (alpha and beta adrenergic) and direct neuronal connections to both the sympathetic and parasympathetic systems. Fetal mediators of the relationships between increased pregnancy and labour blood pressure and newborn irritability. Fetal EEG, while feasible, has not yet made its way into clinical practice. Dev. Heart rate variability in sleeping preterm neonates exposed to cool and warm thermal conditions. doi: 10.1159/000475744, Patural, H., Pichot, V., Flori, S., Giraud, A., Franco, P., Pladys, P., et al. Transl. 596, 57095722. Hill, M. A. 82, 19. periodic accelerations can indicate all of the following except: A. Stimulation of fetal chemoreceptors B. Tracing is maternal C. Umbilical vein compression A. Stimulation of fetal chemoreceptors All of the following are likely causes of prolonged decelerations except: A. Neurosci. Meas. Clin. PLOS ONE 8:e74431. Integr. doi: 10.1093/humrep/der437, Soma-Pillay, P., Nelson-Piercy, C., Tolppanen, H., and Mebazaa, A. doi: 10.1002/bdra.23045, Lattimore, K. A., Donn, S. M., Kaciroti, N., Kemper, A. R., Neal, C. R., and Vazquez, D. M. (2005). Best Pract. Dev. Endocrinol. The placenta can be defined as a neuro-immune-endocrine secretive organ, with the essential role of conveying nutrients and developing modulatory signals to fetuses, limiting their exposure to any factors that could alter their physiologic developmental patterns. Intrapartum management of category II fetal heart rate tracings: towards standardization of care. Res. Med. Micronutrient deficiencies in pregnancy worldwide: health effects and prevention. The influence of corticosteroids on fetal heart rate variability: a systematic review of the literature. doi: 10.1080/07420528.2018.1439499, Jarrell, J. An update on the controversies of tocolytic therapy for the prevention of preterm birth. J. Perinat. The production of testosterone in male fetuses begins during the 2nd month of pregnancy and reaches the maximum in the 2nd trimester (Chung and Auger, 2013), just before when vagal tone starts to rise (Mulkey and du Plessis, 2019). Catecholamine C. Sympathetic - CORRECT ANSWERS A. Baroreceptor 181, 816821. Fetal neurobehavioral effects of exposure to methadone or buprenorphine. 130, 5764. doi: 10.1016/j.ajog.2003.12.023, Stallworth, J. C., Yeh, S.-Y., and Petrie, R. H. (1981). Although the ANS and vagus nerve activity appear to have an endogenous circadian rhythm (Hilton et al., 2000; Kentish et al., 2013), with a pacemaker system that regulates its behavior regardless of sleep-awake states (Malpas and Purdie, 1990; Hilton et al., 2000), a circadian variation pattern of vagal activity can be recorded via HR variations. doi: 10.1016/j.placenta.2016.12.003, Persson, M., Winkvist, A., Dahlgren, L., and Mogren, I. Med. (2003). Clin. 35, 12911301. Brain Dev. It is possible, therefore, to assume that the mother, considering the limited light-dark variation during intrauterine life, entrains the developing circadian rhythm of the fetus to this cycle (Mirmiran et al., 2003). The effects of maternal hyperoxia on fetal breathing movements, body movements and heart rate variation in growth retarded fetuses. Proc. (2017). 118, 487488. (2008). Res. (2000). 25, 7381. Impaired autonomic function in adolescents born preterm. Sex differences in the fetal heart rate variability indices of twins. Ultimately, any influence on heart rate is mediated by one or more of these structures. Birt. Front. Available online at: https://embryology.med.unsw.edu.au/embryology/index.php/Neural_System_Development (Accessed April 23, 2021). Obstet. Furthermore, the diminished vagal cardiovascular capacity to respond to hypoxic and hypercapnic states in the fetus, due to the abolishment of the serotonergic neurotransmission to cardiac vagal neurons caused by PNE, has been hypothesized as a likely link to SIDS (Kamendi et al., 2006, 2009). doi: 10.1002/icd.688, Praud, J.-P., Miura, Y., and Frasch, M. G. (2017). Even early prenatal exposure to the virus, indeed, seems to create a chronic hypoxic environment to the fetus, affecting vagus nerve developmental patterns, and imprinting postnatally the ANS cardiac pacemaker activity (Herry et al., 2021). Gynaecol. Decelerations from cord compression can lead to severe hypoxemia and decelerations from uteroplacental insufficiency can be present without acidemia. B., and Visser, G. H. A. doi: 10.1159/000307075, Walusinski, O. J. Med. J. Obstet. doi: 10.1097/PCC.0000000000000643, Lobmaier, S. M., Mller, A., Zelgert, C., Shen, C., Su, P. C., Schmidt, G., et al. 1996;8(3):471-82. Scand. doi: 10.1213/00000539-199012000-00018, Visser, G. H. A., Mulder, E. J. H., and Prechtl, H. F. R. (1992). 