Braz. j. . vol.82 número1

www.bjorl.org

Brazilian

Journal

of

OTORHINOLARYNGOLOGY

REVIEW

ARTICLE

Rhinitis

and

pregnancy:

literature

review

夽

Fábio

Azevedo

Caparroz

,

Luciano

Lobato

Gregorio

,

Giuliano

Bongiovanni

,

Suemy

Cioffi

Izu

_,

_Eduardo

_Macoto

_Kosugi

a_{Post-GraduatePrograminMedicine,EscolaPaulistadeMedicina,UniversidadeFederaldeSãoPaulo(UNIFESP---EPM),}

SãoPaulo,SP,Brazil

b_{DepartmentofOtorhinolaryngologyandHeadandNeckSurgery,EscolaPaulistadeMedicina,}

UniversidadeFederaldeSãoPaulo(UNIFESP---EPM),SãoPaulo,SP,Brazil

Received18April2015;accepted23April2015 Availableonline21September2015

KEYWORDS Rhinitis; Pregnancy; Nasalobstruction

Abstract

Introduction:There isacontroversy concerningtheterminologyanddefinitionofrhinitisin pregnancy.Gestationalrhinitisisarelativelycommoncondition,whichhasdrawnincreasing interestinrecentyearsduetoapossibleassociationwithmaternalobstructivesleepapnea syndrome(OSAS)andunfavorablefetaloutcomes.

Objective: Toreviewthecurrentknowledgeongestacionalrhinitis,andtoassessitsevidence. Methods:Structuredliteraturesearch.

Results:Gestationalrhinitisandrhinitis‘‘duringpregnancy’’aresomewhatsimilarconditions regardingtheirphysiopathologyandtreatment,butdifferregardingdefinitionandprognosis. Hormonalchangeshaveapresumedetiologicalrole,butknowledgeaboutthephysiopathology ofgestationalrhinitisisstilllacking.Managementofrhinitisduringpregnancyfocusesonthe minimalinterventionrequiredforsymptomrelief.

Conclusion: Asithasagreatimpactonmaternalqualityoflife,boththeotorhinolaryngologist andtheobstetricianmustbecarefulconcerningtheearlydiagnosisandtreatmentofgestational rhinitis,considering thesafetyoftreatment measures anddrugs andtheir current levelof evidence.

© 2015Associac¸ãoBrasileira de Otorrinolaringologiae CirurgiaCérvico-Facial. Publishedby ElsevierEditoraLtda.Allrightsreserved.

夽 _{Pleasecitethisarticleas:CaparrozFA,GregorioLL,BongiovanniG,IzuSC,KosugiEM.Rhinitisandpregnancy:literaturereview.BrazJ}

Otorhinolaryngol.2016;82:105---11.

∗_{Correspondingauthor.}

E-mail:[email protected](F.A.Caparroz). http://dx.doi.org/10.1016/j.bjorl.2015.04.011

PALAVRAS-CHAVE Rinite;

Gestac¸ão; Obstruc¸ãonasal

Rinitenagestac¸ão:revisãodeliteratura

Resumo

Introduc¸ão:Há grande confusão quanto à terminologia e definic¸ão da rinite na gestac¸ão. Arinitegestacionaléumacondic¸ãorelativamentecomumquevemganhandoimportâncianos últimosanospela descoberta desuaassociac¸ãocomaSAOS maternae possíveisdesfechos desfavoráveisaofeto.Hápoucaevidêncianaliteraturanacionalsobreotema.

Objetivo:Revisaroconhecimentocientíficoatualsobrearinitenagestac¸ãoesuasevidências disponíveis.

Método: Revisãodeliteraturaestruturada.

Resultados: Arinitegestacionalearinite‘‘duranteagestac¸ão’’sãocondic¸õescomalguns pon-tosdefisiopatologiaetratamentosemelhantes,mascomdefinic¸õeseprognósticosdiferentes. Opapeldoshormôniosnessascondic¸õesvemsendosugeridopormuitostrabalhos,maso con-hecimentosobreafisiopatogeniadarinitegestacionalaindaéescasso.Omanejodarinitena gestac¸ãorequeromínimodeintervenc¸ãocomomaioralíviosintomáticopossível.

