All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. (2017). Placenta Microbiome Diversity Is Associated with Maternal Pre-Pregnancy Obesity and Placenta Biogeography. More than the infections themselves, it would seem it is the dysregulation of the placental inflammatory response that could affect the production of placental CRH and stimulate the fetal HPA axis, leading to preterm labor and birth (Parris et al., 2021). Rev. B., de Waard, M., et al. Front. Cell. It is widely known that comorbidities such as NEC or hypoxic-ischemic encephalopathy (HIE) can negatively affect ANS (Schlatterer et al., 2021). Autism spectrum disorder: a neuro-immunometabolic hypothesis of the developmental origins. Front. Maternal heart rate variability during the first stage of labor. Fish intake during pregnancy and foetal neurodevelopmenta systematic review of the evidence. Anat. As aids for the readers, Table 1 contains the meaning of the several HRV metrics cited in the following sections, whereas Figure 1 and Table 2 summarize the main findings of the current review. doi: 10.1016/j.physio.2018.05.001, Cogan, R., and Spinnato, J. J. Physiol. Am J Obstet Gynecol. (1986). (2013). Curr. [Epub ahead of print]. Comp. 160, 127133. Available online at: http://www.ncbi.nlm.nih.gov/books/NBK513398/ (accessed April 23, 2021). Med. J Physiol. Autonomic cardiorespiratory physiology and arousal of the fetus and infant, in SIDS Sudden Infant and Early Childhood Death: The Past, the Present and the Future, eds J. R. Duncan and R. W. Byard (Adelaide, AU: University of Adelaide Press). 143, 243249. Saudi Med. Heart rate variability parameters and fetal movement complement fetal behavioral states detection via magnetography to monitor neurovegetative development. Brain Dev. It reaches a stable set point only when its control functions meet the conditions on convexity and relative goals described in the text. 1:CD010333. doi: 10.1016/j.ajog.2004.05.086, Leiby, J. S., McCormick, K., Sherrill-Mix, S., Clarke, E. L., Kessler, L. R., Taylor, L. J., et al. Behav. Correct oxygenation is paramount for the newborn's development and survival (Ho et al., 2020). Fetal movement, in StatPearls (Treasure Island, FL: StatPearls Publishing). doi: 10.1016/j.clp.2016.04.001, Mowery, N. T., Morris, J. (2013b). doi: 10.1016/S1389-9457(03)00107-2, Frasch, M. G. (2018). 596, 55035504. Regul. 3-15 Chemoreceptors are found in peripheral locations such as in the aortic arch and carotid arteries where they are sensitive to low oxygen levels. On the other hand, clinical behavior has changed considerably. Med. 24, 210213. (2013). The effects of maternal hyperoxia on fetal breathing movements, body movements and heart rate variation in growth retarded fetuses. Fetal heart rate and variability: stability and prediction to developmental outcomes in early childhood. doi: 10.1016/j.earlhumdev.2018.07.003, Mller, F., and O'Rahilly, R. (1989). The occlusions resulted in fetal hypertension and vagally mediated decelerations. Biol. Am. (2016). Maternal and transabdominal ECG recorded in the early third trimester carry information about the chronic exposure of the motherfetus dyad to stress detectable by deep learning, a form of artificial intelligence techniques (Sarkar et al., 2021). Psychiatry 11, 112. Biol. Media Coverage (2018). Epidemiol. Frasch, M. G. (2020). (2000). (2007). Obstet. Moreover, prophylactic antibiotic use during vaginal or cesarean delivery may indirectly lead to epigenetic changes in the fetus, with possible implications in the immune system and stress response (Tribe et al., 2018), consequently involving vagus nerve development and suggesting, therefore, the utility to consider potential alternative approaches (Ledger and Blaser, 2013). Heres how to tell if youre experiencing them. J. Fetal Neonatal Med. doi: 10.1523/JNEUROSCI.09-05-01764.1989, Tsuda, K., Iwata, S., Mukai, T., Shibasaki, J., Takeuchi, A., Ioroi, T., et al. For example, the maternal pain and anxiety due to uterine contractions induce an activation of the sympathetic division (Jones and Greiss, 1982), whereas the release of the hormone oxytocin instead activates the parasympathetic division (Gamer