Full
length
article
Effects
of
exercise
during
pregnancy
in
women
with
short
cervix:
Secondary
analysis
from
the
Italian
Pessary
Trial
in
singletons
Gabriele
Saccone
a,*
,
Vincenzo
Berghella
b,
Roberta
Venturella
c,
Pietro
D
’Alessandro
a,
Bruno
Arduino
a,
Antonio
Raffone
a,
Antonia
Giudicepietro
a,
Silvia
Visentin
d,
Amerigo
Vitagliano
d,
Pasquale
Martinelli
a,
Fulvio
Zullo
a,
The
Italian
Preterm
Birth
Prevention
(IPP)
Working
Group
a
DepartmentofNeuroscience,ReproductiveSciencesandDentistry,SchoolofMedicine,UniversityofNaplesFedericoII,Naples,Italy
b
DivisionofMaternal-FetalMedicine,DepartmentofObstetricsandGynecology,SidneyKimmelMedicalCollegeofThomasJeffersonUniversity,Philadelphia, PA,USA
c
DepartmentofObstetricsandGynecology,SchoolofMedicine,UniversityofCatanzaroMagnaGrecia,Catanzaro,Italy
d
DepartmentofWoman’sandChild’sHealth,UniversityofPadua,Padua,Italy
ARTICLE INFO Articlehistory: Received6July2018
Receivedinrevisedform20August2018 Accepted27August2018 Availableonlinexxx Keywords: Respiratorydistress Prematurity Cerclage Progesterone Pessary
Neonatalintensivecareunit Randomizedtrial
Cesareandelivery Tocolysis Bedrest
ABSTRACT
Objective: Toevaluate effectsof exerciseduring pregnancyin asymptomatic singletonpregnancies
withoutpriorspontaneouspretermbirth(SPTB)butwithshorttransvaginalultrasoundcervicallength
(TVUCL).
Studydesign:ThisisasecondaryanalysisoftheItalianPessaryTrialfortheItalianPretermBirthPrevention
(IPP)WorkingGroup.Intheoriginalprospectiverandomizedcontrolledtrialasymptomaticsingleton
pregnancieswithoutpriorSPTBbutwithTVUCL25mmat180/6–236/7weekswererandomizedinto
1:1ratiotoeithercervicalpessaryornopessary.Duringtheirfollow-upvisits,womenwereaskedabout
theiractivity.Forthepurposeofthissecondaryanalysis,womenwereclassifiedinthefollowinggroups,
usingtheinformationobtainedinthefollow-upvisitonemonthafterrandomization:1)Exercisegroup,
definedaswomenperformingexercise2daysaweekfor20mineachday.2)Noexercisegroup,
definedaswomenperformingexercise<2daysaweekfor20mineachday.Theprimaryoutcomeof
thissecondaryanalysiswasPTB<37weeks.
Results:300womenwereincludedinthisanalysis.99(33.0%)wereincludedintheexercisegroup.201
(67.0%)wereincludedinthenoexercisegroup.Ofthe201womeninthenoexercisegroup,90(44.8%)
affirmedthattheyhadreducedtheiractivityafterthediagnosisofshortcervixdespitetheresearchstaff
recommendations,whiletheother111(55.2%)womenperformedasedentarylifestyleevenbeforethe
diagnosisofshortcervix.PTB<37weeksoccurredin22women(22.2%)intheexercisegroup,and66
women(32.8%)inthenoexercisegroup(aOR0.65,95%CI0.33–1.03).
Conclusion:Inasymptomaticsingletonpregnancieswithshortcervix,performingexercise2daysa
weekfor20mineachdaydoesnotincreasetheriskofPTBbutisindeedassociatedwitha
non-significantreductioninPTB<37weeksby32%.
©2018ElsevierB.V.Allrightsreserved.
Introduction
Pretermbirth(PTB)isaleadingcauseofperinatalmorbidityand mortality[1].Overthelastfewyears,cervicalassessmenthasmoved fromdigitalexaminationtoultrasoundevaluation,andultrasoundof thecervixhasbeenthefocusofmuchresearch[2–10].