Conclusão:Dadoograndeimpactonaqualidadedevidadagestante,tantoo otorrinolaringol-ogista quanto o obstetra devem estar atentospara o diagnóstico precoce e manejodesta entidade,considerandooperfildeseguranc¸aeoníveldeevidênciadasmedidasemedicamentos disponíveisatualmente.

©2015Associac¸ãoBrasileira deOtorrinolaringologiaeCirurgiaCérvico-Facial.Publicadopor ElsevierEditoraLtda.Todososdireitosreservados.

Introduction

Gestationalrhinitisisarelativelycommoncondition,butis seldomdiscussed in the national literature. It hasgained importance in recent years, mainly due to the discov-ery of its association with snoring and obstructive sleep apnea syndrome (OSAS) during pregnancy, and indirectly withpreeclampsia, aleadingcause ofmaternal morbidity and mortality.1 _{Additionally, studies have shown its}

asso-ciationwithgestationalhypertension,intrauterinegrowth retardation,andlowerApgarscoresinneonates.1,2

The first studies that associated the nasal obstruction symptomwithfemalehormonesappearedinthelate nine-teenth century.1 _{In 1884, MacKenzie}3 _{presented a series}

of observations on the increased volume of the infe-riorturbinatesduringmenstruationandsexualstimulation, expandinghistheories topregnancyin1898.4 _However,it

wasonly in1943 that Mohun5 _{presented aseriesof cases}

onthis entity that would be the precursor of gestational rhinitis,termingit‘‘vasomotorrhinitisofpregnancy.’’Nasal symptoms appear between the third and seventhmonths of pregnancyand usually normalizewithin ten daysafter delivery.5

Gestational rhinitis terminology still creates much confusion.Someauthorsemphasizetheimportanceof dif-ferentiatingrhinitis ‘‘during pregnancy’’ from gestational rhinitis(orpregnancy-inducedrhinitis).Rhinitisduring preg-nancyisanentitythatincludesalltypesofrhinitis(allergic, drug,non-allergic,withvasomotorcomponent,among oth-ers), which would be present before, during, and after pregnancy by definition.6 _{Gestational rhinitis, in turn, is}

definedasnasalobstructionthatisnotpresentbefore preg-nancy, typically occurs in the second or third trimesters, with a duration equal to or greater than six weeks, shows no allergic cause or upper airway infection signs

and symptomsresolve completely withintwoweeks after delivery.1,7,8

Theaimofthisstudywastoconductaliteraturereview ongestationalrhinitisandextendsomeconceptswitha com-parativebasis(suchasphysiopathologyandtreatment)for othertypesofrhinitisinpregnancy.

Methods

AliteraturereviewwascarriedoutinthePubMed,MEDLINE, and SciELO databasesusing theterms ‘‘rhinitisand preg-nancy’’.Ofthe506initiallylistedarticles,tworesearchers independently selected 66 and 59 of them, respectively, using as selection criteria articles that had gestational rhinitis or other types of rhinitis during pregnancyas the main topic. Subsequently, 40 common articles were cho-sen from the two selections, includingthe most relevant regarding the criteria of definition, diagnosis, etiology, etiopathogenesis,differential diagnosis, andtreatment of bothgestationalrhinitisandrhinitisduringpregnancy.The distributionofarticlesfoundaccordingtotopicisshownin Table1.

Incidence

and

prevalence

Approximately20%---40%ofwomenreportrhinitissymptoms during childhood or adolescence, and 10%---30% of these womenreportsymptomworseningduringpregnancy.9

Pop-ulation studies withrelativelysmall samplesoften donot differentiategestationalrhinitisfromothertypesof rhini-tis,showingaprevalencerangingbetween18%and30%(for alltypesofrhinitisduringpregnancy).7_Thelargest

Table1 Typeofarticlesfoundandcorrespondenceinthe references.