and Bchel, 2012). doi: 10.1080/02724999208250616, Ledger, W. J., and Blaser, M. J. Rochester, NY: Social Science Research Network. Am. Received: 07 June 2021; Accepted: 19 August 2021; Published: 20 September 2021. Front. Mercury exposure and heart rate variability: a systematic review. (2007). Obstet Gynecol. J. Obstet. The major critical events that can affect vagus nerve and ANS development occur in premature births and delivery by CS at term (Hillman et al., 2012; Tribe et al., 2018; Mulkey et al., 2019). Nonetheless, when used correctly, the temperature can also help newborns to correctly develop: indeed, therapeutic hypothermia in newborns with 36 WGA in case of HIE can help reduce brain and injury brain inflammation, thus having positive effects on neurodevelopment (Massaro et al., 2017; Lemyre and Chau, 2018). Surg. Rev. 74, 174184. 2008 Sep; 112(3):661-6. For instance, whereas hypoxic-ischemic injuries in the right hemisphere seem to depress SNS tone, vaso-occlusive strokes in the same hemisphere appear to increase SNS tone. doi: 10.1111/j.1467-8624.2007.01099.x, DiPietro, J. Indian Pediatr. Am. Is less noise, light and parental/caregiver stress in the neonatal intensive care unit better for neonates? doi: 10.1038/npp.2015.171, McKenna, D. S., Ventolini, G., Neiger, R., and Downing, C. (2006). 1977 Feb 15; 127(4): 414-24. Natl. It could also affect the role of placenta as the immune pacemaker of pregnancy, increasing the risk of preterm birth (Allen, 2001; Peterson et al., 2020) and thus impairing vagal development during the last weeks of gestation. 92, 691693. The relationship between heart rate and asphyxia in the animal fetus. 214, 627.e1627.e16. Gestational diabetes is associated with changes in placental microbiota and microbiome. 1981 Dec 1; 141(7):797-806. There appears to be an association between multiple courses of sGCs prenatal administrations and infant neurodevelopmental abnormalities (Spinillo et al., 2004). The degree of oxygen saturation of fetal hemoglobin can be estimated based on the different absorption of red and near infrared light by oxygenated and deoxygenated fetal hemoglobin. Stress revisited: a critical evaluation of the stress concept. The pathologies that induce chronic hypoxemia in the mother, including SBD (Pien and Schwab, 2004) and anemia, may induce dysregulations in the vagal control systems. These patterns are altered by pain and could hence not only be pre-emptive for negative outcomes for labor and birth (Goldenberg et al., 2008), but also suggest their influence on the neurodevelopment of the fetal vagal system itself (Borovikova et al., 2000; Tracey, 2009; Frasch et al., 2016). (1998). doi: 10.1109/ICATE.2016.7754700, Roux, S. G., Garnier, N. B., Abry, P., Gold, N., and Frasch, M. G. (2021). In particular, several studies have shown how vagus nerve is involved in many vital processes during fetal, perinatal, and postnatal life: from the regulation of inflammation through the anti-inflammatory cholinergic pathway, which may affect the functioning of each organ, to the production of hormones involved in bioenergetic metabolism. Gynecol. 77: Palpation . Gynecol. In order to prevent severe brain injury from a lack of oxygen, your doctor must revive the fetus and quickly address the source of late decels. doi: 10.1038/s41390-021-01460-3, Ray-Griffith, S. L., Wendel, M. P., Stowe, Z. N., and Magann, E. F. (2018). I. Qualitative aspects. N. Y. Acad. Similar hints can also be gained by monitoring organ development due to the research regarding the CAP and the systemic interactions of the vagus nerve (Bonaz et al., 2021). There is no clarity on its usefulness in decreasing perinatal mortality or cerebral palsy when measured by a CTG which has been explained by the incorrect focus of EFM on prediction of acidemia, a poor correlate to fetal injury, instead of predicting fetal cardiovascular decompensation per se as well as the limitations of CTG technologies in capturing the short-term time scale fluctuations of HRV reflecting vagal modulations (Alfirevic et al., 2017; Frasch et al., 2017; Frasch, 2018; Gold and Frasch, 2021). 97, 14861490. 