Womenfoundtohaveashorttransvaginalultrasoundcervical length(TVUCL)areatincreasedriskofspontaneousPTB(SPTB) [2,3]. Different strategies have been studies for prevention of SPTB in singleton gestations with short TVU CL [11–17]. The evidencesupportsthedailyuseofvaginalprogesterone[11,14], while cervical cerclage seems to be beneficial only in the subgroupofsingletongestationswithbothpriorSPTBandTVU CL25mm[12],andnotinsingletonswithoutpriorSPTB[16], norin multiple gestations [15].Cervical pessary hasalso been studiedinsingletonpregnancieswithshortcervixwithcon flict-ingresults.17]
*Correspondingauthorat:DepartmentofNeuroscience,ReproductiveSciences andDentistry,SchoolofMedicine,UniversityofNaplesFedericoII,Naples,Italy.
E-mailaddress:gabriele.saccone.1990@gmail.com(G.Saccone).
https://doi.org/10.1016/j.ejogrb.2018.08.582
0301-2115/©2018ElsevierB.V.Allrightsreserved.
EuropeanJournalofObstetrics&GynecologyandReproductiveBiology229(2018)132–136
ContentslistsavailableatScienceDirect
European
Journal
of
Obstetrics
&
Gynecology
and
Reproductive
Biology
Inthepast,somepregnantwomenhavebeenadvisedagainst exercise because of presumed increasedrisk of PTB [18–20]. However, some studies showedthat exercise mayreduce the riskofPTBbydecreasingoxidativestressaswellasincreasing bloodvolume[20–23].Recentevidencefromrandomizedtrials showedthatexercise forabout30–60minutesthree to seven timesperweekduringpregnancyisassociatedwithareduction intheincidenceofPTB,[24,25]aswellaswithareductioninthe riskofgestationalhypertensivedisordersandcesareandelivery. [26,27].
EvidenceoftheeffectsofexerciseinwomenatriskofSPTB, such as women with short TVU CL, is however limited. In a secondary analysis of a randomized trial on progesterone for prevention of PTB among nulliparous women with singleton gestationsandTVUCL<30mm,activityrestrictiondidnotreduce therateofPTB,whiletheeffectofexercisewasnotevaluated[28]. AccordingtotheAmericanCollegeofObstetriciansand Gynecol-ogists(ACOG)[29],cervicalinsufficiencyisanabsolute contrain-dicationtoexercise, whilenorecommendationsweremadefor asymptomaticwomenwithshortmidtrimesterTVUCL.
Objective
Theaimof thisstudywastoevaluateharmsandbenefitsof exerciseduringpregnancyinasymptomaticsingletonpregnancies withoutpriorSPTBbutshortTVUCL.
Methods
Studydesignandparticipants
ThisisasecondaryanalysisoftheItalianPessaryTrialforthe ItalianPretermBirthPrevention(IPP)WorkingGroup,aprospective randomizedcontrolledtrialofcervicalpessary inasymptomatic singletonpregnancieswithoutprior SPTBbutwithTVUCL25
mm.30
TheItalianPessaryTrialwasasinglecentertrialof asymptom-atic singleton pregnancies without prior SPTB and with TVU CL25mmat180/6–236/7weekswhowererandomizedinto1:1 ratiotoeithercervicalpessaryornopessary,attheUniversityof NaplesFedericoII(Naples,Italy)fromMarch 1,2016toMay25, 2017.Inclusioncriteriafortheoriginaltrialwere:18–50yearsof age, singleton pregnancy, TVU CL25mm, gestational age at randomizationbetween180/6and236/7weeks,nopriorSPTB, definedasspontaneouspretermdeliveryat160/7–366/7weeksin a prior pregnancy. Full detailsof thestudy protocolhave been previouslyreported[30].
In this trial, no bed rest or activity restriction was recommended.Theresearchstaffsrecommendedtoallenrolled womentocontinuetheirroutineactivityasbeforetheTVUCL screening.
