Reduced short-term variation following antenatal administration of betamethasone: Is reduced fetal size a predisposing factor?

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Length

Article

Reduced

short-term

variation

following

antenatal

administration

of

betamethasone:

Is

reduced

fetal

size

a

predisposing

factor?

Tullio

Ghi

*

,

Andrea

Dall

’Asta

,

Gabriele

Saccone

,

Federica

Bellussi

,

Tiziana

Frusca

,

Pasquale

Martinelli

,

Gianluigi

Pilu

,

Nicola

Rizzo

a

ObstetricsandGynecologyUnit,UniversityofParma,Parma,Italy

b

DepartmentofNeuroscience,ReproductiveSciences,andDentistry,SchoolofMedicine,UniversityofNaplesFedericoII,Naples,Italy

c

DepartmentofMedicalandSurgicalSciences,AlmaMaterStudiorumUniversityofBologna,Bologna,Italy

ARTICLE INFO

Articlehistory: Received3March2017

Receivedinrevisedform5July2017 Accepted7July2017 Keywords: Nonstresstest Antenatalsteroids Pretermbirth Cardiotocography Fetalgrowth ABSTRACT

Objective:Toassesstheassociationbetweenfetalsizeandtheincidenceofreducedshort-termvariability

(STV)followingbethametasoneadministrationforfetallungmaturity.

Studydesign:Thiswasaretrospective,multicenter,cohortstudyconductedintwoTertiaryUniversity

Units.Onlyuncomplicatedsingletonpregnanciesadmittedforthreatenedpretermlaborbetween26and

34weeksandsubmittedtobetamethasoneforfetallungmaturitywereincluded.Deliveryoccurring

within 72h from betamethasone administration represented criteria for exclusion. Computerized

cardiotocographywascarriedoutonadailybasis.CaseswereidentifiedbypersistentlyreducedSTV,

defined as<5th percentileforgestational ageand lastingforat least72hafter the firstdose of

betamethasone.Theprimaryoutcomewasestimatedfetalweight(EFW)atultrasoundinfetuseswith

normalandinthosewithpersistentlyreducedSTV.Pregnancyoutcomeswerealsoevaluated.

Results:PersistentlyreducedSTVoccurredin33/405oftheincludedpatients(8.1%).Comparedtowomen

withnormal STV,thosewithpersistentlyreducedSTVhad significantlylowerEFW(1472435 vs

1812532g,p0.04),lowerbirthweight(2353635vs2857796g,p<0.01)andearliergestationalage

atdelivery(35.14.2vs37.32.4weeks,p<0.01),whereasalltheothervariablesincludinggestational

ageonadmissionwerecomparable.

Conclusions: Reduced STV following maternal betamethasone administrationamong appropriately

grown fetuses seems tocorrelatewith lowerfetalsize. Furthermore, fetuses with suchabnormal

responsetosteroidsseemtocarryahigherriskofperinatalcomplications,includinglowerbirthweight

andearliergestationalageatdelivery.

©2017PublishedbyElsevierIrelandLtd.

Introduction

A course of antenatal steroids between 24 weeks and 34 weeks+6daysisuniversallyrecommendedinpregnantwomenat riskfor impending deliveryas ithasbeen consistently demon-strated to decrease the occurrence of perinatal mortality and morbidityinpreterminfants[1,2].

Betamethasone (BMT) hasshown toproducesometransient effectsincludingareduction inbodyandbreathing movements andadecreaseintheshort-termvariability(STV)observedwith computerizedcardiotocography(cCTG)[3–7].Inasmall propor-tionofcasessuchprofounddepressiveeffectsonthefetalheart

ratevariabilitymaypersistupto3daysafteritsadministration[4], leading toinappropriate clinicaldecisions if theyare misinter-pretedasasignofbrainhypoxia.

Itisstillunclearwhyonlysomefetusesexhibitareducedheart ratevariabilityfollowingsteroidsadministration[6].