9, 477483. Maternal consumption of a low vitamin D diet retards metabolic and contractile development in the neonatal rat heart. Endocrinol. Afferent and efferent components of the cardiovascular reflex responses to acute hypoxia in term fetal sheep. Neurosci. In fact, fHRV is a non-invasive marker whose changes have been associated with ANS development, vagal modulation, systemic and neurological inflammatory reactions, and even fetal distress during labor. Reproduction 60, 193199. Maternal depression is associated with DNA methylation changes in cord blood T lymphocytes and adult hippocampi. J. Calif. Perinat. In particular, a steep rise in PNS tone can be detected around 3738 WGA and basal fetal cardiovascular function becomes more influenced by the PNS. Martin CB Jr, de Haan J, van der Wildt B, Jongsma HW, Dieleman A, Arts TH. We have attempted to produce a succinct review the physiology of fetal heart rate control that is relevant to the clinician caring for women in labor. (2018). Res. doi: 10.1093/pch/pxy028, Liu, H. L., Garzoni, L., Herry, C., Durosier, L. D., Cao, M., Burns, P., et al. Antony, K. M., Ma, J., Mitchell, K. B., Racusin, D. A., Versalovic, J., and Aagaard, K. (2015). Outlook 67, 169189. Pediatr. J. Perinatol. Historically, research findings oriented to understand the mediators that underlie the basis of fetal programming pointed out the HPA axis disregarding the role of ANS. J. Psychiatry 164, 12061213. Semin. Machine learning model on heart rate variability metrics identifies asymptomatic toddlers exposed to Zika virus during pregnancy. doi: 10.1002/14651858.CD010333.pub3, AlSaif, S., Mumtaz, S., and Wray, S. (2015). (2015). First Foods and Gut Microbes. At birth, the higher cortical networks controlling the ANS increase their connectivity (Schlatterer et al., 2021) and, in low-risk newborns at around 1 day of age, coherence between electrocortical activity and brainstem-mediated autonomic tone, especially parasympathetic, can be easily detected (Mulkey et al., 2021). Once born, newborns have to deal with the extrauterine environment that, especially for preterm babies, is constituted by the incubator. Induction of labor with oxytocin in pregnancy with low-risk heart disease: a randomized controlled trial. Am. The endotoxemia, through lipopolysaccharide molecules, seems to interfere with the cardiac pacemaker synchronization system, altering the fHRV pattern (Frasch and Giussani, 2020). Indeed, a prone position improves oxygenation, increases PNS tone, and lowers both salivary cortisol and stress behavior (Gomes et al., 2019). Fetal cerebral perfusion is better than fetal acidaemia for the prediction of brain injury and might be assessable by sophisticated fetal heart rate metrics. 9, 7685. doi: 10.1053/sper.2001.27546, Rantakari, K., Rinta-Koski, O.-P., Metsranta, M., Hollmn, J., Srkk, S., Rahkonen, P., et al. J. Perinat. 41, 662669. J. Ind. The rapidity of heart rate change is related to the rapidity of the conditions that trigger the change. 1993;19:105-11. Res. A possible critical event during the first stage of labor is certainly the risk of cardiac events. Assessed occupational exposure to chlorinated, aromatic and Stoddard solvents during pregnancy and risk of fetal growth restriction. Child Dev. Ther. As revealed by HRV analysis, the ANS constantly develops. In this sense, hormones may play a crucial etiological role, as literature shows that gonadal hormones have a significant impact on the sex-dependent differentiation of the entire nervous system (Chung and Auger, 2013). Fetal and neonatal responses following maternal exposure to mobile phones. Likewise, there is no single marker that reliably excludes metabolicacidemia. ABP, arterial blood pressure; ANS, autonomic nervous system; ASD, autism spectrum disorders; CAM, cardiac autonomic modulation; CAN, central autonomic network; CAP, cholinergic anti-inflammatory pathway; CNS, central nervous system; CRH, corticotropin-releasing hormone; CS, cesarean section; CTG, cardiotocography; ECG, electrocardiography; EEG, electroencephalography; EFM, electronic fetal monitoring; EMF, electromagnetic field; ENS, enteric nervous system; FASD, fetal alcohol spectrum disorders; fHR, fetal