Typeofarticle Numberof articles

References

Subjectreview 5 1,7,11,20,41

Diagnostic 2 9,28

Historicalarticles 3 3---5

Prevalenceand incidenceonly

1 10

Physiopathologyand physiopathogeny

10 8,12---19,26

Treatment 5 6,24,27,35,38

Outcomeandassociated conditions

15 2,21,22,23,25,29,

30---34,36,37,39,40

whoalreadyhadsignsofrhinitisbeforepregnancy,revealing aprevalenceofgestationalrhinitisof22%.10

Another recent study, however, assessed 109 pregnant womenthroughquestionnairesandanteriorrhinoscopyand reached aprevalence of 9%for gestationalrhinitis,which wasconsistentwithotherstudies.11_{TherewerenoBrazilian}

dataongestationalrhinitisprevalence.Thisprevalence vari-ationisduenotonlytothedifficultyofhavingaccesstoand diagnosingthediseaseandtheneedforastrictcriterion,but alsothefactthatrhinitisandasthmamayworsen,improve, orremainunchangedthroughoutthecourseofpregnancy,as wellasthefactthattheymayvaryintermsofclinical pre-sentation throughoutthe gestationalweeksandaccording toeachpatient’sgeneticsusceptibility.9

Etiology

and

physiopathogeny

Althoughmanyetiologicalfactorshavebeenproposed,the currentknowledgeaboutthephysiopathologyofgestational rhinitisisstillscarce.7,9_{Itis presupposedthatthe}

placen-taltrophoblastichormonecanstimulatehypertrophyofthe nasal mucosa during pregnancy.9 _{Moreover, estrogen may}

contributetothiseffectbyincreasinghistaminereceptors inepithelialcellsandthemicrovasculature.12_Progesterone

mayalsoplayarolebyoptimizinglocalvasodilationinthe nosebyincreasingthecirculatingbloodvolumethatoccurs physiologicallyduringpregnancy.13

Nasal physiology studies have shown significant alter-ationsinanteriorrhinoscopy,rhinomanometry,andspecific rhinitis questionnaire scores compatible with decreased patencyofairpassagethroughthenasalcavityduringthe course of pregnancy.14 _{However, all these data ---}

includ-ing the role of hormones---are conflicting, as there have beenstudiesdemonstratingnasalobstructionimprovement duringthe course ofpregnancy in asignificant numberof patients.15

Regarding risk factors for the development of gesta-tional rhinitis, smoking was the only one identified with significantevidence.7,16_{Thesamestudyfoundthatthe}

spe-cific IgE to house dust mites was a predisposing factor forthedevelopmentofthedisease.16 _Thereisno

associa-tionbetweengestationalrhinitisandpre-existingasthma.8

Also,noassociationwasobservedwithmaternalage, ges-tational age,child’s gender, andparity.1,7,17 _{Inrelation to}

theactualallergicrhinitis,itwasobservedthattheelectron microscopyfindingsinpregnantwomenwithnasalsymptoms wereidenticaltothosewithallergicrhinitis.18

Consideringthisandthefactthataconsiderable propor-tionofpatientswithgestationalrhinitishavesensitivityto housedustmites,itwassuggestedthatpatientswith gesta-tionalrhinitisrepresentanallergicrhinitissubgroup,albeit withspontaneous resolution after birth, according tothe definition.7_{Additionally,serummarkersforallergicdisease}

suchassolubleintercellularadhesionmolecule-1(sICAM-1) arenotelevatedingestationalrhinitis.7

