Fetal heart rate changes on the cardiotocograph trace secondary to maternal COVID-19 infection

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Full length article

Fetal heart rate changes on the cardiotocograph trace secondary to maternal COVID-19 infection

Anna Gracia-Perez-Bon ﬁls

^a,b,

*, Oscar Martinez-Perez

^c,d,e

, Elisa Llurba

^f

, Edwin Chandraharan

^g

aHospitalGeneraldel'Hospitalet,Barcelona,Spain

bAutonomousUniversityofBarcelona,Spain

cObsSimulationUnit,Spain

dPuertadeHierro-MajadahondaUniversityHospital,UniversidadAutónomadeMadrid,Spain

eUniversidadCatólicadeMurcia,Spain

fSantPauUniversityHospital,Barcelona,Spain

gGlobalAcademyofMedicalEducation&Training,London,UnitedKingdom

ARTICLE INFO

Articlehistory:

Received28April2020 Accepted25June2020

Keywords:

COVID-19 CTG

Cardiotocograph Cytokinestorm

PhysiologicalCTGinterpretation ZigZagpattern

ABSTRACT

Objective:Todeterminethecardiotocograph(CTG)changesinwomenwithsymptomaticCOVID-19 infection.

Studydesign:12anonymisedCTGtracesfrom2hospitalsinSpainwereretrospectivelyanalysedby2 independentassessors.CTGparameterswerestudiedbasedonfetalpathophysiologicalresponsesto inﬂammationandhypoxiathatwouldbeexpectedbasedonthepathogenesisofCOVID-19patients.

Correlationwasmadewithperinataloutcomes(Apgarscoreat5minandumbilicalcordpH).

Results:AllfetusesshowedanincreasedbaselineFHR>10percentcomparedtotheinitialrecording,in addition toabsenceof accelerations.10out of 12 CTGtraces(83.3 percent) demonstratedlate or prolongeddecelerationsand7outof12fetuses(58.3percent)showedabsenceofcycling.Notasingle caseofsinusoidalpatternwasobserved.ZigZagpatternwasfoundin4CTGtraces(33percent).Excessive uterineactivitywasobservedinallCTGtraceswhereuterineactivitywasmonitored(10outof12).Apgar scoresat5minwerenormal(>7)andabsenceofmetabolicacidosiswasfoundintheumbilicalcord arterialpH(pH>7.0)inthecasesthatwereavailable(11and9,respectively).

Conclusion: Fetuses of COVID-19 patients showed a raised baseline FHR (>10 percent), loss of accelerations,latedecelerations,ZigZagpatternandabsenceofcyclingprobablyduetotheeffectsof maternalpyrexia,maternalinﬂammatoryresponseandthe“cytokinestorm”.However,theperinatal outcomes appear to be favourable. Therefore, healthcare providers should optimise the maternal environment ﬁrst torectify the reactiveCTG changes instead of performing an urgent operative intervention.

Introduction

Theparametersrecordedonthecardiotocograph(CTG)reﬂect theactivity offetalautonomicand somaticnervoussystems,as well as the oxygenation of the fetal myocardium [1]. A fetus responds to hypoxia by reducing the myocardial workload to maintain a positive aerobic metabolism in the heart, seen as decelerationsontheCTGtrace[1]. Excessiveuterineirritability may reduce utero-placental circulation by compressing the

myometrialbloodvessels,aswellascausingcompressionofthe umbilicalcord[2].

CTGchangesarealsoinﬂuencedbymaternalstatus.Hypoxic and inﬂammatory conditions, as wellas maternal pyrexia, can causeabnormalfetalheartratechanges.Maternalfeverincreases heroxygenrequirement(therebyreducingutero-placentaloxygen transfer),aswellasincreasesplacentaloxygenconsumptiongiven theaugmented metabolismof the feto-placentalunit. This can resultinfetalhypoxicneurologicalinjury.