heart rate; fHRV, fetal heart rate variability; FM, fetal movement; GM, general movement; HIE, hypoxic-ischemic encephalopathy; HPA, hypothalamic-pituitary-adrenal; HR, heart rate; HRV, heart rate variability; NAS, neonatal abstinence syndrome; NC, neural crest; NEC, necrotizing enterocolitis; NOWS, neonatal opioid withdrawal syndrome; PAE, prenatal alcohol exposure; PGP, pelvic girdle pain; PNE, prenatal nicotine exposure; PNS, parasympathetic nervous system; REM, rapid eye movements; SDB, sleep-disordered breathing; sGC, synthetic glucocorticoid; SIDS, sudden infant death syndrome; SNS, sympathetic nervous system; sOT, synthetic oxytocin; SSRI, selective serotonin reuptake inhibitor; VAS, vibroacoustic stimulation; WGA, week gestational age; ZIKV, Zika virus. Effect of antenatal betamethasone and dexamethasone administration on fetal heart rate variability in growth-retarded fetuses. Biol. Fetal Heart Rate Monitoring. [Epub ahead of print]. In this sense, dysregulations in mother circadian rhythm, due to disturbed sleep-awake patterns, could interfere with the development of circadian control systems of the fetus and, consequently, with the circadian profile of the vagus nerve, impacting the physiologic vagal neurodevelopment itself. Rivolta, M. W., Stampalija, T., Casati, D., Richardson, B. S., Ross, M. G., Frasch, M. G., et al. 4, 569577. In fetal life, pulmonary ventilation does not occur and is not a source of fetal oxygenation. Clin. Factors that contribute to progressive oxygen debt are strength, duration and frequency of decelerations. Biol. 99, 712. The effect of magnesium sulfate on fetal heart rate variability and uterine activity. A decrease in the heart rate b. Labor is usually induced through the administration of synthetic oxytocin (sOT). Board Fam. Front. The last column shows an additional mechanism thought to be present with marked fetal acidemia where the heart rate slows due to direct myocardial effects. In particular, several studies have shown how vagus nerve is involved in many vital processes during fetal, perinatal . Hypotension indicates failing fetal compensation. Life Sci. 23, 151158. J. Gastrointest. Acta Obstet. Heart rate variability in sleeping preterm neonates exposed to cool and warm thermal conditions. 176, 112118. Acad. For instance, although we know that folate deficiency can impede the neural tube closure or that alcohol can induce dramatic brain modifications (Moore et al., 2016), we still lack knowledge about more subtle influences, that is, the precise effects of just some alcohol during the first weeks of pregnancy or the early effects of maternal stress (Avalos et al., 2014; Caspers Conway et al., 2014; Antonelli et al., 2021). 840, 4550. Pediatrics 139, S38S49. Fetal heart rate and motor activity associations with maternal organochlorine levels: results of an exploratory study. Psychopathol. Fetal heart rate is a vital indicator of your babys health. Environ. Am J Obstet Gynecol. J. Acad. (2018). Alterations in maternally perceived fetal movement and their association with late stillbirth: findings from the Midland and North of England stillbirth casecontrol study. doi: 10.1136/jclinpath-2020-206536, Passi, R., Doheny, K. K., Gordin, Y., Hinssen, H., and Palmer, C. (2017). (2011). doi: 10.1515/jpm-2014-0031. Whereas, 1 differs already at birth, the other metrics show different trajectories after 3040 days, hinting at different ANS development due to the experienced postnatal comorbidities (Schlatterer et al., 2021). Montreal, QC: Acta Medica Publ. J. Obstet. 13415. doi: 10.1111/joa.13415, Kuperman, A. Heart rate variability in the perinatal period: a critical and conceptual review. doi: 10.7326/0003-4819-134-5-200103060-00012. Auton. (2020). Neurosci. World Inst. This would also be the case if other tests indicate any issues with your baby. J. Physiol. This event shows how the fetal ANS quickly reacts in the face of a stressor. Cahill AG, Tuuli MG, Stout MJ, Lpez JD, Macones GA. A prospective cohort study of fetal heart rate monitoring: deceleration area is predictive of fetal acidemia. (2007). doi: 10.1016/j.wombi.2018.12.001, Fox, G. P. P., and Matthews, T. G. (1989). Doussard-Roosevelt, J. Antibiotics, inflammation, and preterm labor: a missed conclusion. Sleep Med. It is interesting that fetal ANS impairment can also have consequences on infant temperament at both 3 and 6 months (Howland et al., 2020). Moore, K. L., Persaud, T. V. N., and Torchia, M. G. (2016). Med. doi: 10.1016/j.scitotenv.2018.09.212. 