Diagnosis

and

clinical

significance

Gestationalrhinitisischaracterizedbynasalobstructionin thelastsixormoreweeksofgestation,withcomplete res-olutionwithintwoweeksafterdelivery.1,7,8_{Thediagnosisis}

clinicalandcanbesuspectedonlybytheworseningofnasal obstructionsymptoms(whichwerenotpresentpreviously) inpregnantpatients,andisnotsecondary toother condi-tions--- thedifferentialdiagnosisincludessinusitis,allergic rhinitis,drug-inducedrhinitis,acuteorsubacuteupper air-wayinfection,andpregnancygranuloma.1,9

Itisimportanttobecautiousregardingthenasal obstruc-tioncriteriainpregnantwomen,consideringaspositiveonly aworseningpatternorasymptomthathassignificantimpact onpatientqualityoflife,asthisisanalterationthatispart ofthenormalphysiologyofpregnancy.19 _{Inadditiontothe}

obstruction,patientswithgestationalrhinitisoftenpresent withrhinorrhea.1

Allergicrhinitisisusuallyanexistingclinicalpicturethat canalsooccurduringpregnancy.Unlikegestationalrhinitis, inwhich nasal obstruction is the main symptom, patients withallergicrhinitisduringpregnancyhaverhinorrhea, pru-ritus,sneezing,aswellasnasalcongestion.9

Thenasalobstruction causedbyrhinitis---either gesta-tionalor not---maybeassociatedwitha worseningofthe pregnantwoman’s qualityof sleep, inaddition tosnoring andobstructivesleepapnea(OSA),althoughthelattermay betheresultofacombinationoffactors,involving weight gainduringpregnancy.20

Oral breathing caused by nasal obstruction worsening duringgestationalrhinitismayleadtoadecreasein inhala-tionofnitricoxide(NO)---producedmainlyinthemaxillary sinuses---tothelung,whichdecreasesvascularresistance, inadditiontoimprovinglocaloxygenation.1,7_Thereduction

inpulmonaryNOinhalationcanhaveadeleteriouseffecton the fetus, leading to maternal hypertension, intrauterine growthretardation,preeclampsia,andlowerApgar scores ofnewborns.1,2_{Additionally,nasalobstruction,withquality}

ofsleepimpairment,canleadtotheabuseoftopicalnasal decongestants,leadingtoanassociateddrug-induced rhini-tis,whichdoesnotusuallyresolveafterdelivery.21_However,

there is insufficient evidence to establish an association betweengestationalrhinitisandanunfavorableoutcomein pregnancy.7

Some authors, when comparing birth weight between atopic and non-atopic pregnant women, suggested that atopy, by favoring a Th2 pattern of immune response, wouldleadtobetterpregnancyoutcomes.21_{However,these}

Table2 Non-pharmacologicalmeasuresforthetreatment ofrhinitisduringpregnancy.

Measure Benefit

Educational Adjuvant,clarificationofdoubts, andreducedchanceofusing harmfulsubstances7,24,25

Physicalexercise Nasalobstructionimprovement26

Nasalirrigationwith salinesolution

Temporarysymptomrelief7

higherprevalenceinhighersocioeconomicgroups,whotend tohave better nutritional care.7,22 _{In a national study of}

230 pregnant women, there was no association between repeatedmiscarriageandatopy.23

Treatment

Regardingtreatment, most of thestudies show a consen-sus about theimportance of educationalmeasures asthe firstchoiceandasanadjuvantmeasureforthemanagement of gestational rhinitis, mainly because symptoms resolve spontaneouslyafterdelivery.7,24_{Whenadvisedearlyin}

preg-nancy,patientstendtoresortlesstotopicaldecongestants andwillhavelowerchancesofdevelopingdrug-associated rhinitis.25

Physicalexercisehasawell-establishedeffectonnasal obstruction improvement,26 _{on the pregnant woman’s}

weightcontrol,andonsleeppatternimprovement.24

Rais-ing the head of the bed to 30◦_---45◦ _{may also help in}

improving nasal obstruction during the night. Addition-ally, nasal irrigation with saline solution provides good temporarysymptom relief,although there arenospecific studies for gestational rhinitis.7 _{Table 2 summarizes}

non-pharmacological measures for the control of gestational rhinitisorrhinitisduringpregnancy.