Theaimofthisstudywastwo-fold:toassesstheincidenceof reducedSTVfollowingBMTadministrationforfetallungmaturity inagroupoffetusesatriskofpretermdeliveryandidentifywhich factorsmaypredisposetothisabnormalresponse.

Methods

Studydesignandstudypopulation

This was a retrospective, multicenter, cohort study. Clinical recordsofallconsecutivewomenadmittedforthreatenedpreterm labor (PTL) to the Department of Obstetrics of the University *Correspondingauthorat:DepartmentofObstetricsandGynecology,University

ofParma,ViaAntonioGramsci14,43126Parma,Italy. E-mailaddress:tullio.ghi@unipr.it(T.Ghi).

http://dx.doi.org/10.1016/j.ejogrb.2017.07.010 0301-2115/©2017PublishedbyElsevierIrelandLtd.

ContentslistsavailableatScienceDirect

European

Journal

of

Obstetrics

&

Gynecology

and

Reproductive

Biology

Hospital of Bologna (Bologna,Italy) and to the Department of Reproductive Science, University of Naples Federico II (Naples, Italy)fromJanuary2009 toDecember 2014werecollectedina dedicatedmergeddatabase.

Allchartsrecordedinthedatabasewerereviewed.Allvariables reportedwerecollectedforallthesubjectsincludedinthestudy. All patients were aged 18 or above and submitted to BMT administrationforfetallungmaturitybetween26and34weeksof gestation.Inthisgroup,twodosesofBMT12mgwere adminis-tered intramuscularly 24hours (h)apart as recommended [1]. ThreatenedPTL was defined bythe presenceof regularuterine contractions (2_–3 every 10min) associated with early cervical changes at clinical examination (effacement and/or dilatation >1cm).AsperinternalprotocoloftheCentresinvolved,tocolysis wasadministeredinallwomensubmittedtoRDSprophylaxisfor threatened PTL. Cervical length measurement at transvaginal ultrasoundorresultofthefibronectintestwerenotconsideredfor thepurposeofthisstudy.

Exclusioncriteriaweremultiplepregnancy,congenital anoma-lies,intrauterinegrowthrestriction(IUGR),definedbyabdominal circumference(AC)or ultrasoundestimated fetal weight(EFW) <10thcentilewithorwithoutumbilicalarteryDopplerpulsatility index >95th percentile, any preexisting medical condition includinghypertensivedisorders,chronicdrugconsumptionand diabetesmellitus or gestationaldiabetes, abnormal CTGand/or cCTG on admission and delivery within 72h from steroids administration.Women withprematurerupture of membranes (PROM)andantepartumhaemorrhage(APH)werealsoexcluded. Management

AllwomenincludedinthestudyreceiveddailycCTGassessing fetalheart rate andSTV startingfromadmission. Algorithmfor cCTGwerebasedonDawes/RedmanantepartumCTGanalysisby usingSonicaid(SonicaidObstetricSolutions,Huntleigh)[8,9].The recordings were at least 45min in duration. STV values were recordedforeachassessment.cCTGswereperformedonadaily basis in themorning. We considered“day 1 cCTG” only those performedatleast12hafterBMTadministration.

Thestudycohortwasdividedintwogroupsaccordingtothe STVfindings:groupA (cases)showed persistentlyreducedSTV definedbyvaluesbelowthe5thpercentileforgestationalage[10]

followingBMTadministrationandlastingupto72hafterthe1st dose;groupB(controls)STV>5thpercentileafterthe administra-tionofBMTor<5thpercentileforlessthan72hafterfirstdose. Ultrasoundassessment of fetal weightwas performed inall caseswithin3daysfromadmissionandaccordinglytothelocal referencecharts[11].

