PubMedCentral-PMC5139811.pdf

(1)

ContentslistsavailableatScienceDirect

Vaccine

jo u rn al h om ep a g e :w w w . e l s e v i e r . c o m / l o c a t e / v a c c i n e

Non-reassuring

fetal

status:

Case

deﬁnition

&

guidelines

for

data

collection,

analysis,

and

presentation

of

immunization

safety

data

Courtney

Gravett

a

_,

_Linda

_O.

_Eckert

b

_,

_Michael

_G.

_Gravett

b

_,

_Donald

_J.

_Dudley

c

_,

Elizabeth

M. Stringer

d

_,

_Tresor

_Bodjick

_Muena

_Mujobu

e

_,

_Olga

_Lyabis

f

_,

_Sonali

_Kochhar

g

_,

Geeta

K. Swamy

h,∗

_,

_The

_Brighton

_{Collaboration}

_{Non-reassuring}

_fetal

_status

_Working

_Group

1

a_Global_Alliance_to_Prevent_Prematurity_and_Stillbirth,_Seattle_Children’s_Hospital,_Seattle,_USA b_University_of_Washington,_USA

c_University_of_Virginia,_USA d_University_of_North_Carolina,_USA

e_University_of_Kinshasa,_The_Democratic_Republic_of_the_Congo f_Sanoﬁ_Pasteur,_Russia

g_Global_Healthcare_Consulting,_India h_Duke_University,_USA

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received9March2016 Accepted15March2016

Keywords:

Non-reassuringfetalstatus Fetaldistress

Fetalintolerancetolabor Adverseevent Immunization Guidelines Casedeﬁnition

1. Preamble

1.1. Needfordevelopingcasedeﬁnitionsandguidelinesfordata collection,analysis,andpresentationfornon-reassuringfetal statusasanadverseeventfollowingimmunization

Non-reassuringfetalstatusisatermusedtodescribesuspected fetalhypoxiaandismeanttoreplacethemoreubiquitousterm “fetaldistress.”Fetaldistress,deﬁnedasprogressivefetalhypoxia and/oracidemiasecondarytoinadequatefetaloxygenation,isa termthatisusedtoindicatechangesinfetalheartpatterns,reduced fetalmovement,fetalgrowthrestriction,andpresenceof meco-niumstainedﬂuid[1].Althoughfetaldistressmaybeassociated

∗_{Corresponding}_author._Tel.:₊₁₉₁₉₆₈₁_5220.

E-mailaddress:contact@brightoncollaboration.org(C.Gravett).

1 _Brighton_{Collaboration}_homepage:_{http://www.brightoncollaboration.org.}

withneonatalencephalopathy,thegenerictermhaspoor predic-tivevalueforneonataloutcomes;mostneonateswillbevigorous andhealthyatbirthdespiteadiagnosisoffetaldistress.Fetal dis-tresscanonlybeobservedindirectly,usuallyviaelectronicfetal heartratemonitoringwhichissubject tohighintra-and inter-observervariabilityindatainterpretation[2–4].Forthisreason, manyexpertsrecommendabandoningthetermfetaldistress,and adoptingthetermnon-reassuringfetalstatustodescribeclinical interpretationoffetalwell-being[1,5,6].Consistentwithcurrent opinionintheﬁeld,werecommenduseofthetermnon-reassuring fetal status for use in monitoring fetal response following immunization.

Non-reassuring fetal status is not an adverse event per se, but rather an indicator of anunderlying conditionresulting in temporaryorpermanentoxygendeprivation tothefetuswhich may lead to fetal hypoxia and metabolic acidosis. Since fetal oxygenation isdependent upon maternaloxygenation and pla-centalperfusion,perturbationsofmaternaloxygenation,uterine

http://dx.doi.org/10.1016/j.vaccine.2016.03.043

(2)

bloodsupply, placental transferorfetal gastransport maylead tofetal hypoxia and non-reassuringfetal status [7].Conditions commonly associated with non-reassuring fetal status include maternalcardiovasculardisease,anemia,diabetes,hypertension, infection,placentalabruption,abnormalpresentationofthefetus, intrauterinegrowthrestrictionand umbilicalcordcompression, amongotherobstetric,maternalorfetalconditions.

Thefetusexperiencesthreestagesofdeteriorationwhenoxygen levelsaredepleted:transienthypoxiawithoutmetabolic acido-sis,tissuehypoxiawithariskofmetabolicacidosis,andhypoxia withmetabolicacidosis[7,8].Fetalresponse tooxygen depriva-tionisregulatedby theautonomousnervoussystem,mediated by parasympathetic and sympathetic mechanisms.The fetus is equippedwithcompensatorymechanismsfortransienthypoxia during labor, but prolonged, uninterrupted fetal hypoxia may lead progressively to acidosis with cell death, tissue damage, organfailureandpotentiallydeath.Inresponsetohypoxia,fetal compensatorymechanismsinclude 1) a decreasein heart rate; 2) a reduction in oxygen consumption secondary to cessation of nonessential functionssuch as gross body movements; 3) a redistributionofcardiacoutputtopreferentiallyperfuseorgans, such as the heart, brain, and adrenal glands; and 4) a switch to anaerobic cellular metabolism [9]. Prolonged fetal hypoxia isassociated withsigniﬁcant perinatalmorbidityand mortality withparticularconcernfor short-and long-term complications includingencephalopathy,seizures,cerebralpalsy,and neurode-velopmentaldelay[10,11].Thefetalheartratechangesmarkedly inresponsetoprolongedoxygendeprivation,makingfetalheart ratemonitoringapotentiallyvaluableandcommonlyusedtoolfor assessingfetaloxygenationstatusinrealtime.Non-reassuringfetal heartratepatternsareobservedin approximately15%oflabors

[12].

The two most common methods of monitoring fetal heart rate are cardiotocography (CTG) and intermittent auscultation. In highresourcesettings, continuouselectronicfetal heart rate monitoring,viacardiotocographyisthemostprevalentmethod. ContinuousCTGinvolvesmonitoringthefetalheartrateand uter-inecontractilitysimultaneouslytodetectfetalheartratepatterns associatedwithdeﬁcientfetaloxygensupply[8].NormalCTG trac-ingsarecharacterizedby1)stablebaselinefetalheartrate(FHR) of120–160beatsperminute(bpm),2)FHRvariabilitybetween5 and25bpmaboveandbelowbaselineFHR,and3)periodicchanges inthebaselineFHR(accelerationsabovebaselineordecelerations belowbaseline)[13].Whileaccelerationsareassociatedwithfetal well-being,decelerations,especially prolongedbradycardia, late decelerations,andseverevariabledecelerationsareindicativeof fetalstressandshouldpromptthecliniciantoevaluateand initi-ateintrauterineresuscitationwithconsiderationfordeliveryofthe fetusasindicated.Abnormalfetalheartratepatternshavehigh sen-sitivity,butlowspeciﬁcityandlowpredictivevaluetodiscriminate betweenneonateswithorwithoutmetabolicacidosis[14].Whilea normalfetalheartratepatternisusuallyindicatesreassuringfetal status,anabnormalfetalheartratepatterndoesnotnecessarily equatewithhypoxiaoracidosis.