COVID-19 infection is associated with maternal pyrexia,

“cytokinestorm”andhypercoagulability,whichincreasestherisk of placental intervillous thrombosis and infarction, as well as maternal hypoxia secondary to adult respiratory distress syn- drome(ARDS).

*Correspondingauthorat:HospitalGeneraldel'Hospitalet,Barcelona,Spain.

E-mailaddresses:[email protected],

Anna.GraciaPerez-Bonﬁ[email protected](A.Gracia-Perez-Bonﬁls).

ContentslistsavailableatScienceDirect

European Journal of Obstetrics & Gynecology and Reproductive Biology

j o u r n a l h o m e p a g e : w w w . e l s ev i er . c o m / l o c a te / ej o g r b

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Table1

AnalysisofCTGfeaturesinwomenwithCOVID-19infection.

Case Gestationalage BaselineFHR>10% Variability Cycling Accelerations Decelerations Sinusoidal Uterineirritability Apgar5 CordarterialpH

1 37 + N – – Late – + 10 7.3(V)

Prolonged

2 39.5 + N + – Late – + 10 7.12

3 36.4 + N – – Late – NotRecorded 10 –

4 40.6 + Reduced – – Late – + 10 –

5 28 >200 – – – – – NotRecorded N/A N/A

6 40 + Reduced – – Late – + 10 7.14

7 37.3 + ZigZag + – Late – + 10 7.28

Prolonged

8 37.6 + N + – Variable – + 10 7.23

9 38.3 + ZigZag + – Late – + 10 7.28

10 40.6 + ZigZag + – Late – + 9 7.31

11 39.4 + Reduced – – Late – + 9 7.26

12 39 + ZigZag – – Late – + 9 7.23

FHR=fetalheartrate;N=normal;V=venous.

Table2

AnticipatedCTGfeaturesinCOVID-19patients.

CTGfeature Normalparameters COVID-19

LikelychangesinCOVID-19 Underlyingreason Correlationpathogenesis BaselineFHR 110 160bpmAfter40weekstheupper

limitis150bpm(strongvagal dominance)

IncreasedFHR>10%bpmor

>10%aboveexpectedfor gestationalage

Fetalreactiontomaternal pyrexia

Maternalinﬂammatoryresponse characterisedbypyrexia.

Grossfetaltachycardia(FHR

>180bpm)

Fetalresponsetointense maternalinﬂammation.

"CytokineStorm"

Acutefetalbradycardia Placentalintervillous thrombosisoracute maternalhypoxia.

HypercoagulablestateandARDS leadingtomaternalhypoxiaand reductioninplacentalcirculation.

Baseline variability

5 25bpm Reducedvariability(<5

bpm)

FetalCNSdepression secondarytomaternal hypoxia,medicationsand theeffectsofinﬂammatory cytokines

COVID-19isassociatedwithARDSand

"CytokineStorm",releasingTNF-alfa, interferonsandinterleukinsthatcan crosstheplacentaandthefetalblood- brainbarriercausingdepressionoffetal CNS.OpiatesandotherCNSdepressants canalsocausedepressedvariability.

Increasedvariability(>25 bpm)resultingintheZigZag pattern.

Fetalautonomicinstability secondarytomaternal pyrexiaandinﬂammatory cytokines.

Maternalpyrexiamayincreasefetal corebodytemperature.The"Cytokine Storm"maycausefetalautonomic instability.

Cycling Alternateperiodsofnormaland reducedvariability(approx.oncein every50min)duetoactiveandquiet fetalsleep

Lossofcyclingwitheither theabsenceofthequiet epochorpersistentreduced variability.

DepressionofthefetalCNS duetopersistentmaternal pyrexiaand/or inﬂammatorymediators thatcrosstheplacenta.

Maternalpyrexiaandthe"Cytokine Storm"

Accelerations AtransientriseintheFHRwiththe amplitudeof15bpmlastingfor15s,at least2episodesin20min.

Lossofaccelerations Fetusconservebody movementsduringhypoxia.

ARDSleadingtomaternalhypoxiaand theresultantreductioninplacental circulation.