Inrelationtotopicaldecongestants,theycanbedivided into short acting --- phenylephrine; intermediate-acting ---naphazoline; and long-acting drugs --- oxymetazoline and xylometazoline. All these drugs are given a ‘‘C’’ classifi-cationby theFood andDrugAdministration (FDA)27 _---the

complete FDA classification of drugs for use during preg-nancy,showninTable3.

Acase---controlstudyshowedanassociationbetweenthe useofphenylephrineduringpregnancyandtheoccurrence ofcongenitaldefects.28_{Otherstudies,however,havefailed}

toreplicatethisresult.29---31_{Thesestudieshavealsofailedto}

showadverseeffectsofintermediateandlong-actingtopical decongestants.

Thus,limitedevidencesuggeststhatoxymetazolinemay be used occasionally in one or a few episodes of more severe nasal obstruction, which may be interfering with the patient’s sleep, always at the lowest possible dose and preferably after the first trimester, and never close todelivery.28 _{In this sense, it has been shown that after}

a single dose of topical nasal oxymetazoline, therewere nosignificantchangesineithermaternalbloodpressureor heartrate,orchangesintheuterinearteryfloworumbilical vessels.32

Table3 FDAdrugclassificationduringpregnancy.27

Risk Evidence

RiskA Thereisnoevidenceofriskin pregnantwomen.

Well-controlledstudieshaveshowed noproblemsinthefirsttrimesterof pregnancyandthereisnoevidence ofproblemsinthesecondandthird trimesters.

RiskB Therearenoadequatestudiesin pregnantwomen.

Animalexperimentshavedetected norisks.

RiskC Therearenoadequatestudiesin pregnantwomen.

Thereweresomesideeffectsonthe fetusinanimalexperiments,butthe productbenefitmayjustifythe potentialriskduringpregnancy.

RiskD Thereisevidenceofriskinhuman fetuses.

Onlytobeusedifthebenefit outweighsthepotentialrisk: life-threateningsituations,orin casesofseverediseasesforwhich saferdrugscannotbeused,orif thesedrugsareineffective.

RiskX Studieshavedisclosedabnormalities inthefetusorevidenceofrisktothe fetus.

Therisksduringpregnancyoutweigh thepotentialbenefits.Shouldnotbe usedduringpregnancyunderany circumstances.

FDA,UnitedStatesFoodandDrugAdministration.

However, in a more recent study, with 12,734 cases and7606controlsconductedwithchildrenfromtheUnited StatesandCanada,an association wassuggested between theuseoftopicalnasaldecongestantsinthefirsttrimester and hypertrophic pyloric stenosis, as well as the use of topical oxymetazoline in the second trimester with renal collecting system abnormalities in newborns.33 _However,

thestudy didnotmentionthe amountand timeofuse of drugs.

Many authors recommend the use for no more than five, or even three days of topical nasal decongestants duetotheprovenriskofdrug-inducedrhinitis,whichdoes not resolve after delivery.7 _{It is noteworthy that even}

the nighttime use only of decongestants can lead to this condition.24

Themostcommonlyusedsystemicdecongestant, pseu-doephedrine,hasalsoreceiveda‘‘C’’classificationbythe FDA.27,28_{Case---controlstudieshaveshownastatistically}

Table4 Safetylevelofthemostcommonlyuseddrugsforthetreatmentofpregnantwomenwithrhinitis.

FDA

classification

Drugclass Indication Nameofsubstance Detailedinformation

AandB

Oral

anti-histaminics

AR Cetirizine Provensafetyinanimalsandhumans.40

Chlorpheniramine Loratadine Intranasal

corticosteroid

AR Budesonide Safelyusedinasthmaticpregnantwomen.35

NotrecommendedinGR.