143, 243249. Am. 29, 218223. Horm. (12), Over that last decade mounting evidence based on recent animal experimentation with very sensitive sensors and finer time resolution, has produced more information about hand chemoreceptors and their role in the production of decelerations. Neurosci. Am. Analg. This paper will also focus on which factorsi.e., fetal characteristics and behaviors, maternal lifestyle and pathologies, placental health and dysfunction, labor, incubator conditions, and drug exposuremay affect the development of the vagus. Neurosci. As a consequence, by relying on appropriate animal models, several authors have defined potential critical windows related to human brain development (see, for instance, Figure 1 in Morrison et al., 2018). Computational experiments finally demonstrate that size attenuation results in the paradoxical . Core temperature variation is associated with heart rate variability independent of cardiac index: a study of 278 trauma patients. Effect of halogen light in fetal stimulation for fetal well-being assessment. 115, 7783. We show that deletion of insulin-like growth factor-1 receptor (IGF-1R) limits firing rate homeostasis in response . A. Maternal stress during pregnancy alters fetal ANS by entraining fetal heart rate (fHR) with maternal HR decelerations during respiratory effort (Lobmaier et al., 2020). Development of extrinsic innervation in the abdominal intestines of human embryos. noradrenaline) biosynthesis and autonomic functions (e.g., temperature, breathing, and satiety regulation) including the area postrema greatly develop around birth (Gokozan et al., 2016). N. Y. Acad. Physiol. doi: 10.1542/neo.15-12-e537, Capogna, G. (2001). Ther. J. Matern. Sound reduction management in the neonatal intensive care unit for preterm or very low birth weight infants. 80, vii94. BJOG Int. The first stage may take about 12 hours to complete and is divided into three phases: latent, active, and transition. A. doi: 10.1016/j.psyneuen.2005.04.014, Thome, J., Densmore, M., Frewen, P. A., McKinnon, M. C., Thberge, J., Nicholson, A. J. Obstet. Fetal motor activity, therefore, results closely tied to breathing and cardiovascular patterns, which are modulated by the ANS (Zizzo et al., 2020). Am. Reconsidering fetal pain. On the other hand, clinical behavior has changed considerably. Maternal selective serotonin reuptake inhibitor use during pregnancy and newborn neurobehavior. Women's experiences of pregnancy related pelvic girdle pain: a systematic review. 115, 3845. Another common complication during labor is given by cardiac repercussions that can affect the fetus. Studies on developmental neurology in the human fetus. Ther. 4, 167170. Rep. 7:45645. doi: 10.1038/srep45645, Bassols, J., Serino, M., Carreras-Badosa, G., Burcelin, R., Blasco-Baque, V., Lopez-Bermejo, A., et al. Eur. (2013). J. Matern. Ann. J. Obstet. Beyond the headlines: fetal movement awareness is an important stillbirth prevention strategy. When they suspect fetal hypoxia, they must determine the delivery timing to prevent serious consequences for your newborn. In this paragraph, we will consider the studies that simulate the 1st stage of labor. 12:652828. doi: 10.3389/fphys.2021.652828, Kentish, S. J., Frisby, C. L., Kennaway, D. J., Wittert, G. A., and Page, A. J. 12, 274289. Nutrients 7, 69246937. The psychoneuroimmunology of pregnancy. The thermoregulatory theory of yawning: what we know from over 5 years of research. The patterns of cytokine response and the neuroimmune physiology of the fetus and the placenta mirror the maternal ones throughout pregnancy (Sherer et al., 2017, 2018; Prins et al., 2018; Peterson et al., 2020). 