AlthoughcontinuousCTGistheacceptedstandard ofcarein mosthighresourcesettings,useofcontinuousCTGinlowresource setting is not feasible or recommended [15]. Continuous CTG requirescostlyequipment,expertmaintenance,supplychainfor consumables,and extensivetrainingand highlevel oftechnical skilltointerprettracings.Additionally,continuousCTGcanlead tohigherratesofun-necessaryinterventionsthatmaypose addi-tionalrisktomothersinsettingswheresafecesareandeliveryis notreadilyavailable[16].

InsettingswhereCTGisunavailable,intermittentauscultationis recommendedforalllaboringparturients[17].Intermittent auscul-tation(IA)involvesassessingthefetalheartrateatpredetermined

intervals witheither a fetal stethoscope, or handheld Doppler. AbnormalheartrateﬁndingsbyIAindicative ofnon-reassuring fetal status include prolongedfetal tachycardia or bradycardia, presence of repetitive or prolonged decelerations, and uterine tachysystole(morethan5uterinecontractionsina10minperiod). ThereisnoevidencethatIAperformsworsethanCTGin reduc-ingmorbidityandmortalityassociatedwithfetalacidosis.Studies comparingCTGtoIAshownoreductionintheriskofperinataldeath orcerebralpalsy[16,18].Intermittentauscultation,characterized bylowcostandlowtechnologyequipment,ismorefeasiblethan CTGinlowresourcesettings.However,itrequiresahighlevelof trainingandskill,frequentinteractionbetweenpatientandhealth careprovider,anddoesnotprovideassophisticatedalevelof infor-mationthatmaybeneededinhighriskpopulations.

Severaleffortstodevelopstandardsfordefiningnon-reassuring fetal statushave beenmadeinresponse toconfusionin recog-nizingand managingfetal heartratepatternsindicative offetal compromise.Themostwidelyacceptedstandardsforclassifying non-reassuringfetalheartratescomefromtheNationalInstitute ofChildHealthandHumanDevelopment(NICHD)intheUnited StatesandTheInternationalFederationofGynecologyand Obstet-rics(FIGO)(Table1).In1997,NICHDconvenedaworkshopwith theexpresspurposeofdeveloping“astandardizedandrigorously, unambiguouslydescribedsetofdefinitionstoquantitatefetalheart monitoring[19].Theworkshopproducedstandardized nomencla-tureforcharacterizingfetalheartratepatterns,whichwaswidely adoptedbywesternobstetricsocieties.In2008,afollow-up work-shopincludingtheSocietyfor MaternalFetalMedicineandthe American College of Obstetricians and Gynecologists was con-vened,resultinginthedevelopmentofathree-tieredclassification systemoffetalheartratepatternstoguidemanagementoffetal compromise[20,21].TheWorkingGroupusestheseguidelinesas abasisforthehighestlevelofcertaintyfordefiningacaseof non-reassuringfetalstatus.TheNICHDguidelinesarelimitedindefining fetalstatusinallsettingsastheyareonlyintendedforusewithCTG. Asecondimportantsetofguidelines,moreapplicabletoall sett-ingswasfirstintroducedbyFIGOin1986andwasupdatedin2015

[17,22–26].TheFIGOguidelinesaretheonlyguidelineswithbroad

internationalconsensus,andaresimpliﬁed,withlessemphasison decelerationscomparedtotheNICHDguidelineswhenevaluating CTGtracings.FIGO alsoprovidesrecommendationsfor evaluat-ingandcategorizingfetalheartrateviaintermittentauscultation, makingthese guidelinesmore useful forlow resource settings. WhenCTGisnotavailable,theWorkingGrouprecommends incor-poratingheart ratepatternsfromIAintothecasedeﬁnitionfor non-reassuringfetalstatus.

Littleisknownabouttherelationshipsamongnon-reassuring fetalstatusandmaternalimmunization,especiallyinLMICwhere fetalassessmentmaynotberoutine.Therearefewpublications reportingonfetalstatusfollowingimmunization;thosethatdoare casereports orsmallseriesthathavefrequentlynotused stan-dardizeddefinitions[27–29].Possiblereasonsthatimmunization surveillancehasfailedtoreportoncasesofnon-reassuringfetal statusincludethefactthatacausalrelationshipisrarelyifever established,thelowpredictivevalueofnon-reassuringfetalstatus topredictadverseneonataloutcomes,thedifficultyoftemporally associatingvaccinationwithfetalstatus,asthetwoeventsarelikely tobemonitoredatverydifferenttime-pointsinpregnancy,the failuretoincludefetalstatusasanoutcomevariablein immuniza-tiontrialsorsurveillance.Estimatesoftheincidenceoffetalstatus followingmaternalimmunizationhavebeenhamperedbylimited dataandlackofstandardcasedefinitions.

(3)

Table1

ComparisonofNICHDandFIGOguidelinesforinterpretationoffetalheartrateviacontinuouscardiotocography.FHR=fetalheartrate,bpm=beatsperminute.

NICHDthree-tierfetalheartrateinterpretationsystem(2008) FIGOconsensusguidelinesonintrapartumfetalmonitoringCTGtracing classiﬁcations(2015)

FHRdesignation Description FHRdesignation Description

CategoryItracing Baselineheartrate: 110–160bpm

Variability: Moderate

Decelerations: Nolatedecelerations

Earlydecelerationsmaybepresentorabsent Accelerationsmaybepresentorabsent

Normal Baselineheartrate:

110–160bpm

Variability: 5–25bpm

Decelerations:

Norepetitivedecelerations

CategoryIItracing FHRtracingdoesnotmeetcriteriaforcategoryI orcategoryIII

Suspicious Lackingatleastonecharacteristicofnormality, butwithnopathologicfeatures

CategoryIIItracing 1)Variability:

AbsentFHRbaselinevariability ANDanyofthefollowing: Recurrentlatedecelerations Recurrentvariabledecelerations Bradycardia(FHR<110bpm) OR

2)Sinusoidalpattern

Pathological Baselineheartrate:

<100bpm

Variability:

Reducedvariabilityfor>15min Increasedvariabilityfor>30min OR

Sinusoidalpatternfor>30min

Decelerations:

Repetitivelateorprolongeddecelerationsduring >30minor20minifreducedvariability OR

Oneprolongeddecelerationwith>5min

interpretation and promote the scientiﬁc understandingof the event.

1.2. Methodsforthedevelopmentofthecasedeﬁnitionand guidelinesfordatacollection,analysis,andpresentationfor non-reassuringfetalstatusasanadverseeventsfollowing immunization

Following the process described in the overview paper as well as on the Brighton Collaboration Website http://www.

brightoncollaboration.org/internet/en/index/process.html, the

BrightonCollaborationFetalDistressWorkingGroupwasformedin 2015andincludedmembersofclinicalandacademic,aswellas publichealthbackground.Membershaveexperienceinhighand lowresourcessettings.Thecompositionoftheworkingand refer-encegroupaswellasresultsoftheweb-basedsurveycompleted bythereferencegroupwithsubsequentdiscussionsintheworking groupcan be viewedat: http://www.brightoncollaboration.org/

internet/en/index/workinggroups.html.