Outcomes

A comparison of demographics, clinical characteristics and pregnancyoutcomeswasperformedbetweencaseswith persis-tently reduced vs those with normal STV following BMT administration. Due to its retrospective design, the study did not affect theclinical management of thepatients, which was baseduponthejudgementoftheattendingphysician.Asthiswasa retrospectiveanalysisof routinelycollectedanonymized clinical data,noethicalcommitteeapprovalwasnecessaryaccordingto nationalregulations.

TheprimaryoutcomewasmeanEFWatultrasound.Secondary outcomesweremeanbirthweightingrams,prevalenceofsmallfor gestationalage(SGA)atbirth,gestationalageatdelivery,modeof delivery.SGAneonatesweredefinedasthosewhosebirthweight was below the 10thcentile according tothe national neonatal

charts [12].Neonataloutcomes,includingApgarscore at5min, umbilicalarterypHandbaseexcessatdeliverywerealsorecorded. Statisticalanalysis

StatisticalanalysiswasperformedusingStatisticalPackagefor Social Sciences(SPSS)v.19.0(IBMInc.,Armonk,NY,USA).Data wereshownasmeanstandarddeviationorasnumber (percent-age).CategoricalvariableswerecomparedusingtheChi-squareor Fisher exact test. Between-group comparison of continuous variables was undertaken using T-test for parametric analysis. StandardizedscoreswerecreatedtoassessZ-scoreforbirthweight andultrasoundEFW.

Twosidedp-valueswerecalculatedandpvalues<0.05were consideredas statisticallysignificant.The studywas performed followingtheSTROBEguidelines[13].

Results

Overthestudyperiod,4120womenwereadmittedbetween26 and34weeksforPTLandreceivedprophylacticBMT.Ofthem,405 (9.8%)mettheinclusioncriteriaandwereincludedinthestudy (Fig.1).

Mean gestational age at admission and at delivery was 31.52.4 weeks and 36.23.1 weeks, respectively. Overall, 33 fetuses (8.1%)showedSTVbelowthe5thcentilefollowingBMT administrationandlastingupto72hwhereas372hadnormalor temporarily reduced STV <5th percentile lasting <72h. No significant differences werenoted in terms of maternal demo-graphicsbetweenthetwogroups(Table1).

WomenwithpersistentlyreducedSTVfollowingBMT admin-istration had significantly lower EFW and EFW Z-score on admission (1472+435 vs 1812+532g,p 0.04 and 0.0020.411 vs0.4010.612,p0.04,respectively)andlowerbirthweightand birthweight Z-score (2353+635 vs 2857+796g, p<0.01 and 0.4630.470vs 0.1030.315,p0.03,respectively)compared withthosewithnormalSTVshowed.TheincidenceofSGAatbirth wassignificantlyhigher(18.2%vs7.8%,p0.04)andthegestational ageatdeliverywaslower(35.1+4.2vs37.3+2.4,p<0.01)among fetuseswhoshowedpersistentlyreducedSTVfollowingsteroids administration(Table2).

Discussion

OurstudyconfirmedthatareducedSTVisobservedatcCTGina small proportion of fetuses (8.1%) following antenatal BMT administration for fetal lung maturity. Interestingly,despite all fetusesofthisserieswereofappropriatesizeforgestationalageat inclusion,thosewhopresentedthereducedSTVfollowingsteroids appeared significantly smallerthan those with normal STV. In addition, pregnancyoutcome appeared tobedifferent in those withreducedSTVaftersteroidscomparedtocontrols,astheywere deliveredacoupleofweeksearlierandhadasmallerbirthweight andahigherincidenceofSGAneonates.

Thetransientdepressiveeffectofantenatalbetamethasoneon fetal heart rate variability has beenlargely documented [3–7]. AvailabledatahaveshownthatadecreaseintheSTVwithin72h fromthefirstdoseis notrelatedtoacid–basechanges[14] but mightbeduetoadirecteffectofbetamethasoneonglucocorticoid receptors. Such receptors are believed to be present in the brainstem and otherareas of the humanbraininvolved in the controlofthefetalheartactivity[4,5,15,16].