Forthepurposeofthisplannedsecondaryanalysis,atthetime ofrandomizationandduringthefollow-upvisitonemonthafter randomization,womenwereaskedabouttheiractivityusingthe followingquestions:
Question A:Since thebeginning of pregnancy (or since the diagnosisoftheTVUCLatthefollow-upvisit)haveyouexercised inyourleisuretime,inasupervisedprogram,oronyourown?Yes orNo.Ifyes,gotoQuestionB
QuestionB:Howmanydaysperweekdidyouexercise?2or <2daysaweek.If2daysaweek,gotoQuestionC
QuestionC:Takingintoaccountthetotaldurationofphysical exercisecontinuously,howlongdidyouexerciseeveryday?20 or<20minperday
Thosewhodidnotanswerthesequestionswereexcludedfrom thissecondaryanalysis.
For the purpose of this secondary analysis women were classifiedinthefollowinggroups,usingtheinformationobtained inthefollow-upvisitonemonthafterrandomization:
1)Exercisegroup,definedaswomenperformingexercise2days aweekfor20mineachday.
2)Noexercisegroup,definedaswomenperformingexercise<2 daysaweekfor20mineachday.
Definitionofphysicalexercise,as2daysaweekfor20min each day, was definition used in prior trials on exercise in pregnancy[27].
Outcomes
The primary outcome of this secondary analysis was the incidence of PTB<37 weeks. The secondary outcomes were incidence of PTB<34, <32, and <28 weeks. The neonatal outcomes were admission to a neonatal intensive care unit, neonataldeath(deathof alive-borninfant withinthe first28 days of life), and a composite of adverse perinatal outcomes definedasatleast1ofthefollowing:necrotizingenterocolitis, intraventricular hemorrhagegrade 3or 4, respiratorydistress syndrome,bronchopulmonarydysplasia,retinopathyof prema-turity requiring therapy, blood-culture proven sepsis, and neonataldeath.
Dataanalysis
StatisticalanalysiswasperformedusingStatisticalPackagefor SocialSciences(SPSS)v.19.0(IBMInc.,Armonk,NY,USA).
Data are shown as meansstandard deviation (SD), or as number (percentage). Univariate comparisons of dichotomous data wereperformed with theuse of the chi-square test with continuity correction. Comparisons between groups were per-formedwiththeuseofthet-testtotestgroupmeanswithSDby assumingwithin-groupvariances.
Logistic regression, presented as unadjusted odds ratio (crude OR) or adjusted odds ratio (aOR) with the 95% confidence interval (CI) was performed for primary and secondary outcomes. Adjusted analysis was performed to correctdataforrelevantbaselinecharacteristics.Twoadjusted analyses were performed, one in which covariates were includediftheystatisticallydifferedbetweenthetwostudied groups, and one in which all potentially relevant baseline characteristics were added to the model as covariates. The latter analysis was performed to show robustness of our results.All resultspresentedintheabstract andtextreferto thesecondadjustedanalysis.Relevantbaselinecharacteristics tobe consideredascovariates were:maternalage,ethnicity, body mass index (BMI), smoking during pregnancy, parity, priorcervicalsurgery(eitherLEEP orconebiopsy), CLatthe timeofrandomization,useofvaginalprogesterone,anduseof cervicalpessary.
A2-sidedPvaluelessthan0.05wasconsideredsignificant. Results
300asymptomaticsingletonpregnancieswithoutprior SPTB butwithTVUCL25mmat180/6–236/7weeksagreedtotake partinthetrial[30],underwentrandomization,andwereenrolled and followed up. No women were lost or excluded after randomization and at follow-up. Allof them responded tothe questionsregardingactivityatthetimeofrandomizationandone month after the randomization, and were included in this secondaryanalysis.
Characteristicsofthestudypopulation
Outofthem300womenanalyzed,noneofthemwasprescribed anyformofactivityrestrictionfromtheresearchstaff.99women (33.0%)performedexerciseduringpregnancy2daysaweekfor 20mineachdayonemonthafterthediagnosisofshortTVUCL andwereincludedintheexercisegroup.201(67.0%)wereincluded inthenoexercisegroup.
Ofthe201womeninthenoexercisegroup,90(44.8%)affirmed thattheyhad reducedtheiractivity afterthediagnosisofshort cervixdespitetheresearchstaffrecommendations,whiletheother 111(55.2%)womenperformedasedentarylifestyleevenbefore thediagnosisofshortcervix.
