This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1113/JP27071

Giussani, DA

Lees, CC

Shaw, CJ

PubMed

Apollo (Cambridge)

J Physiol 594.5 (2016) pp 1279–1280 1279TheJournalofPhysiologyTRANSLAT IONAL PERSPECT IVESVariations on fetal heart ratevariabilityC. J. Shaw1,2, C. C. Lees2and D. A. Giussani11Department of Physiology, Developmentand Neuroscience, University of Cambridge,Cambridge, UK2Institute of Reproductive andDevelopmental Biology, Imperial CollegeLondon, London, UKEmail: dag26@cam.ac.ukIntrapartum electronic fetal monitoring(EFM) is widely used throughout thedeveloped and developing world. Thispractice is based on the understandingthat fetal heart rate (FHR) is sensitive tohypoxia. During labour, the fetus may beexposed to acute hypoxia during uterinecontractions or intrapartum insults,and has well-established cardiovascularcompensatory defence mechanisms,which ideally prevent hypoxic–ischaemicencephalopathy by maintaining perfusionpressure and substrate delivery to essentialorgans (Giussani et al. 1993). Failure ofthese compensatory mechanisms resultsin a progressively worsening metabolicacidosis. Development of severe acidaemia(pH < 7.05) is a key turning point afterwhich fetuses are unable to maintain fetalcardiovascular defence mechanisms andcerebral perfusion, rendering them at riskof asphyxial brain injury (Gunn & Bennet,2009). Therefore, intrapartum EFM aimsto identify, via changes in FHR patterns,fetuses unable to initiate or maintain suchcompensatory adaptations in responseto hypoxia, which become acidotic, anddeliver them before they are at risk ofasphyxia, severe acidosis, cardiovascularcollapse, end organ damage or death.Retrospective analysis of intrapartum EFMrecords shows that reduced or absent FHRvariability with decelerations is the mostconsistent predictor of newborn acidaemiaand poor outcome (Parer & Ikeda, 2007).However, the fetal physiology underlyingthese changes is far from clear, as are thechanges in FHR patterns and variabilitypreceding this critical end-stage. Whileknowledge of both fetal physiology and thecontrol of heart rate variability in the adulthas advanced greatly in the last 50 yearssince intrapartum EFM was introduced,little of it has translated into uncontestedinterpretation of FHR patterns. It is clearthat without understanding the physiologyunderlying the control of FHR and itsvariability in normal and complicatedpregnancy, we will not move forwardsfrom retrospective analysis to prospectiveprediction of abnormalities in the control ofFHR and how these can be detected by intra-partum EFM. Such a change in approach islong overdue. A recent Cochrane review of13 randomised controlled trials concludedthat intrapartum EFM has not reduced therates of fetal mortality or cerebral palsyand it has increased the rates of obstetricintervention in labour, caesarean section,operative vaginal delivery and delivery ofnon-acidotic babies (Alfirevic et al. 2013).Invasive adjuncts to EFM monitoring, suchas fetal blood sampling, as well as fetal pulseoximetry and fetal electrocardiography(measured as the T/QRS ratio) haveall been applied with limited success inreducing operative delivery and withoutsignificant improvement in neonataloutcome (East et al. 2014). Guidelines andrecommendations for the interpretationof intrapartum EFM exist, such as therule-based category colour-coded FHRmanagement framework championed byParer & Ikeda (2007). Adoption of suchframeworks in a single centre with dedicatedtraining reduced the number of babiesborn severely acidotic without altering therates of operative or instrumental delivery(Katsuragi et al. 2014). However, despitea general move towards standardisedassessment and the training of cliniciansto interpret intrapartum EFM withreference to such guidelines, there remainsa well-acknowledged poor reliabilityof EFM assessment between clinicians(Blackwell et al. 2011). The chronicallyinstrumented fetal sheep preparation inlate gestation, which is uncomplicated bygeneral or local anaesthesia and in whichstudies follow full post-surgical recovery,provides an incomparable window intofetal physiology that is inaccessible in thehuman fetus. Not only can we control theexact nature of the fetal insult in termsof magnitude, duration and frequency,but the preparation permits detailed fetalcardiovascular function analysis overprolonged periods, which can be correlatedto fetal endocrine as well as blood gas,metabolic and acid/base status. Using thisexperimental model, previous studies haveshown that acute hypoxia activates botharms of the autonomic nervous systemcontrolling FHR but in favour of vagaldominance and that activation of thesympathetic nervous system (SNS) is keyto providing rapid support to increase fetalperipheral vascular resistance and maintainblood pressure despite slowing of the fetalheart rate (Giussani et al. 1993). Further,advancing gestational age (Fletcher et al.2006) and antenatal