662, 118134. Cerebral blood flow changes during vagus nerve stimulation for depression. Eur. Moreover, preterm birth often involves invasive treatments (e.g., invasive respiratory support) or drugs that can stress even more the immature ANS. Disord. Caton Alissa, R., Bell Erin, M., Druschel Charlotte, M., Werler Martha, M., Lin Angela, E., Browne Marilyn, L., et al. Developmental milestones of the autonomic nervous system revealed via longitudinal monitoring of fetal heart rate variability. Brain Dev. ArXiv200108264 Q-Bio. However, the intrinsic spatiotemporal complexity of ANS development and the complex species differences in the timelines of neural development from which inferences are often drawn to human development make it difficult to identify specific or exclusive critical windows, although we might point to particular periods: 48 WGA, due to organogenesis; 12 WGA, due to subplate and fHRV-FMs coupling appearance; 1824 WGA, due to nociception, CAN, and spleen development and myelination; the 3rd trimester, due to PNS development and change in FMs and hormones production; and birth, due to ANS adaptation to interact directly with the external environment. Fetal or birth complications affecting ANS development may have consequences on organic functions and mortality right after birth and in the following months. 1977;7(6):373-6. (2017). MgSO4, which is often administered between 23 and 27 WGA or intrapartum for its tocolytic effect to delay labor onset in pregnancy at risk for preterm birth (Ramsey and Rouse, 2001; Ingemarsson and Lamont, 2003), does not seem to show a significant change in fHRV (Stallworth et al., 1981; Nensi et al., 2014). Changing patterns of birth asphyxia and trauma over 20 years. Physiol. Clinical study of fetal neurobehavior by the KANET test. Using fetal oximetry probes many centers reported images of deep decelerations with little or no change in fetal oxygen saturation. Gender does not affect fetal heart rate variation. . Gynecol. Meas. View of environmental pollution and the fetus. 74, 174184. (1980). Early Hum. doi: 10.1016/j.psyneuen.2011.05.007, Gartstein, M. A., and Skinner, M. K. (2018). If the fetal heart rate pattern is atypical, then your obstetrician will initially try to determine the underlying problem. Perinatol. doi: 10.7363/040237, Busnel, M., Granier-Deferre, C., and Lecanuet, J. Effects of antihypertensive drugs on the unborn child. Cahill AG, Roehl KA, Odibo AO, Macones GA. Association and prediction of neonatal acidemia. Pediatr. Fetal cerebral perfusion is better than fetal acidaemia for the prediction of brain injury and might be assessable by sophisticated fetal heart rate metrics. In particular, the subplate (a central hub for cortical connectivity) becomes visible and begins to receive connection from the thalamus, basal forebrain, and brainstem. 87, 814826. Citalopram use in pregnancy: prospective comparative evaluation of pregnancy and fetal outcome. Hypertension 51, 960969. Proc. doi: 10.1016/S0140-6736(08)60074-4. The impact of maternal obesity on childhood neurodevelopment. 4, 7182. J. 22, 337358. Fetal autonomic brain age scores, segmented heart rate variability analysis, and traditional short term variability. Examining to what extent pregnancy-related physical symptoms worry women in the first trimester of pregnancy: a cross-sectional study in general practice. J. Gynecol. A growing body of evidence suggests the placenta's role in modulating fetal development. Methods Mol. doi: 10.1136/thorax.57.6.555, Eid, R. S., Chaiton, J. The placenta harbors a unique microbiome. 7, 7683. 446, 2233. doi: 10.1016/0002-9378(89)90399-2, Peleg, D., and Goldman, J. doi: 10.1016/j.earlhumdev.2019.01.011, Nordenstam, F., Norman, M., and Wickstrm, R. (2019). Am. Infants born with CS delivery following a period of labor have a higher and more developed ANS tone compared to those born with CS without labor (Mulkey et al., 2019). Copyright 2021 Cerritelli, Frasch, Antonelli, Viglione, Vecchi, Chiera and Manzotti. J. Autism Dev. doi: 10.1371/journal.pone.0200799, Schneider, U., Fiedler, A., Schrder, B., Jaekel, S., Stacke, A., Hoyer, D., et al. 11:578898. doi: 10.3389/fphys.2020.578898, Keywords: fetal development, autonomic nervous system, vagus nerve, cholinergic anti-inflammatory pathway, heart rate variability, critical window, maternal health, Citation: Cerritelli F, Frasch MG, Antonelli MC, Viglione C, Vecchi S, Chiera M and Manzotti A (2021) A Review on the Vagus Nerve and Autonomic Nervous System During Fetal Development: Searching for Critical Windows.