Ofthe99womenintheexercisegroup,82(82.8%)performed aerobicexercise, including running/jogging, swimming, cycling, and walking, while 17 (17.2%) performed anaerobic exercise, includingpowerliftingandsprinting(Table1).Table1showsthe baselinedemographicandclinicalcharacteristicsforeachgroup. 81(81.8%)womenintheexercisegroup,and177(88.1%)intheno exercise group werefound to haveTVU CL20mm and were prescribedvaginalprogesterone200mgdaily.
Outcomes
Tables 2 and 3 showthe primary and secondary outcomes. PTB<37 weeks occurred in 22 women (22.2%) in the exercise group,and66women(32.8%)inthenoexercisegroup(aOR0.65, 95%CI 0.33–1.03). There were nosignificant differences in the incidenceofPTB<34, <32,and <28weeks,and intheneonatal outcomes.
Discussion Mainfindings
This planned secondary analysisof the Italian Pessary Trial evaluated harms and benefits of exercise during pregnancy in asymptomaticsingletonpregnancieswithoutpriorSPTBandwith TVUCL25mm.Pertrialprotocolwerecommendedallwomento continue their routine exercise as before the randomization. Despite this recommendation, 90 women (30.0%) their activity afterthediagnosisofshortcervix.Thevastmajorityoftheincluded women(210women,70.0%)continuedtheyactivityasbeforethe diagnosis of short cervix. 111 (37.0%) women performed a sedentarylife styleas before thediagnosisofshort cervix,and 99 women (33.0%) continued to exercise 2 days a week for 20min.
Wefoundthatperformingexercise2daysaweekfor20min each day was associated with a non-significant reduction in PTB<37weeksby32%.Notably,incidencesofPTBatallcut-offs werelesscommon(Table2),intheexercisegroupcomparedtothe non-exercisegroup.However,noneoftheoutcomesreachedthe statisticalsignificance.
Strengthsandlimitations
Ourstudyhasseveralstrengths.Thisisasecondaryanalysisofa largeandhigh-qualityprospectiverandomizedcontrolledtrial.To bestofourknowledge,therearelimiteddatafromrandomized trialsontheeffectofexerciseinwomenwithshortcervix[31]. However,evenifthisisasecondaryanalysisofarandomizedtrial, this studywas limited by thenonrandomizedapproach. In the originaltrialwomenwererandomizedinto1:1ratiointoeither pessaryornopessarygroup.Inthisstudy,womenweredivided into two groups according to the exercise activity. Therefore findingsfromthisstudycanbebiasedfromunbalancedvariables betweenthetwogroups.Theopenlabelstudydesignofthetrial canbeasourceofbias.Thisstudywasnotpoweredforthereported outcomes.Forthepurposeofthissecondaryanalysis,womenwere classifiedinexerciseandnon-exercisegroupsusingthe informa-tionobtainedinthefollow-upvisitonemonthafter randomiza-tion.Themeangestationalageatrandomizationwas22.4weeks. Therefore this studyassessed theeffects of exercise performed before24weeksofgestationontheriskofpretermbirth.Thereis no information on theeffects of exercise performed after 24 weeks of gestation on the risk of preterm birth. We used a definitionofphysicalexerciseusedinprior trialsonexercisein pregnancy[27].Differentdefinitionsmayleadtodifferentresults. Forexample,performinghigherfrequencyexercise,inwomenwith shortcervixmayincreasetheriskofPTB.Intheno-exercisegroup we included both women who reduced their activity after the
Table1
Characteristicsoftheincludedwomenforexerciseandnoexercisegroup. Exercise N=99 Noexercise N=201 p-value Running/Joggingn(%) 20(20.2%) – – Swimmingn(%) 31(31.3%) – – Cyclingn(%) 8(8.1%) – – Walkingn(%) 23(23.2%) – – Powerliftingn(%) 15(15.2%) – – Sprintingn(%) 2(2.0%) – – Age meanSD(years) 29.75.6 28.26.5 0.06 Ethnicity Caucasiann(%) Othern(%) 89(89.9%) 10(10.1%) 179(89.1%) 22(10.9%) 0.98 BMI meanSD(Kg/m2) 26.56.2 26.56.2 0.95 Smokingn(%) 9(9.1%) 30(14.9%) 0.21 Nulliparousn(%) 70(70.7%) 139(69.2%) 0.89 Priorcervicalsurgery
LEEPn(%) Conebiopsyn(%) 2(2.0%) 0(0%) 7(3.5%) 3(1.5%) 0.74 0.55 CL meanSD 20mmn(%) 12.06.6 81(81.8%) 12.05.4 177(88.1%) 0.94 0.20 Reducedactivity* – 90(44.8%) – LEEP,loopexcisionoftransformationzone;SD,standarddeviation;CL,cervical length.