85, 633638. Environ. 37, 558562. 43, 481486. An increase in the heart rate c. An increase in stroke volume d. No change a. This association is important because all contemporary EFM classification methods place high reliance upon baseline fetal heart rate variability to exclude the presence of metabolic acidosis.23-30 The 2008 NICHD Update publication in which the Category I, II, III classification method was first described includes a statement that moderate variability reliably predicts the absence of metabolic acidemia at the time that it is observed.24 This concept was softened in the 2009 ACOG Practice Bulletin 106 with the statement The data relating FHR variability to clinical outcomes, however, are sparse.25 This practice bulletin endorsed the 3-level categorization of tracings where the third level required absent baseline variability. What is amiss is the understanding and acting upon the fact that each fetus and newborn are not truly new, but, rather, come with weeks and months of experience in utero. C Embryo Today Rev. In fact, one could consider that the substantial reduction the rates of intrapartum-related neonatal encephalopathy seen in numerous regions around the world demonstrate a remarkable achievement. Standards of measurement, physiological interpretation, and clinical use. Fetal acidosis and hypotension during repeated umbilical cord occlusions are associated with enhanced chemoreflex responses in near-term fetal sheep. Total Environ. Despite this evidence, other authors claim that placental microbiome does not existthe aforementioned results would be just due to methodological errorsor that there is only extremely low biomass, probably leading to minor clinical effects (Lauder et al., 2016; Leiby et al., 2018; Kuperman et al., 2020; Parris et al., 2021). doi: 10.1038/s41390-021-01420-x. Arch. The thermoregulatory theory of yawning: what we know from over 5 years of research. With the passing of the weeks, however, sex-specific differences in the sympathovagal balance start to be detected. Rep. 7:45645. doi: 10.1038/srep45645, Bassols, J., Serino, M., Carreras-Badosa, G., Burcelin, R., Blasco-Baque, V., Lopez-Bermejo, A., et al. Prenat. doi: 10.1542/peds.2015-4271, Conradt, E., Crowell, S. E., and Lester, B. M. (2018). 446, 2233. Effect of oxytocin and oral prostaglandin E2 on uterine contractility and fetal heart rate patterns. (2017). Opin. Scand. We have shown how alterations in CAN activity and sensorimotor behaviors can give hints about the developing ANS function. Occupational hazards and pregnancy outcomes. Sci. Of the neonates in this series, 20% will have neurological consequences including cerebral palsy and HIE (Goldaber et al., 1991; DuPont et al., 2013). Psychol. Environ. Environment and fetal programming: the origins of some current pandemics. J. Pediatr. 93, F298F301. (2019). Neonatal Nurs. Arch Dis Child Fetal Neonatal Ed. Dis. Another common complication during labor is given by cardiac repercussions that can affect the fetus. Persistent low variability is concerning, especially when present on admission or associated with decelerations and tachycardia.16 Low variability must not be ignored, but it appears that moderate variability does not guarantee the absence of acidemia. Several factors can normally affect the sleep states of the mother during pregnancy: the hormonal, biomechanical, and behavioral changes that occur during the three trimesters, often lead to increased sleep disturbances, particularly in the last trimester (Sahota et al., 2003; Pien and Schwab, 2004; Facco et al., 2010; Mindell et al., 2015). Autonomic nervous system immaturity due to fetal or postnatal complications (e.g., maternal pathologies, birth difficulties) could then impair the whole brain development and, therefore, behavior, stress response, and mood