Lossoffetalmovementsasa resultofCNSdepressiondue toinﬂammatorymediators.

COVID-19isassociatedwithmaternal

"CytokineStorm"andthesetoxic cytokinesmaycrosstheplacenta.

Increasedaccelerations Intrauterinefetalconvulsion Maternalpyrexiamayincreasefetal corebodytemperatureleadingtofetal hyperpyrexiaandfebrileconvulsion.

Deceleration Lateor"shallow"

declarationswithdelayed recoverytothebaseline.

Utero-placental insufﬁciencydueto maternalhypoxiaand placentalintervillous thrombosis.

ARDSleadingtomaternalhypoxiaand reductioninplacentalcirculationas wellasduetothehypercoagulable state.

AtransientdecreaseintheFHRofat least15bpmfromthenormalbaseline lastingaminimumof15s.

Atypicalvariable decelerations

Placentalthrombosiscan causelongstandingutero- placentalinsufﬁciency,fetal redistributionand oligohydramnios.

HypercoagulablestateinCOVID-19 patientsmayleadtoplacental thrombosisandinfarction.

Singleprolonged

deceleration(>30bpmdrop, for>3min)andanacute fetalbradycardia(>30bpm dropfor>10min).

Infarctionandthrombosisof

>50%ofplacenta,and/or secondarytoanacute reductioninutero-placental perfusion.

Hypercoagulabilitymayleadtomassive placentalthrombosisandinfarction ARDSleadingtoanacutematernal hypoxiaand/orhypotensioncausingan acutereductioninplacental oxygenation.

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Although,thereiscurrentlynoevidencetosuggestthatCOVID- 19infectionhasadirecteffectonfetalmorbidityandmortality, maternalchangessecondarytoCOVID-19infectionmayresultin fetalheartratechanges.

PathogenesisoftheCOVID-19infection

Recent studies have suggested that hypoxia and adult respiratorydistresssyndrome(ARDS)maycausethereleaseofa Table2(Continued)

CTGfeature Normalparameters COVID-19

LikelychangesinCOVID-19 Underlyingreason Correlationpathogenesis Sinusoidal

Pattern

Typical Smoothundulatedoscillationsofthe FHRbaselinewithamplitudeof15bpm andfrequency2 5/min,reduced variabilityandabsenceofaccelerations.

Duetofetalthumb-suckingand physiologicalglotticmovementsthat occurforupto30min.

Persistenceoftypical sinusoidalpatternforlonger than30min

Chronicfetalanaemiaand acidosis

Destructionofredcellshavebeen reportedinpatientswithCOVID-19.

Thismaynotonlyreduceoxygen carryingcapacityofmaternalbloodto theplacenta,ifasimilareffectoccursin afetusthismayleadtoachronicfetal anaemia.

Uterine contractions

Atypical Sharp,“Shark-teeth-like”oscillationof thebaselineFHR,persistingforupto10 minsecondarytofetalthumbsucking.

Persistence>30min Acutefeto-maternal haemorrhageleadingto fetalhypovolemiaand hypotension,andthe resultantautonomic instability.

DIChasbeenreportedinCOVID-19 patients.Ifsimilarchangesaffectthe fetoplacentalunit,thismayresultinan acutefeto-maternalhaemorrhageand fetalhypovolemia.

3 4in10min,lasting<60swithinter- contractionintervalof>90s.

Excessiveuterineactivity Myometrialirritability secondarytomaternal pyrexiaandinﬂammation.

Increasedtemperatureand inﬂammatoryresponse.

FHR=Fetalheartrate;ADRS=AdultDistressSyndrome;DIC=DisseminatedIntravascularCoagulation;bpm=beatsperminute.

Fig.1.AbsenceofaccelerationsintheCTGtraceofapatientwithCOVID-19infection.