Toguidethedecision-makingforthecasedefinitionand guide-lines, literature was searched using Medline, Embase and the CochraneLibraries, includingtheterms vaccines,vaccination,or immunization(ortermsbeginningwithvaccin-,immuni-,inocular -) and non-reassuring fetal status, fetal distress, intrapartum fetal asphyxia, non-reassuring fetal heart rate, fetal compromise, fetal hypoxia,fetalintoleranceoflabor.Toidentifycasedefinitionsand measuresoffetaldistressinallsettings,theabovesearchterms were also searched with the terms developing country or low resourcesetting.Thesearchwaslimitedtopublicationswrittenin Englishwithhumansubjects.Thesearchresultedinthe identifi-cationof105references.Allabstractswerescreenedforpossible reportsofnon-reassuringfetalstatus,orfetaldistress,following immunization.Eighteenarticleswithpotentiallyrelevantmaterial werereviewedinmoredetail,inordertoidentifystudiesusingcase definitionsor,intheirabsence,providingclinicaldescriptionsof thecasematerial.Thisresultedinadetailedsummaryof2articles, includinginformation onthestudytype, thevaccine, the diag-nosticcriteriaorcasedefinitionputforth,thetimeintervalsince immunization,andothersymptoms.Multiplegeneralmedicaland obstetrictextbooksandobstetricsocietypublicationswerealso searched.

Mostpublicationsweresinglecasereports.Theterminologyand casedefinitionswereinconsistentamongstudies,withveryfew reportingcasedefinitionsatall.Aninventorycomprising5relevant casedefinitionsofnon-reassuringfetalstatuswasmadeavailable toworkinggroupmembers.

1.3. Rationaleforselecteddecisionsaboutthecasedeﬁnitionof non-reassuringfetalstatusasanadverseeventfollowing immunization

1.3.1. Thetermnon-reassuringfetalstatus

Several related terms are commonly used to describe fetal statusincluding“fetaldistress”,“birthasphyxia”,and“fetal intol-erance tolabor”. The Working Groupwas initially tasked with developing a case deﬁnitionfor “fetaldistress”,but for reasons previouslydiscussed,thistermwasabandonedandreplacedwith “non-reassuringfetalstatus”.TheWorkingGroupchosenottouse theterm“fetalintoleranceoflabor”becausespecifyingsucha nar-rowtimeframefailstocapturenon-reassuringfetalstatusinthe antepartumperiodpriortotheonsetoflabor.

Indevelopingacasedefinitionfornon-reassuringfetalstatus, theWorkingGroupincludedonlycasesforwhichfetalheartrate canbeascertained.Theinabilitytomeasurefetalheartratedoes notpermitadiagnosisofnon-reassuringfetalstatusatany accept-ablelevelof diagnosticcertainty.Withinthedefinitioncontext, however,thethreediagnosticlevelsmustnotbemisunderstoodas reflectingdifferentgradesofclinicalseverity.Theyinsteadreflect diagnosticcertainty(seebelow).AllLevelsareconsidered accept-abledependingontheavailabilityofdiagnostictoolsineachsite.

1.3.2. Theterm“birthasphyxia”

(4)

birthasphyxia,theWorkingGroupdidnotincludethisterminthe developingthecasedeﬁnition.

1.3.3. Formulatingacasedefinitionthatreflectsdiagnostic certainty:weighingspecificityversussensitivity

Asdetectionofnon-reassuringfetalstatusisdependentonthe typeoftechnologyused,andvariableinterpretationoffetalheart ratetracings,theevidencedocumentingfetalstatusmayvary con-siderably.Thecasedefinitionhasbeenformulatedsuchthatthe LevelIdefinitionismaximallyspecificforthecondition,andrelies onthehighestlevelofevidenceandtechnologyavailabletodetect theevent.Two additionaldiagnostic levelshave beenincluded in the definition, offering a stepwise decrease in technological requirements,inanattempttobeinclusiveofsettingswithless sophisticatedmeansofdetectingfetalwell-being.Inthisway,our intentisthatallpossiblecasesofnon-reassuringfetalstatusinall settingscanbecaptured.

Importantly,thegradingofdefinitionlevelsisbasedentirely ondiagnosticcertainty,notclinicalseverityofanevent.Thus, a clinicallysevereeventmayappropriatelybeclassifiedasLevelTwo orThreeratherthanLevelOneifitcouldreasonablybedueto non-reassuringfetalstatus.Detailedinformationabouttheseverityof theeventshouldadditionallyalwaysberecorded,asspecifiedby thedatacollectionguidelines.

1.3.4. Themeaningof“suddenonset”and“rapidprogression”in thecontextofnon-reassuringfetalstatus

Theterm“suddenonset”referstoaneventthatoccurred unex-pectedlyandwithoutwarningleadingtoamarkedchangein a woman’spreviouslystablecondition.

Theterm“rapidprogression”isaconventionalclinicalterm.An exacttime-frameshouldnotbeofferedsince thiscouldreferto awiderangeofsignsandsymptomswithoutascientiﬁcevidence base.Usinganarbitrarilyrestrictivesetpointmightbiasfuturedata collectionunnecessarily.

1.3.5. Rationaleforindividualcriteriaordecisionmaderelatedto thecasedeﬁnition

1.3.5.1. Radiologyfindings. Dopplersonographyutilizesultrasound tomeasure the changein frequency of energy wave transmis-sionwhen relative motionoccurs between thesource and the observer. Doppler sonography is used for non-invasive assess-mentofcirculationinmanyclinicalconditions.Inobstetrics,fetal umbilical artery (UA) doppler velocimetry provides a noninva-sivemeasureofthefetoplacentalhemodynamicstate.Abnormal UADopplerindicesindirectly reflectimpedanceof downstream circulation and have been associated with fetal hypoxia, fetal acidosis, and adverse perinatal outcomes[30–33]. Randomized trialsintegrating UADoppler velocimetryintoantepartumfetal surveillanceofhighriskpregnancieshavedemonstratedefficacy inthesettingoffetalgrowthrestrictionorpreeclampsia[34].In additiontoUADoppler,middlecerebralartery(MCA)Doppleris usedin thesettingofsuspectedfetal anemia.ObstetricDoppler imaging requires a high level of training and technical ultra-soundequipment, is not usually performed duringlabor when CTGisthepreferredand superiormodalitytoassessfetal well-being, and is not suitable for low resource settings. For these reasons,theWorkingGroupdecidedthatDopplersonographydoes notmeritinclusioninthecasedefinitionofnon-reassuringfetal status.

1.3.5.2. Laboratoryﬁndings.

1.3.5.2.1. Fetal blood sampling. Discontinuous fetal blood samplinghasbeenused tomonitorfetalacid–base metabolism intheintrapartumperiod,whenfetalheartratetracingsare sug-gestiveofhypoxicinsult.Fetalbloodsamplingallowsanalysisof

pH,lactateconcentrations,partialpressureoxygen(pO2)and car-bondioxide(pCO2)fromwhichbaseexcessiscalculated(BE).Fetal bloodpHlessthanorequalto7.20,pO2>65mmHg,andBE>−9.8, andlactate>4.8mmol/Lindicatemetabolicacidosisrequiring inter-ventiontorestoreadequateoxygensupplytothefetus[26,35,36]. Fetalbloodsamplingisproblematicindiagnosingnon-reassuring fetalstatusforseveralreasons.Fetalbloodsamplingisan inva-siveanduncomfortableprocedure,requiringrupturedmembranes andincisionintothefetalscalptosampleblood,thusexposingthe fetustoriskofinfection[37].Theprocedurerequiresahighlevel oftrainingandtechnicallaboratoryequipmentincludingrealtime bloodgasanalysis[38].Fetalbloodsamplingisseldomperformed inhighresourcesettingsandisnotsuitableforlowresource sett-ings.Forthesereasons,theWorkingGroupconcludedthatfetal bloodsamplingdoesnotmeritinclusioninthecasedeﬁnitionof non-reassuringfetalstatus.