glucocorticoid therapy(Jellyman et al. 2005) affect the magnitudeand pattern of the FHR response to hypoxiaand of the fetal endocrine and metaboliccompensation, all of which contribute toalterations in FHR variability. Surprisingly,despite their physiological and clinicalimportance, how gestational age or fetalglucocorticoid status affects FHR variabilityand how the mechanisms mediating FHRvariability during acute hypoxia are alteredin the chronically hypoxic IUGR fetus withor without antenatal glucocorticoid therapystill remain to be elucidated.Increasing the body of knowledge ofthe physiology underlying the controlof FHR variability, an interesting studyusing the chronically instrumented fetalovine preparation by Lear and colleaguesin this issue of The Journal of Physio-logy challenges the long held assumptionthat the sympathetic nervous system(SNS) mediates FHR variability in labour.This finding directly contradicts the longheld clinical interpretation that preservedFHR variability implies adequate fetalphysiological compensation. In this study,analysis of fetal sheep which had beenchemically sympathectomised showed thatFHR variability between episodes of briefrepeated asphyxia or elevation of the STsegment during asphyxia was unalteredrelative to sham control fetal sheep. Rather,the data imply that the predominantmediator of increased FHR variabilitybetween episodes of brief intermittentasphyxia was increased parasympatheticactivity. Therefore, if the SNS doesnot influence FHR variability betweensimulated contractions, interpretation ofFHR variability is unlikely to help monitorchanges in SNS activity during labour, asignificant change from traditional clinicalC© 2016 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society DOI: 10.1113/JP270717This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distributionand reproduction in any medium, provided the original work is properly cited.1280 Translational perspectives J Physiol 594.5understanding. Perhaps it is time tore-examine the maxim, now 30 yearsold and the basis of many obstetricguidelines, that the fetus with a normal FHRvariability is at a low risk of immediatedeath or brain injury caused by asphyxia,regardless of the presence of decelerationsor bradycardia. There is an urgent need todesign experiments to address the under-lying physiology mediating alterations inFHR variability in healthy and complicatedpregnancy at different stages of gestation,with and without exposure to commonantenatal therapies, such as treatment withsteroids. There is also the possibility thatthe fetal heart may show intrinsic variabilityin its heart rate, independent of auto-nomic innervation, which can be altered bygestational age, medications or the qualityof the intrauterine environment. Onceobtained, this information should be rapidlytranslated into frameworks for intrapartumEFM interpretation, either by clinicians or,more reliably, by a computer algorithm.Only then will basic and clinical science actin tandem to begin to reliably identify thefetus at risk of decompensating, rather thanthe already decompensated fetus.ReferencesAlfirevic Z, Devane D & Gyte GM (2013).Cochrane Database Syst Rev 5, CD006066.Blackwell SC, Grobman WA, Antoniewicz L,Hutchinson M & Gyamfi Bannerman C(2011). Am J Obstet Gynecol 205, 371–375.East CE, Begg L, Colditz PB & Lau R (2014).Cochrane Database Syst Rev 10, CD004075.Fletcher AJW, Gardner DS, Edwards CM,Fowden AL & Giussani DA (2006). Am JPhsyiol Heart Circ Physiol 291, 3023–3024.Giussani DA, Spencer JA, Moore PJ, Bennet L &Hanson MA (1993). J Physiol 461, 431–449.Gunn AJ & Bennet L (2009). Clin Perinatol 36,579–593.Jellyman JK, Gardner DS, Edwards CM, FowdenAL & Giussani DA (2005). J Physiol 567,673–688.Katsuragi S, Parer JT, Noda S, Onishi H, KikuchiH & Ikeda T (2014). J Matern Fetal NeonatalMed 29, 1–6.Lear CA, Galinsky R, Wassink G, Mitchell CJ,Davidson JO, Westgate JA, Bennet L & GunnAJ (2016). Sympathetic neural activation doesnot mediate heart rate variability duringrepeated brief umbilical cord occlusions innear-term fetal sheep. J Physiol 594,1265–1277.Parer JT & Ikeda T (2007). Am J Obstet Gynecol197, 1–6.Additional informationCompeting interestsNone.FundingD.G. is Professor of Cardiovascular Physiologyand Medicine at the Department of Physiology,Development and Neuroscience at the Universityof Cambridge, Professorial Fellow and Directorof Studies in Medicine at Gonville & CaiusCollege, Cambridge, a Lister Institute Fellow anda Royal Society Wolfson Research Merit AwardHolder. He is supported by the British HeartFoundation RG/11/16/29260. C.C.L. is supportedby the National Institute for Health Research(NIHR) Biomedical Research Centre based atImperial College Healthcare NHS Trust andImperial College London.C© 2016 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society

Variations on fetal heart rate variability.

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