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cytokinestorm leadingtomulti-organ failure.A deadly uncon- trolledsystemicinﬂammatoryresponseresultingfromtherelease oflargeamountsofpro-inﬂammatorycytokines(IFN-a,IFN-g,IL- 1b, IL-6, IL-12, IL-18, IL-33, TNF-a, TGFb, etc.) and chemokines (CCL2,CCL3,CCL5,CXCL8,CXCL9,CXCL10)havealsobeenreported [3].Moreover,ithasbeensuggestedthatrecruitmentofaberrant CD45RA+TcellsistheimmunologicfeatureofCOVID-19[4].

Furthermore, it has been postulated that SARS-CoV-2 can dissociate oxy-Hb, carboxy-Hb and glycosylated Hb. This may resultinprolongedandprogressivehypoxiaeventuallyleadingto desaturationandrespiratorydistress.

Excessive secretion of erythropoietin to stimulate the bone marrow (in order to secrete new red blood cells to compensateforprogressiveand profoundhypoxia)mayleadto thrombocytosisandaresultanthypercoagulablestate.Evidenceof disseminatedintravascularcoagulation(DIC)signiﬁcantlyhigher D-dimer (p < 0.05), ﬁbrin degradation products (FDP) levels (p<0.05),andprolongedPT(p<0.05)andAPTT(p<0.05)has beendocumented[5].Acasewithpoorneonataloutcomewithan Apgarscoreof0andunsuccessfulneonatalresuscitation[6]and theadverseeffectonthetype2Pneumocyteshavebeenrecently reported[7].

Therefore,COVID-19resultsinanimmunologicalresponseina pregnantwomanwhoseimmunesystem isalready alteredasa resultofnormalphysiologicalchangesofpregnancy.Despitethe lackofstrongevidencethatCOVID-19istransferredinsufﬁcient loadacrosstheplacentatocausefetalinfectionoraninﬂammatory

response[8–10],itislikelythattherewouldbeareactiveresponse of the fetus secondary to a maternal inﬂammatory state. In addition,maternalpyrexia,inﬂammatorymediatorsandcytokines mayirritate theuterinemyometrium leading toa reduction in utero-placentaloxygentransfer.

Materials&methods

Retrospective analysis of 12 anonymised CTG traces from pregnantwomenwithsymptomaticCOVID-19infection,fromtwo differenthospitalsin Spain,was performed.(Table 1).The CTG traceswereindependentlyanalysedbytwoassessors(AGPBand EC) to determine the expected changes in maternal COVID-19 infection(Table2)andcorrelatedwithperinataloutcomes(Apgar Scoreat5min,andumbilicalcordpH).Poorneonataloutcomes weredeﬁnedby5minApgarScore<7,umbilicalcordarterialpH<

7.0andunexpectedadmissiontotheneonatalunit.

Theory

Maternalinﬂammatoryresponseandfeverwillaffectthefetal heartrate (FHR),therebyresultingin changesontheCTGtrace.

Firstly,basedonthefactthatmaternalinterleukinesandcytokines havetheabilitytocrosstheplacenta,itis reasonabletoexpect reactivefetaltachycardia.The“cytokinestorm”islikelytoincrease thefetalheartrate>180bpmduetoitsdirecteffectonthefetal myocardium,inadditiontoaninﬂammatoryresponse.Secondly,

Fig.2. LatedecelerationsintheCTGtraceofapatientwithCOVID-19infection.

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the placental metabolism will be increased leading to relative utero-placentalinsufﬁciency.ThismightbeseenintheCTGtrace aschemo-receptormediated“latedecelerations”.

Ontheotherhand,ifinﬂammatorymediatorsaffectthefetal centralnervoussystem,onewouldexpecttoseechangesinfetal variability, includingtheloss of cyclingand the ZigZagpattern secondarytoautonomicinstability[11].

Moreover,duetomaternalhypercoagulablestate,theremaybe increasedincidenceofintrauterinefetalgrowthrestriction(IUGR), and sudden bradycardia secondary to placental or umbilical venousthrombosis.

Lastly, in cases of severe maternal hypoxia or anaemia, sinusoidalpatternsmayoccur.

The anticipated CTG changes based on the pathogenesis of COVID-19infectionareprovidedinTable2.