1.3.5.2.2. Umbilicalcordbloodsampling. Immediately follow-ing birth, metabolic acidosis in the fetus can be detected by analyzingarterialandvenousbloodfromtheumbilicalcord.Cord bloodanalysisforpH,pCO2,andthederivativebicarbonate(HCO3) andbasedeficit(BD)valuesishighlyrecommendedinallcases ofsuspectedfetalhypoxia/acidosis.Metabolicacidosisisdefined asthemeasurementoftheumbilicalarterybloodpH<7.00and BD>12mmol/L[39].TheWorkingGroupincludedcordblood anal-ysisaspartofthecasedefinitionfornon-reassuringfetalstatusas theonlymethodtoobjectivelyascertaintheoccurrenceoffetal hypoxia/acidosisimmediatelypriortobirth.Recognizingthatnot allsettingswillbeequippedtoperformcordbloodanalysis,the workinggroupdidnotinclude thesecriteria acrossalllevelsof diagnosticcertainty.

1.3.5.2.3. Pathologyfindings:autopsy. Thetermnon-reassuring fetalstatusdoesnothavehighpositivepredictivevalueforneonatal morbidityandmortality.Furthermore,non-reassuringfetalstatus doesnotproducepathognomonic post-mortemfeatures. There-fore,post-mortemfindingsarenotincludedinthecasedefinition ofnon-reassuringfetalstatus.

1.3.5.2.4. Physicalfindings. TheAPGARscoreisastandardized assessmentoftheneonate’sphysiologicalconditionimmediately followingbirth,aswelltheneonatalresponsetoresuscitation,if required[40].TheAPGARscoreevaluatescolor,heartrate,reflexes, muscletone,andrespiration.LowAPGARscoresmaybeobserved asaresultofintrapartumfetalcompromise.Fetalhypoxicinsult mayprecedelowAPGARscoreswhenthehypoxicinjuryis suffi-cienttoaffectthepulmonary,neurologicorcardiovascularsystem ofthefetus,butAPGARscoresalonearenotsufficientlysensitive orspecificfordiagnosing fetalhypoxiaoracidosis andareonly weaklyassociatedwithnon-reassuringfetal heartratepatterns. Thereisalowcorrelationbetweenlow1and5minAPGARscores andmetabolicacidosis[41,42],butmanyotherconditions, includ-ingneonatalsepsis, trauma,maternaldruguse, fetal anomalies andgestationalagethatmaycontributetolowAPGARscoresas well,makingcausalinferenceproblematic[8].Furthermore,APGAR scoringinnotwellstandardized,andisinconsistentlyusedinthe globalsetting.TheWorkingGroupdidnotincludeAPGARscores aspartofthecasedefinitionfornon-reassuringstatus,butwedo recommendthat1,5,and10minAPGARscoresbecollectedfor vaccinemonitoringandsurveillancepurposes.

(5)

immediatedeliveryofacompromisedfetus.Treatmentresponse willvarydependingontheseverityoffetalheartratepatterns,the durationofalteredheartrate,theclinician’sassessmentofthese factors,andtheresourcesavailableforintervention.

1.3.7. Timingpostimmunization

Speciﬁctimeframesforonsetofsymptomsfollowing immu-nizationarenotincludedforthefollowingreasons:

Timefromimmunizationwasnotincludedfordeﬁning non-reassuringfetalstatusbecausefetalstatusmaychangeatunknown periodsintheante-orintra-partumperiods.Althoughwe recog-nizefetalstatusismostlikelytobeobservedintheintrapartum periodwhenfetalheartratemonitoringisdeployed,wedidnot wanttonarrowthetime frametotheexclusion offetal events intheantepartumperiod.TheWorkingGroupdoesrecommend thatthetimeelapsedfromvaccineadministrationtoobservation ofnon-reassuringfetalstatusberecordedasacriticalvariablefor datacollection.

Wepostulatethatadeﬁnitiondesignedtobeasuitabletoolfor testingcausalrelationshipsrequiresascertainmentoftheoutcome (e.g.non-reassuringfetalstatus)independentfromtheexposure (e.g.immunizations).Therefore,toavoidselectionbias,a restric-tivetimeintervalfromimmunizationtoonsetofnon-reassuring fetal status shouldnot beanintegral part ofsucha deﬁnition. Instead,wherefeasible,detailsofthisintervalshouldbeassessed andreportedasdescribedinthedatacollectionguidelines.

Further,non-reassuringfetal statusoften occurs outsidethe controlledsetting ofaclinicaltrialorhospital.In somesettings determiningacleartimelineoftheeventmaybeimpossible, par-ticularly in less developed or rural settings. In order to avoid selectingagainstsuchcases,theBrightonCollaborationcase deﬁ-nitionavoidssettingarbitrarytimeframes.

1.4. Guidelinesfordatacollection,analysisandpresentation

Asmentionedintheoverview,thecasedeﬁnitionis accompa-niedbyguidelineswhicharestructuredaccordingtothestepsof conductingaclinicaltrial,i.e.datacollection,analysisand presenta-tion.Neithercasedeﬁnitionnorguidelinesareintendedtoguideor establishcriteriaformanagementofillinfants,children,oradults. Bothweredevelopedtoimprovedatacomparability.

1.5. Periodicreview

SimilartoallBrightonCollaborationcasedefinitionsand guide-lines,reviewofthedefinitionwithitsguidelinesisplannedona regularbasis(i.e.everythreetofiveyears)ormoreoftenifneeded.