* Womenwhoreducedtheiractivityafterthediagnosisofshortcervix.
Table2
Incidenceofpretermbirthintheexerciseandinthenoexercisegroup.
ExerciseN=99 NoexerciseN=201 CrudeOR(95%CI) aOR*
(95%CI) PTB<37weekn(%) 22(22.2%) 66(32.8%) 0.58(0.33to1.02) 0.65(0.33to1.03)
PTB<34weekn(%) 9(9.1%) 31(31.8%) 0.55(0.25to1.20) 0.64(0.88to2.28)
PTB<32weekn(%) 7(7.1%) 19(9.5%) 0.73(0.30to1.80) 2.58(0.34to19.33)
PTB<28weekn(%) 4(4.0%) 12(6.0%) 0.66(0.21to2.11) 0.78(0.13to4.53)
RR,relativerisk;CI,confidenceinterval;PTB,pretermbirth.
*
diagnosisofshortcervix,andthosewhoperformedasedentarylife styleevenbeforethediagnosisofshortcervix.Thesetwogroups mayhaveadifferentbaselineriskofPTB.Theoriginaltrialfound that spontaneous PTB at less than 34 weeks of gestation was significantlyless commonin thewomen whoreceived cervical pessary. Therefore, in this cohort, pessary placement is an importantmodifieroftheriskofPTB,andwasmorecommonin the exercise group, even if with no statistically significant differences.
Comparisonwithpriorliterature
Differentstrategieshavebeenstudiesforprevention ofPTB, includingcerclage,progesterone,pessary,diet,supplementsand life style modification [5,11–14,16,17,31–44]. Grobman et al. foundthatsomeformof activityrestrictionwasprescribedfor more than one in every three nulliparous women who were diagnosedwithashortCL[28].About70%ofwomenwhohad activityrestrictedwererecommendedtorefrainfromwork,or sexualactivity.Theyfoundthatactivityrestrictiondidnotreduce therateofPTB,buttheydidnotassesstheeffectofexerciseonthe incidenceofPTB.Inourtrialweexplicitlyrecommendedtothe womennottochangetheiractivity,andbedrestoranyformof activity restriction, includingsexual activity, were not recom-mended. Despite these recommendations, a good number of enrolled women reduced their activity. Our findings also concurred with prior level-1 data that showed that exercise duringpregnancymaybebeneficial,anddoesnot increasethe riskofPTB[24–26].
Conclusion
Insummary,inasymptomaticsingletonpregnancieswithshort cervix,performingexercise2daysaweekfor20mineachday doesnotincreasetheriskofPTB.
Disclosure
Theauthorsreportnoconflictofinterest Contributiontoauthorship
Allauthorsfulfilledthejournal’sdefinitionofauthorship PMistheguarantorofthemanuscriptandtheleadauthors.PM affirmsthatthismanuscriptisanhonest,accurate,andtransparent accountofthestudybeingreported;thatnoaspectsofthestudy have been omitted; that any discrepancies from the study as plannedhavebeenexplained;andthatthemanuscript’scontents arenotmisleading.
Financialsupport
Nofinancialsupportwasreceivedforthisstudy
Ethicalapproval
The trial was approved by the local IRB (Comitato Etico UniversitàdegliStudidiNapoliFedericoII,protocolnumber#213/ 15)onNovember27,2015
Acknowledgments None
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