Results

AllfetusesshowedanincreasedbaselineFHR>10%comparedto the initial recording and one fetus (No. 5) showed gross fetal

tachycardia(>210bpm).Allfetusesshowedabsenceofaccelerations (Fig.1).Late(Fig.2)or prolongeddecelerations(Fig.3)wereobserved in10outof12CTGtraces(83.3%)CTGtraces.7outof12fetuses(58.3

%)showedabsenceofcycling(Fig.4).Exaggeratedoraugmented variability>25bpmwasfoundin4outof12cases(33%)conﬁrminga ZigZagpattern(Fig.5).NoneoftheCTGsdemonstratedasinusoidal pattern.AllCTGtraces(100%)whereuterineactivitywasmonitored (10outof12cases)showedevidenceofexcessiveuterineactivity.In thecaseswheredeliverywasaccomplished(11outof12),theApgar scoresat5minwerenormal(>7).UmbilicalcordarterialpHwas available in 9cases, and none showed evidenceof neonatalmetabolic acidosis(deﬁnedaspH<7.0).

Discussion

Toourbestknowledge,thisistheﬁrststudythatanalysedthe CTGchangesinmaternalCOVID-19infectionusingpathophysiol- ogyaccordingtotheInternationalPhysiologicalCTG Guidelines producedby36CTGexpertsfrom14countriesin2018(https://

physiological-ctg.com/guideline.html). As expected, all fetuses

Fig.3.ProlongeddecelerationintheCTGtraceofapatientwithCOVID-19infection.

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showedanincreasedbaselineFHR>10%comparedtotheinitial recording, which was suggestive of reactive fetal response to maternal pyrexia and inflammatory response. The gross fetal tachycardia(>210bpm)seeninonecasewasmostlikelysecondary to the maternal “cytokine storm” resulting in excessive fetal sympatheticresponseand/orduetocardiacarrythmiasecondary toexcessiveinflammatorymediators.Allfetusesshowedabsence of accelerations(Fig.1).This was most likelysecondary tothe depressionofthefetalsomaticnervoussystembyinflammatory mediators or due to ongoing hypoxia as a result of increased maternalorplacentaloxygenconsumptionleadingtoconservation of fetal somatic muscle activity. Late (Fig. 2) or prolonged decelerations(Fig.3)whichwereobservedin10outof12CTG traces (83.3 %), were either secondary to increased placental metabolismandresultantreducedutero-placentaloxygentransfer (i.e.arelativeutero-placentalinsufficiency),orduetoplacental intervillousthrombosis secondary tomaternal hypercoagulable stateinCOVID-19infection.

58.3%showedabsenceofcycling(Fig.4),whichwasmostlikely due to the loss of the normal active and quiet sleep epochs secondarytoplacental transferofmaternalinflammatorymedi- ators,andresultantdepressiveeffectonthefetalbrain.Exagger- atedoraugmentedvariability>25bpmfoundin33%confirminga ZigZag pattern, was most likely secondary to an autonomic instabilityasaresultoffetalinflammatoryresponsesecondaryto maternal cytokine storm and pyrexia. None of the CTGs

demonstrated asinusoidal patternwhich was suggestivethata chronic fetal anaemia secondary to haemolysis is a rare phenomenon in maternal COVID-19 infection. All CTG traces (100%)whereuterineactivitywasmonitored(10outof12cases) showed evidence ofexcessive uterineactivity,which was most likelysecondarytomyometrialirritabilityduetomaternalpyrexia and inﬂammatory response. In the cases where delivery was accomplished(11outof12),theApgarscoresat5minwerenormal (>7).UmbilicalcordarterialpHwasavailablein9cases,andthese showedabsenceofevidenceofneonatalmetabolicacidosis(pH>