2. Casedeﬁnitionofnon-reassuringfetalstatus

Level1ofdiagnosticcertainty

•CategoryIIIfetalheartratetracingsdetectedviacontinuous car-diotocographyasdeﬁnedbyNICHD[20]

◦AbsentbaselinefetalheartratevariabilityANDanyofthe follow-ing:

-recurrentlatedecelerations -recurrentvariabledeceleration -bradycardia(<110bpm)

OR

◦Sinusoidalpattern AND

•Umbilicalcordbloodanalysisconsistentwithmetabolicacidosis (pH<7.0andBasedeﬁcit>12mmol/L)

•CategoryIIIfetalheartratetracingsdetectedviacontinuous car-diotocographyasdeﬁnedbyNICHD[20]

◦AbsentbaselinefetalheartratevariabilityANDanyofthe follow-ing:

-recurrentlatedecelerations -recurrentvariabledeceleration -bradycardia(<110bpm)

OR

◦Sinusoidalpattern

•Fetalheartpatterndetectedviaintermittentauscultation sugges-tiveoffetalhypoxia[17]

◦BaselineFHR<110bpmor>160bpm

◦Presenceofrepetitiveorprolonged(>3min)decelerations

◦Morethan5contractionsina10minperiod

Majorandminorcriteriausedinthecasedeﬁnitionof

non-reassuringfetalstatus

Majorcriteria

Cardiovascular CTG:

CategoryIIIheart Ratetracing

•AbsentbaselinefetalheartratevariabilityANDanyofthe follow-ing:

-recurrentlatedecelerations -recurrentvariabledeceleration -bradycardia<110beats/min

OR

•Sinusoidalpattern

IA: Abnormal Findings

•FHR<110bpmOR>160bpm

•Presenceofrepetitiveorprolongeddecelerations

•Morethan5contractionsina10minperiod

Minorcriteria

Laboratory

•CordbloodpH≤7.0

•Cordbloodbasedeﬁcit≥12mmol

3. Guidelinesfordatacollection,analysisandpresentation

ofnon-reassuringfetalstatus

The consensus of the BrightonCollaboration Non-Reassuring Fetal DistressWorkingGroupfor non-reassuringfetalstatus was torecommendthefollowingguidelinestoenablemeaningfuland standardizedcollection,analysis,andpresentationofinformation aboutnon-reassuringfetalstatus.However,implementationofall guidelinesmight notbepossiblein allsettings.Theavailability ofinformationmayvarydependinguponresources,geographical region,andwhetherthesourceofinformationisaprospective clin-icaltrial,apost-marketingsurveillanceorepidemiologicalstudy, or an individual report of non-reassuring fetal status. Also, as explainedinmoredetailintheoverviewpaperinthisvolume,these guidelineshavebeendevelopedbythisworkinggroupforguidance

(6)

only,andarenottobeconsideredamandatoryrequirementfordata collection,analysis,orpresentation.

3.1. Datacollection

Theseguidelinesrepresentadesirablestandardforthe collec-tionofdataonavailability followingimmunizationtoallowfor comparabilityofdata,andarerecommendedasanadditiontodata collectedforthespeciﬁcstudyquestionandsetting.Theguidelines arenotintendedtoguidetheprimaryreportingofnon-reassuring fetalstatustoasurveillancesystemorstudymonitor.Investigators developingadatacollectiontool basedonthesedatacollection guidelinesalsoneedtorefertothecriteriainthecasedeﬁnition, which are not repeated in these guidelines. The Brighton Col-laborationhas developed guidelines for datacollection https:// brightoncollaboration.org/public/resources/standards/guidelines. html;anddatacollectionformshttps://brightoncollaboration.org/

public/resources/data-collection-forms.html.

Guidelines numbersbelow have been developed to address dataelementsforthecollectionofadverseeventinformationas speciﬁedin generaldrug safety guidelinesby theInternational ConferenceonHarmonizationofTechnicalRequirementsfor Reg-istration ofPharmaceuticals for HumanUse (43), and theform forreportingofdrugadverseeventsbytheCouncilfor Interna-tionalOrganizationsofMedicalSciences(44).Thesedataelements include anidentiﬁable reporter and patient, one or more prior immunizations,and adetaileddescriptionoftheadverseevent, inthis case,of non-reassuringfetal statusfollowing immuniza-tion.Theadditionalguidelineshavebeendevelopedasguidancefor thecollectionofadditionalinformationtoallowforamore com-prehensiveunderstandingofnon-reassuringfetalstatusfollowing immunization.

3.1.1. Sourceofinformation/reporter

Forallcasesand/orallstudyparticipants,asappropriate,the followinginformationshouldberecorded:

1)Dateofreport.

2)Name and contact information of person reporting2 _and/or diagnosing the non-reassuring fetal status as speciﬁed by country-speciﬁcdataprotectionlaw.

3)Nameandcontactinformationoftheinvestigatorresponsible forthepatient,asapplicable.

4)Relationtothepatient(e.g.,immunizer[clinician,nurse],family member[indicaterelationship],other).

3.1.2. Vaccinee/Control

3.1.2.1. Demographics. Forallcasesand/orallstudyparticipants, asappropriate,thefollowinginformationshouldberecorded:

5)Case/studyparticipantidentifiers(e.g.firstnameinitialfollowed bylastnameinitial)orcode(orinaccordancewith country-specificdataprotectionlaws).

6)Dateofbirth,age,andsex.

3.1.2.2. Clinical and immunization history. For all cases and/or allstudyparticipants,as appropriate,thefollowinginformation shouldberecorded:

7)Past medical history, including hospitalizations, underlying diseases/disorders, pre-immunization signs and symptoms

2 _If_the_reporting_center_is_different_from_the_vaccinating_center,_appropriate_and timelycommunicationoftheadverseeventshouldoccur.

includingidentiﬁcationofindicatorsfor,ortheabsenceof,a his-toryofallergytovaccines,vaccinecomponentsormedications; foodallergy;allergicrhinitis;eczema;asthma.

8)Anymedicationhistory (other than treatmentfor theevent described)prior to,during,andafterimmunizationincluding prescriptionandnon-prescriptionmedicationaswellas med-ication or treatment with long half-life or long term effect. (e.g.immunoglobulins,bloodtransfusionand immunosuppress-ants).

9)Immunization history (i.e. previous immunizations and any adverse event following immunization (AEFI)), in particular occurrenceofnon-reassuringfetalstatusafteraprevious immu-nization.

3.1.3. Detailsoftheimmunization

Forallcasesand/orallstudyparticipants,asappropriate,the followinginformationshouldberecorded:

10)Dateandtimeofimmunization(s).

11)Descriptionofvaccine(s)(nameofvaccine,manufacturer,lot number,dose(e.g.0.25mL,0.5mL,etc.),compositionofany diluentadministeredseparatelyoraddedtothevaccine,and numberofdoseifpartofaseriesofimmunizationsagainstthe samedisease).

12)Theanatomicalsites(includingleftorrightside)ofall immun-izations(e.g.vaccineAinproximalleftlateralthigh,vaccineB inleftdeltoid).

13)Routeandmethodofadministration(e.g.intramuscular, intra-dermal,subcutaneous, and needle-free (including type and size),otherinjectiondevices).

14)Needlelengthandgauge.

3.1.4. Theadverseevent

15)Forallcasesatanylevelofdiagnosticcertaintyandforreported eventswithinsufficientevidence,thecriteriafulfilledtomeet thecasedefinitionshouldberecorded.

Speciﬁcallydocument:

16)Clinicaldescriptionofsignsandsymptomsofnon-reassuring fetalstatus,andiftherewasmedicalconﬁrmationoftheevent (i.e.patientseenbyphysician).

17)Date/timeofonset,3_ﬁrst_observation4_and_diagnosis,5_end_of episode6_and_ﬁnal_outcome.7

18)Concurrent signs, symptoms, and diseases (e.g. maternal conditions, known fetal conditions, abnormalities of labor, abnormalitiesofdelivery).

19)Timeintervalsinceimmunization 20)Measurement/testing

•Valuesandunitsofroutinelymeasuredparameters(paper trac-ingsofEFM)(e.g.temperature,blood pressure)–inparticular thoseindicatingtheseverityoftheevent;

3_The_date_and/or_time_of_onset_is_deﬁned_as_the_time_post_{immunization,}_when theﬁrstsignorsymptomindicativefornon-reassuringfetalstatusoccurred.This mayonlybepossibletodetermineinretrospect.