The STV reduction due to BMTadministration seems to be inverselyrelatedtothegestationalageatsteroidsadministration

[14,17].InourgroupoffetuseswithreducedSTVthegestational ageatBMTexposurewasnotdifferentcomparedwiththosewith

normalCTGresponseandtheonlysignificantdifferencewasthe smallerweightnotedintheformergroup.

Thisobservationleadsustospeculatethatthedepressiveeffect ofBMTonfetalbrainmaybefavoredincasesofslightlyreduced placental reserve. As recently proposed, early stage placental insufficiency does not lead to fetal smallness but may induce

relevanthaemodynamicchanges.Moreindetails,fetalbiometryat ultrasoundmayremainwithinthenormalrangebuttheweight percentile is smaller compared to previousmeasurements and bloodflowredistributionmaybenoted[18].Recently,areduced cerebroplacental ratio has been described during the third trimester in normal sized fetuses with subtle placental Fig.1.Flowchart(accordingtoSTROBEguidelines)forinclusionofcases.BMT,Bethametasone;HDP,hypertensivedisorderofthepregnancy;DM,diabetesmellitus;SGA,smallfor gestationalage;IUGR,intrauterinegrowthrestriction;PPROM,prematurepretermruptureofthemembranes;APH,antepartumhaemorrhage;CTG,cardiotocography.

insufficiency whoserisk ofperinatalcomplicationsseemstobe significantlyhigher[19,20].SomeAuthorspreviouslydescribeda higherfrequencyofreducedSTVafterBMTinfetuseswithcerebral vasodilatationatDoppler ultrasound[21]. Unfortunately,in our studygroupthefetalcerebralflowwasnotassessedandweare unable to con_firm if Doppler _findings witnessed blood _flow redistributionandreducedplacentalreserveinthosefetuseswith reducedSTV,whoseweightpercentilewasinthelowerrangeof normality.

Ontheotherhand,inthesamegroupoffetuseswithtransiently depressedSTVaftersteroids,asignificantlylowerbirthweightand ahigherincidenceofSGAneonateswasnoted.Thismayleadusto envisagethat theabnormal CNS response at steroids could be lookednotasanincidentalfindingbutasanearlysignofreduced placentalreserveinapparentlynormalsizedfetuses and,atthe sametime,asausefulpredictoroflateonsetplacentaldysfunction and lower birthweight requiring a modified obstetric manage-ment.

On this basis, we suggest that whenever an apparently appropriatelygrownfetusexposedtoBMTexhibitsatransiently reduced STV a comprehensive maternal and fetal Doppler ultrasound shouldbeperformedin order tospotearlysigns of placentaldysfunction.Furthermore,weproposethatif spontane-ous preterm delivery does not occur, these fetuses should be incorporatedin aprogramof intensiveantepartumsurveillance since their risk of late onset placental insufficiency may be increased.

Some limitations need to be acknowledged in this study, including thesmall number ofcases withreduced STV and its retrospectivedesign.Furthermore,havingexcludedthosepatients with a true threatened PTL who delivered within 72h from admission,wecouldonlyassessthedepressiveeffectsonthefetal heartratevariabilityinthosefetuseswhoremainedundelivered and could not generalize our results to all cases exposed to antenatalsteroids.Inthis study,aswidelyreported[22],onlya smallproportionofpatientsadmittedwithPTLactuallydelivered shortlyfollowingBMTadministration.Mostwomenwith threat-enedPTLhaveminimalcervicaldilationonmanualexam,andover 60% do not deliver preterm [23]. Finally,the selection of only normallygrownfetusesatinclusionmayintroduceabiasbythe insufficiencyofmethodstoperformthisselectionanddiscriminate betweenIUGRandnonIUGRfetuses.Ontheotherhand,inclusion ofpregnanciescomplicatedbyIUGRwouldintroduceaconfounder which may impactontheaimand the resultsof thestudy, as chronichypoxiapersemaybecauseoffetalbehavioralchanges includingareducedSTVatcCTG.