7.0).Theseindicatethatdespitetheobservedabnormalpatterns suchasabsenceofaccelerations,increasedbaselineFHRandthe presence of late or single prolonged decelerations on the CTG traces,theperinataloutcomeswerefavourable.Thissuggestthat theobservedabnormalitiesontheCTGtracewerereactivechanges in the fetus secondary to the pathophysiology o the maternal COVID-19infection.Thismayhaveasigniﬁcantclinicalapplication asperforminganurgentoperativedeliveryoradjunctivetestssuch as fetal scalp blood samplingfor a “pathological CTG trace” in COVID-19patientsshouldbe reviewed.Immediatemeasuresto improvethematernalenvironmenttocorrectmaternalhypoxia, maternalpyrexiaandinﬂammatoryresponseshouldbeundertak- entorectifyCTGchanges,priortoconsideringanyintervention basedontheobservedabnormalCTGchanges.Thisisbecausethe primarycausesofabnormalCTGchangesin maternalCOVID-19 infectionarepresentwithinthematernalcompartment.Itisalso Fig.4. AbsenceofcyclingintheCTGtraceofapatientwithCOVID-19infection.

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importanttoanticipatetheCTGchangeswehavehighlightedin maternalCOVID-19infections.Bydoingsounnecessaryoperative interventionsbased onCTG guidelines -whichare produced to detectintrapartumhypoxia-couldbeavoidedinmaternalCOVID- 19infection,wheretheprimarypathologyisinﬂammationandnot hypoxia.

Themainstrengthofourstudyisthattheauthorsanalysedthe CTG features that would be expected in maternal COVID-19 patientsbasedontheknowledgeofpathophysiology,insteadof relyingonstandardCTGguidelines(FIGO,NICE,ACOGorNational) which are intended to recognise intrapartum hypoxia and not inflammation.COVID-19infectioniscurrentlyofimmenseclinical significanceandtherefore,wehopethefindingsinourstudywill helpavoidunnecessaryoperativeinterventionsforabnormalCTG changes. This may help avoid additional metabolic and stress responsetoanoperativeinterventioninawomanwhoisalready symptomaticofCOVID-19infection.

Themainlimitationofourstudyisthesmallnumber.However, symptomaticmaternal COVID-19infection is a novel, relatively rarecondition,andtherefore,thereisanurgentneedtoinform

frontlinecliniciansoftheabnormalCTGchangesobservedandthe associated perinatal outcomes. So that unnecessary operative interventionsareavoidedinpregnantwomenwithsymptomatic COVID-19infection.

Conclusion

MaternalCOVID-19infectionappearstocausechangesinthe cardiotocograph(CTG)traceduetoacombinationofeffects.These include maternal hypoxia, “cytokine storm”, maternal pyrexia, uterineirritabilityanddiminishedtransferofoxygenthroughthe placenta. This can be a consequence of increased placental metabolic demands and / or placental intervillous thrombosis secondarytomaternalhypercoagulablestate.However,asthese areduetothepathologyinthematernalenvironment,despitethe abnormal features observed on the CTG trace, the neonatal outcomeappearstobefavourable.Therefore,whenabnormalities areobservedontheCTGtrace,cliniciansshouldaimtocorrectthe pathology related to COVID-19 within the mother, in order to eliminatethedetrimentaleffectsofthematernalenvironmenton Fig.5. ZigZagpattern(exaggeratedvariability)intheCTGtraceofapatientwithCOVID-19infection.

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thefetalheartrate.Wheneverpossible,thisshouldbedonepriorto rapidly transferring the mother for an operativedelivery for a

“pathologicalCTG”.Itishighlylikelythatbycorrectingtheadverse maternalenvironment,theCTGchangessecondarytotheeffectsof COVID-19 infection could be reversed. It is hoped that future researchmayhelpdeterminethetimetakenfortheCTGchangesto resolveafterthecorrectionofadversematernalenvironment.

DeclarationofCompetingInterest

The authors declare that they have no known competing ﬁnancial interests or personal relationships that could have appearedtoinﬂuencetheworkreportedinthispaper.

Acknowledgements

TotheteamofPuertadeHierrohospital(Madrid)andGermans TriasiPujolhospital(Badalona)whokindlyprovideduswiththe CTGs.

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