4_The_date_and/or_time_of_ﬁrst_observation_of_the_ﬁrst_sign_or_symptom_indicative fornon-reassuringfetalstatuscanbeusedifdate/timeofonsetisnotknown.

5_The_date_of_diagnosis_of_an_episode_is_the_day_post_immunization_when_the_event metthecasedeﬁnitionatanylevel.

6_The_end_of_an_episode_is_defined_as_the_time_the_event_no_longer_meets_the_case definitionatthelowestlevelofthedefinition.

7_E.g._recovery_to_{pre-immunization}_health_status,_spontaneous_resolution, ther-apeuticintervention,persistenceoftheevent,sequelae,death.

(7)

•Methodof measurement (e.g. cardiotocograph,doppler, feto-scope,etc.Includeunitsoffetalhearttrace(1cm/min,etc.));

•Resultsoflaboratoryexaminations,surgicaland/orpathological ﬁndingsanddiagnosesifpresent(cordbloodgases,pH)

•APGARSat1,5,10minforneonate

•Occurrenceofneonatalseizures

Treatmentgiven fornon-reassuringfetalstatus,especially spec-ifywhatanddosing.Outcome6_at_last_{observation.Objective}_clinical evidencesupportingclassiﬁcationoftheeventas“serious”8_(e.g. 10minAPGARof3orless;presenceofneonatalseizures,newborn resuscitation required)Exposures other than the immunization 24h before and after immunization (e.g. food, environmental, placentalabruption,abdominaltrauma)consideredpotentially rel-evanttothereportedevent.Neonataldisposition

•Gestationalage

•Birthweight

•Birthoutcome(e.g.,livebirth,stillbirth)

•Delivery method (e.g. spontaneous vaginal, assisted vaginal, cesareansection)

•1,5and10minAPGARscores

•Presenceofmeconium

3.1.5. Miscellaneous/General

26)Theduration ofsurveillance for non-reassuring fetal status shouldbepredeﬁnedbasedon

•Biologiccharacteristicsofthevaccinee.g.liveattenuatedversus inactivatedcomponentvaccines;

•Biologiccharacteristicsofthevaccine-targeteddisease;

•Biologiccharacteristicsofnon-reassuringfetalheartrate includ-ingpatternsidentiﬁedinprevioustrials(e.g.early-phasetrials); and

•Biologiccharacteristicsofthevaccinee(e.g.nutrition,underlying diseaselikeimmunodepressingillness).

27)Theduration offollow-up reportedduring thesurveillance period should be predeﬁned with continued follow-up to resolution oftheevent. For non-reassuringfetal status,the follow-upperiodshouldcontinuethroughtheante-and intra-partumperiods,aschangesinfetalwell-beingcanoccuratany pointinpregnancy.

28)Methodsofdatacollectionshouldbeconsistentwithinand betweenstudygroups,ifapplicable.

29)Follow-upofcasesshouldattempttoverifyandcompletethe informationcollectedasoutlinedindatacollectionguidelines 1–24.

30)Investigators of patients with non-reassuring fetal status shouldprovideguidancetoreporterstooptimizethequality andcompletenessofinformationprovided.

31)Reports of non-reassuring fetal status should be collected throughoutthestudyperiod regardlessofthetime elapsed betweenimmunizationandtheadverseevent.Ifthisisnot fea-sibleduetothestudydesign,thestudyperiodsduringwhich safetydataarebeingcollectedshouldbeclearlydeﬁned.

8_An_AEFI_is_deﬁned_as_serious_by_{international}_standards_if_it_meets_one_or_more_of thefollowingcriteria:1)itresultsindeath,2)islife-threatening,3)itrequires inpa-tienthospitalizationorresultsinprolongationofexistinghospitalization,4)results inpersistentorsigniﬁcantdisability/incapacity,5)isacongenitalanomaly/birth defect,6)isamedicallyimportanteventorreaction.

3.2. Dataanalysis

Thefollowingguidelinesrepresentadesirablestandardfor anal-ysisofdataonnon-reassuringfetalstatustoallowforcomparability ofdata,andarerecommendedasanadditiontodataanalyzedfor thespeciﬁcstudyquestionandsetting.

32)Reportedeventsshouldbeclassifiedinoneofthefollowing five categories includingthe three levelsof diagnostic cer-tainty.Eventsthatmeetthecasedefinitionshouldbeclassified accordingtothelevelsofdiagnosticcertaintyasspecifiedin thecasedefinition.Eventsthatdonotmeetthecasedefinition shouldbeclassifiedintheadditionalcategoriesforanalysis.

Eventclassiﬁcationin5categories9

Eventmeetscasedeﬁnition

1)Level1:Criteriaasspeciﬁedinthenon-reassuringfetalstatus casedeﬁnition

Eventdoesnotmeetcasedeﬁnition

Additionalcategoriesforanalysis

4)Reportednon-reassuringfetalstatuswithinsufﬁcientevidence tomeetthecasedeﬁnition10

5)Notacaseofnon-reassuringfetalstatus

33)The interval between immunization and reported

non-reassuringfetal statuscouldbedefined asthedate/timeof immunizationtothe date/timeofonset2 _of _the_first symp-tomsand/orsignsconsistentwiththedefinition.Iffewcases arereported,theconcretetimecoursecouldbeanalyzedfor each;foralargenumberofcases,datacanbeanalyzedinthe followingincrements:

Subjectswithnon-reassuringfetalstatusbyintervalto

pre-sentation

Interval* _Number

<1hafterimmunization 1h–<7daysafterimmunization 7days–<30daysafterimmunization >30days–deliveryafterimmunization

Total

34)Thedurationofapossiblenon-reassuringfetalstatuscouldbe analyzedastheintervalbetweenthedate/timeofonset1_of_the

9_To_determine_the_appropriate_category,_the_user_should_first_establish,_whether areportedeventmeetsthecriteriaforthelowestapplicablelevelofdiagnostic certainty,e.g.Levelthree.Ifthelowestapplicablelevelofdiagnosticcertaintyof thedefinitionismet,andthereisevidencethatthecriteriaofthenexthigherlevel ofdiagnosticcertaintyaremet,theeventshouldbeclassifiedinthenextcategory. Thisapproachshouldbecontinueduntilthehighestlevelofdiagnosticcertainty foragiveneventcouldbedetermined.Majorcriteriacanbeusedtosatisfythe requirementofminorcriteria.Ifthelowestlevelofthecasedefinitionisnotmet,it shouldberuledoutthatanyofthehigherlevelsofdiagnosticcertaintyaremetand theeventshouldbeclassifiedinadditionalcategoriesfourorfive.

(8)

firstsymptomsand/orsignsconsistentwiththedefinitionand theendofepisode5_and/or_final_outcome.6_Whatever_start_and endingareused,theyshouldbeusedconsistentlywithinand acrossstudygroups.

35)Ifmorethanonemeasurementofaparticularcriterionistaken andrecorded,thevaluecorrespondingtothegreatest magni-tudeoftheadverseexperiencecouldbeusedasthebasisfor analysis.Analysismayalsoincludeothercharacteristicslike qualitativepatternsofcriteriadeﬁningtheevent.