regulation, with negative consequenceseven serious neurological or psychological pathologiesin infants, adolescent, and adult life (Mulkey et al., 2018; Mulkey and du Plessis, 2019). Scand. Impaired autonomic function in adolescents born preterm. Clin. Analg. Maternal periconceptional alcohol consumption and congenital limb deficiencies: alcohol consumption and limb deficiencies. (1992). Front. doi: 10.1302/2046-3758.47.2000387, Shekhawat, H., Shrivastava, D., Dhurve, K., Shelke, U., and Deo, A. 371, 7584. Homeostatic control of neural function can be mediated by the regulation of ion channel expression, neurotransmitter receptor abundance, or modulation of presynaptic release. 86, 319325. Increases baseline b. Decreases baseline b. Oxytocin specifically enhances valence-dependent parasympathetic responses. Such hypoxic states can also be secondary to infections, including chorioamnionitis, leading to several hemodynamic abnormalities, and cardiovascular compromise (Frasch, 2018). Homeo-static intrinsic plasticity is outside the scope of this review, but has been reviewed in detail [e.g. Moreover, the prolonged administration of MgSO4 seems to be associated with a change in fetal breathing movements (Peaceman et al., 1989) and to affect fHRV dose-dependently (Cardosi and Chez, 1998; Kamitomo et al., 2000). At 10 WGA the corticospinal connectivity begins to develop, together with an increase in synaptogenesis, and, as a result, body reflexes in the upper limbs start to appear (Borsani et al., 2019). doi: 10.1038/s41372-019-0342-9, Siddiqui, S., Fifer, W. P., Ordonez-Retamar, M., Nugent, J. D., and Williams, I. Lack of detection of a human placenta microbiome in samples from preterm and term deliveries. The neurodevelopmental impact of prenatal infections at different times of pregnancy: the earlier the worse? Although there are not evident depressive effects on non-stress test reactivity or variability in the case of daily opioid use for chronic pain (Brar et al., 2020), the current guidelines recommend a prescription at the lowest effective dose (Ray-Griffith et al., 2018). Indeed, dysfunctional CAP can fail in regulating inflammation, thus letting the immune system go unchecked and free to induce tissue damage, shock, and even death, whereas, on the other hand, a functional CAP can prevent microglia activation, thus showing a neuroprotective effect (Garzoni et al., 2013; Frasch et al., 2016). (2000). Use Misuse 49, 14371445. Environ. Neurosci. doi: 10.2147/IJWH.S151845, Reich, D. A., Govindan, R. B., Whitehead, M. T., Wang, J., Chang, T., Kota, S., et al. doi: 10.1016/j.earlhumdev.2017.07.003, Desrosiers, T. A., Lawson, C. C., Meyer, R. E., Stewart, P. A., Waters, M. A., Correa, A., et al. Regarding the PNS, the vagus nerve has been recognized as a fundamental afferent pathway for sensing the milieu interior in peripheral tissues, thus allowing the organism to respond by activating complex networks involving the whole ANS, endocrine, metabolic, innate, and adaptive immune systems (Frasch et al., 2018b; Bonaz et al., 2021). Despite knowing that the CAN coordinates autonomic function and that left and right hemispheres modulate PNS and SNS tone, respectively (Mulkey et al., 2021), we have conflicting results on how the brain precisely controls ANS in newborns. In a series of sheep experiments they applied 60 second complete cord compressions every 5 minutes in one group and an identical cord compression every 2.5 minutes in a second group. 7:1031. doi: 10.3389/fmicb.2016.01031, Oberlander, T. F., Gingrich, J. Gynaecol. doi: 10.1161/HYPERTENSIONAHA.109.129098, Cerritelli, F., Cardone, D., Pirino, A., Merla, A., and Scoppa, F. (2020). 196: Communication of Fetal Heart Monitoring Information . (2018). doi: 10.31887/DCNS.2016.18.4/tbale, Barlow-Anacker, A. J., Fu, M., Erickson, C. S., Bertocchini, F., and Gosain, A. For instance, too high oxygenation can easily induce lung injury, thus increasing inflammation and stressing the already immature CAP, whereas too low oxygenation can cause neurodevelopmental impairment and HIE (Rantakari et al., 2021). doi: 10.1016/j.ijgo.2007.08.012, Sahota, P. K., Jain, S. S., and Dhand, R. (2003).