Despite these limitations, we have observed that among apparentlynormalsized fetusesadepressiveeffectofantenatal steroidsismorelikelyiftheweightpercentileisinthelowerrange andthiseffectmayheraldanincreasedriskforlateonsetplacental insufficiencyandlowerbirthweight.Thisoriginalfindingisworthy tobereportedandconfirmedprospectivelyinalargerstudywhere acomprehensiveDopplerassessmentfollowingantenatal admin-istrationisincluded.

Disclosureofinterests

Theauthorsreportnoconflictofinterest. Contributiontoauthorship

 TullioGhi,NicolaRizzo:studydesign

 TullioGhi,AndreaDall’Asta:manuscriptwritingandediting  GabrieleSaccone,FedericaBellussi:datacollection

 TizianaFrusca,PasqualeMartinelli,GanluigiPilu,NicolaRizzo: commentsandfinalreviewofthemanuscript

Ethicalapproval

Thisisaretrospectiveanalysisofroutinelycollectedandfully anonymizedclinicaldataandnoethicalcommitteeapprovalwas requiredaccordingtonationalregulations.

Funding

Nofundingwasreceivedforthisstudy. Acknowledgments

None Table2

Primaryandsecondaryoutcomes.

STV<5thpercentilea N=33 NormalSTV N=372 p-value EFW 1472435 1812532 0.04 EFWZ-score 0.0020.411 0.4010.612 0.04 Birthweight 2353635 2857796 <0.01 BirthweightZ-score 0.4630.470 0.1030.315 0.03 GAatdelivery 35.14.2 37.32.4 <0.01 Modeofdelivery SVD 18(54.5%) 222(59.7%) 0.74 OVD 1(3.1%) 6(1.6%) CD 14(42.4%) 144(38.7%) Vaginaldelivery n=19 n=228 0.53 Spontaneousonset 16(84.2%) 178(78.1%) Inductionoflabor 3(15.8%) 50(21.9%) CD n=14 n=144 0.29 Planned 11(78.6%) 93(65.6%) Emergency 3(21.4%) 51(34.4%) SGA 6(18.2%) 29(7.8%) 0.04 APGARat5min 9.00.4 9.00.6 0.95 UmbilicalarterypH 7.230.04 7.280.08 0.06 Baseexcess 5.81.2 5.52.0 0.21 Datapresentedasnumber(percentage)orasmeanstandarddeviation.Boldface data,statisticallysignificant.

GA,gestationalage;EFW,ultrasoundestimatedfetalweight;SVD,spontaneous vaginaldelivery;OVD,operativevaginaldelivery;CD,cesareandelivery;SGA,small forgestationalage.

Primaryandsecondaryoutcomesincaseswithreducedshort-termvariability(STV) afterbethametasoneadministrationandcontrolswithnormalSTV.

a

AccordingtoSnijdersetal.,FetalDiagnTher1990[10]. Table1

Characteristicsoftheincludedwomen(n=405). STV<5thpercentile N=33 NormalSTV N=372 p-value Age 32.84.9 33.65.3 0.22 BMI 24.32.6 24.93.1 0.37 Ethnicity Caucasian 25(75.8%) 301(80.9%) 0.13 Non-Caucasian 8(24.2%) 71(19.1%) Nulliparous 13(39.4%) 143(38.4%) 0.74 GAatadmission 31.84.2 31.23.4 0.81 STV Beforesteroids 11.21.1 11.43.2 0.61 24h 6.32.2 9.83.1 <0.01 48h 4.41.4 8.82.7 <0.01 72h 6.13.1 8.73.3 0.03 Dataare presented asnumber (percentage)oras meanstandard deviation. Boldfacedata,statisticallysignificant.

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