36)Thedistributionofdata(asnumeratoranddenominatordata) couldbeanalyzed inpredeﬁned increments(e.g.measured values,times),whereapplicable.Incrementsspeciﬁedabove shouldbeused.Whenonlyasmallnumber ofcasesis pre-sented,therespectivevaluesortimecoursecanbepresented individually.

37)Data onnon-reassuring fetal status obtained fromsubjects receivingavaccineshouldbecomparedwiththoseobtained from an appropriately selected and documented control group(s)toassessbackgroundratesofhypersensitivityin non-exposedpopulations,andshouldbeanalyzedbystudyarmand dosewherepossible,e.g.inprospectiveclinicaltrials.

3.3. Datapresentation

Theseguidelines representa desirable standard for the pre-sentationand publicationofdataonnon-reassuringfetal status followingimmunization toallowfor comparabilityofdata, and arerecommendedasanadditiontodatapresented forthe spe-ciﬁcstudyquestionandsetting.Additionally,werecommendedto referringtoexistinggeneralguidelinesforthepresentationand publicationof randomizedcontrolledtrials,systematic reviews, andmeta-analysesofobservationalstudiesinepidemiology(e.g. statementsof ConsolidatedStandardsofReporting Trials (CON-SORT),of Improving thequality of reports of meta-analyses of randomized controlled trials (QUORUM), and of Meta-analysis OfObservationalStudiesinEpidemiology(MOOSE),respectively) (45–47).

38)Allreportedeventsofnon-reassuringfetalstatusshouldbe presentedaccordingtothecategorieslistedinguideline 31 (verifynumbers).

39)Dataonpossiblenon-reassuringfetalstatuseventsshouldbe presentedinaccordancewithdatacollectionguidelines1–24 (verifynumbers) anddataanalysisguidelines31–36(verify numbers).

40)Termstodescribenon-reassuringfetal statussuchas “low-grade”,“mild”,“moderate”,“high”,“severe”or“signiﬁcant”are highlysubjective,pronetowideinterpretation,andshouldbe avoided,unlessclearlydeﬁned.

41)Datashouldbepresentedwithnumeratoranddenominator (n/N)(andnotonlyinpercentages),ifavailable.

Althoughimmunizationsafety surveillancesystems denomi-natordataare usuallynotreadilyavailable,attemptsshouldbe madetoidentifyapproximate denominators. Thesource ofthe denominatordatashouldbereportedandcalculationsofestimates bedescribed(e.g.manufacturerdataliketotaldosesdistributed, reportingthroughMinistryofHealth,coverage/populationbased data,etc.).

42)Theincidenceofcasesinthestudypopulationshouldbe pre-sentedandclearlyidentiﬁedassuchinthetext.

43)Ifthedistributionofdataisskewed,medianandrangeare usu-allythemoreappropriatestatisticaldescriptorsthanamean.

However,themeanandstandarddeviationshouldalsobe pro-vided.

44)Anypublicationofdataonnon-reassuringfetalstatusshould includea detaileddescriptionofthemethodsusedfordata collectionandanalysisaspossible.Itisessentialtospecify:

•Thestudydesign;

•The method, frequency and duration of monitoring for non-reassuringfetalstatus;

•Thetrialproﬁle,indicatingparticipantﬂowduringastudy includ-ingdrop-outsandwithdrawalstoindicatethesizeandnatureof therespectivegroupsunderinvestigation;

•Thetypeofsurveillance(e.g.passiveoractivesurveillance);

•Thecharacteristicsof thesurveillancesystem(e.g.population served,modeofreportsolicitation);

•Thesearchstrategyinsurveillancedatabases;

•Comparisongroup(s),ifusedforanalysis;

•Theinstrumentof datacollection(e.g.standardized question-naire,diarycard,reportform);

•Whetherthedayofimmunizationwasconsidered“dayone”or “dayzero”intheanalysis;

•Whetherthedateofonset2_and/or_the_date_of_ﬁrst_observation3 and/orthedateofdiagnosis4_was_used_for_analysis;_and

•Useofthiscasedeﬁnitionfornon-reassuringfetalstatus,inthe abstractormethodssectionofapublication.11

Disclaimer

Thefindings,opinionsandassertionscontainedinthis consen-susdocumentarethose of theindividualscientificprofessional membersof theworkinggroup.Theydo not necessarily repre-senttheofficialpositionsofeachparticipant’sorganization(e.g., government,university,orcorporation).Specifically,thefindings andconclusionsinthispaperarethoseoftheauthorsanddonot necessarilyrepresenttheviewsoftheirrespectiveinstitutions.

Acknowledgements

The authors are grateful for the support and helpful

comments provided by the Brighton Collaboration (Jan Bon-hoeffer, JorgenBauwens) and the reference group(see https:// brightoncollaboration.org/public/what-we-do/setting-standards/

case-deﬁnitions/groups.html for reviewers), as well as other

expertsconsultedaspartoftheprocess.Finally,wewouldliketo thankthemembersoftheISPESpecialInterestGroupinVaccines (VAXSIG)forthereviewof,constructivecommentson.Brighton CollaborationwouldliketoacknowledgetheTheGlobalAlignment ofImmunizationSafetyAssessmentinPregnancy(GAIA)Project, fundedbytheBillandMelindaGatesFoundation.

References

[1]Parer JT, Livingston EG. What is fetal distress? Am J Obstet Gynecol 1990;162:1421–5,discussion5–7.

[2]BernardesJ,Costa-PereiraA,Ayres-de-CamposD,vanGeijnHP,Pereira-Leite L.Evaluationofinterobserveragreementofcardiotocograms.IntJGynaecol ObstetOffOrganIntFederatGynaecolObstet1997;57:33–7.

[3]BlackwellSC,GrobmanWA,AntoniewiczL,HutchinsonM,GyamﬁBannerman C.InterobserverandintraobserverreliabilityoftheNICHD3-TierFetalHeart RateInterpretationSystem.AmJObstetGynecol2011;205:e1–5,378. [4]Rhose S, Heinis AM, Vandenbussche F, van Drongelen J, van Dillen J.

Inter- and intra-observer agreement of non-reassuring cardiotocography

(9)

analysisandsubsequentclinicalmanagement.ActaObstetGynecolScand 2014;93:596–602.

[5]PenningS,GariteTJ.Managementoffetaldistress.ObstetGynecolClinNAm 1999;26:259–74.

[6]PracticeACoO.Inappropriateuseofthetermsfetaldistressandbirthasphyxia, CommitteeOpinion326.ObstetGynecol2005;106:1469–70.

[7]MartinJrCB.Normalfetalphysiologyandbehavior,andadaptiveresponses withhypoxemia.SemPerinatol2008;32:239–42.

[8]MurrayM.Antepartalandintrapartalfetalmonitoring.3rded.NewYork: SpringerPublishingCompany,LLC;2007.

[9]FaheyJ,KingTL.Intrauterineasphyxia:clinicalimplicationsforprovidersof intrapartumcare.JMidwWomensHealth2005;50:498–506.

[10]Executive summary: neonatal encephalopathy and neurologic outcome, secondedition,reportoftheAmericanCollegeofObstetriciansand Gyne-cologists’TaskForceonNeonatalEncephalopathy.ObstetGynecol2014;123: 896–901.

[11]HankinsGD,SpeerM.Deﬁningthepathogenesisandpathophysiologyof neona-talencephalopathyandcerebralpalsy.ObstetGynecol2003;102:628–36. [12]East CE, Leader LR, Sheehan P, Henshall NE, Colditz PB, Lau R.

Intra-partumfetalscalplactatesamplingforfetalassessmentinthepresenceof anon-reassuringfetalheartratetrace.CochraneDatabaseSystRev2015;5: CD006174.

[13]Ugwumadu A.Understanding cardiotocographic patterns associated with intrapartumfetalhypoxiaandneurologicinjury.BestPractResClinObstet Gynaecol2013;27:509–36.

[14]LowJA,VictoryR,DerrickEJ.Predictivevalueofelectronicfetal monitor-ingforintrapartumfetalasphyxiawithmetabolicacidosis.ObstetGynecol 1999;93:285–91.

[15]HofmeyrGJ,HawsRA,BergstromS,LeeAC,OkongP,DarmstadtGL,etal. Obstetriccareinlow-resourcesettings:what,who,andhowtoovercome chal-lengestoscaleup?IntJGynaecolObstetOffOrganIntFederatGynaecolObstet 2009;107(Suppl.1).S21–44,S-5.

[16]AlﬁrevicZ,DevaneD,GyteGM.Continuouscardiotocography(CTG)asaformof electronicfetalmonitoring(EFM)forfetalassessmentduringlabour.Cochrane DatabaseSystRev2006.CD660060.

[17]LewisD,DowneS.panel.Fifmc.FIGOconsensusguidelinesonintrapartum fetalmonitoring:intermittentauscultation.IntJGynecolObstet2015;131: 9–12.

[18]AlﬁrevicZ,DevaneD,GyteGM.Continuouscardiotocography(CTG)asaformof electronicfetalmonitoring(EFM)forfetalassessmentduringlabour.Cochrane DatabaseSystRev2013;5.CD006066.

[19]Electronicfetalheartratemonitoring:researchguidelinesforinterpretation. NationalInstituteofChildHealthandHumanDevelopmentResearchPlanning Workshop.AmJObstetGynecol1997:177–90,1385.

[20]MaconesGA,HankinsGD,SpongCY,HauthJ,MooreT.The2008National Insti-tuteofChildHealthandHumanDevelopmentworkshopreportonelectronic fetalmonitoring:updateondeﬁnitions,interpretation,andresearchguidelines. ObstetGynecol2008;112:661–6.

[21]AmericanCollegeofGynecologists.Practicebulletinno.116:managementof intrapartumfetalheartratetracings.ObstetGynecol2010;116:1232–40. [22]Ayres-de-Campos D, SabaratnamA.panel.Fifmec.FIGOconsensus

guide-linesonintrapartumfetal monitoring: introduction.IntJGynecolObstet 2015;131:3–4.

[23]Ayres-de-CamposD,SabaratnamA.panel.Fifmec.FIGOconsensusguidelines onintrapartumfetalmonitoring:physiologyoffetaloxygenationandthemain goalsofintrapartumfetalmonitoring.IntJGynecolObstet2015;131:5–8. [24]Ayres-de-CampoD,SpongCY,ChandraharanE.panel.Fifmec.FIGOconsensus

guidelinesonintrapartumfetalmonitoring:cardiotocography.IntJGynecol Obstet2015;131:13–24.

[25]MedicineFsoSiP.Guidelinesfortheuseoffetalmonitoring.IntJGynecolObstet 1987;25:159–67.

[26]VisserG,Ayres-de-CamposD.panel.Fifmec.FIGOconsensusguidelineson intrapartumfetalmonitoring:adjunctivetechnologies.IntJGynecolObstet 2015;131:25–9.

[27]AdedinsewoDA,NooryL,BednarczykRA,SteinhoffMC,DavisR,OgbuanuC, etal.Impactofmaternalcharacteristicsontheeffectofmaternalinﬂuenza vaccinationonfetaloutcomes.Vaccine2013;31:5827–33.

[28]DoneganK,KingB,BryanP.Safetyofpertussisvaccinationinpregnantwomen inUK:observationalstudy.BMJ2014;349:4219g.

[29]MunozFM,BondNH,MaccatoM,PinellP,HammillHA,SwamyGK,etal. Safetyandimmunogenicityoftetanusdiphtheriaandacellularpertussis(Tdap) immunizationduringpregnancyinmothersandinfants:arandomizedclinical trial.JAMA2014;311:1760–9.

[30]KarsdorpVH,vanVugtJM,vanGeijnHP,KostensePJ,ArduiniD,MontenegroN, etal.Clinicalsigniﬁcanceofabsentorreversedenddiastolicvelocitywaveforms inumbilicalartery.Lancet1994;344:1664–8.

[31]MaulikD.Absentenddiastolicvelocityintheumbilicalarteryandits clin-icalsigniﬁcance.In:MaulikD,editor.Dopplerultrasoundinobstetricsand gynecology.2nded.NewYork:Springer-Verlag;2005.

[32]ValcamonicoA,DantiL,FruscaT,SoregaroliM,ZuccaS,AbramiF,etal.Absent end-diastolicvelocityinumbilicalartery:riskofneonatalmorbidityandbrain damage.AmJObstetGynecol1994;170:796–801.

[33]YoonBH,RomeroR,RohCR,KimSH,AgerJW,SynHC,etal.Relationship betweenthefetalbiophysicalproﬁlescore,umbilicalarteryDoppler velocime-try,andfetalbloodacid–basestatusdeterminedbycordocentesis.AmJObstet Gynecol1993;169:1586–94.

[34]AlﬁrevicZ,StampalijaT,GyteGM.FetalandumbilicalDopplerultrasoundin high-riskpregnancies.CochraneDatabaseSystRev2013;11:CD007529. [35]Hopp H, Nonnenmacher A. Evidence-based fetal assessment. Gynakol

GeburtsmedGynakolEndokrinol2008;4:134–48.

[36]SalingE.Bloodgasrelationsandtheacid–baseequilibriumofthefetusin anuncomplicatedcourse ofdelivery.ZeitschriftGeburtshilfeGynakologie 1964;161:262–92.

[37]MaiquesV,Garcia-TejedorA,PeralesA,NavarroC.Intrapartumfetalinvasive proceduresandperinataltransmissionofHIV.EurJObstetGynecolReprodBiol 1999;87:63–7.

[38]JiboduOA,ArulkumaranS.Intrapartumfetalsurveillance.CurrOpinObstet Gynecol2000;12:123–7.

[39]PracticeACoO.ACOGCommitteeOpinionNo.348,November2006:umbilical cordbloodgasandacid–baseanalysis.ObstetGynecol2006;108:1319–22. [40]ApgarV.Aproposalforanewmethodofevaluationofthenewborninfant.Curr

ResAnesAnal1953;32:260–7.

[41]LeuthnerSR,DasUG.LowApgarscoresandthedeﬁnitionofbirthasphyxia. PediatrClinNAm2004;51:737–45.