C

Oral

anti-histaminics

AR Azelastine

Fexofenadine Intranasal

corticosteroid

AR Fluticasone NotrecommendedinGR.24

Whenconsideringtherisk/benefitinAR,itsuse canbemaintainedifthepregnantwomanwas usingbeforepregnancywithgoodresults.38

Triamcinolone Mometasone Systemic

decongestant

ARandGR Pseudoephedrine Possibleriskofgastroschisisinthefetus(first quarter).Maternaltachycardia,anxiety, tremors,andinsomnia.7,28

Phenylpropanolamine Topical

decongestant

RAandRG Phenylephrine Associationwithcongenitalmalformations, especiallyinthefirsttrimester.28,33

Limitedevidencesuggestssafetyforoneora fewdosesofoxymetazolineafterthefirst trimester.27

Naphazoline Oxymetazoline Xylometazoline

FDA,UnitedStatesFoodandDrugAdministration;AR,allergicrhinitis;GR,gestationalrhinitis.

been replicated in later reviews.28 _{A recent case---control}

study,however, foundastatisticallysignificantassociation between the use of phenylephrine in the first trimester and endocardialwall closure defects, aswell asbetween the use of phenylpropanolamine in the first trimester and external ear malformations and hypertrophic pyloric stenosis.33

Recommendationsfortheuseofsystemicdecongestants duringpregnancy varybetweendifferentcountries.Given the lack of evidenceto date and the side effects of sys-temic decongestants, which include tachycardia, anxiety, tremors, and insomnia in pregnant women, they should be especially avoided in the first trimester and their use should be considered as a risk/benefit ratio during pregnancy.7,28

As for topical corticosteroids, their use is well docu-mentedin other types ofrhinitis (allergicor non-allergic) during pregnancy, but their effect on gestational rhini-tisspecificallyhasnotbeen demonstratedand,therefore, is not recommended.7,24 _{Fluticasone propionate showed}

no significant effect in a double-blind placebo-controlled trial of 53 women with gestational rhinitis treated for eight weeks, when assessed by clinical scores of nasal complaints, peak expiratory flow, and acoustic rhinome-try before and after treatment.35 _{The safety of inhaled}

budesonide, demonstratedbyseveralstudies inasthmatic

pregnantwomen,hasstronglysuggestedthattheintranasal route of administration wasalso safe, attributing tothat productcategory‘‘B’’oftheFDAclassificationforuse dur-ing pregnancy.36,37 _{However, given the fact that none of}

thetopicalcorticosteroidsappeartohaveadversesystemic effectsattheirtherapeuticdoses,36_{theAmericanCollegeof}

Allergy,Asthma,andImmunology(ACAAI) evenstatesthat itisperfectlyplausibletocontinuewithadifferenttopical corticosteroid, ratherthan budesonide, in a patient with allergicrhinitiswhousedthedrugwithgoodresultsbefore pregnancy.38

In relation to systemic corticosteroids, there are not enough studies togenerate recommendations on the dif-ferent types of rhinitis during pregnancy.7 _{Their use is}

consideredan exceptionin thesecases,forshortperiods, toalleviatedecongestantuse.Theiruseforlongerperiods oftimeorathigherdosescanleadtoadrenalinsufficiency, lowbirthweight,andcongenitalmalformations,especially cleftpalate.39

Antihistamines,inturn,arereservedforcasesofallergic or non-allergic eosinophilicrhinitis. In general, there are notenough data in the literature tosuggest that antihis-taminesasagrouphaveadeleteriouseffectonpregnancy.28

Sodiumcromoglycateandtopicalipratropium bromide, the latter used when thereare severe complaints of rhi-norrhea, have shown no teratogenic effects and can be safelyusedforallergicrhinitisduringpregnancy.7 _Theuse

ofanti-leukotrienesinhibitors(suchasmontelukast)forthe treatment ofallergic rhinitis duringpregnancy is not rec-ommended, as there are safer alternative drugs.28 _Drug

measurementsinbothgestationalrhinitisandrhinitisduring pregnancyaresummarizedinTable4.

Finally,surgery---volumereductionofinferiorturbinates ---hasalimitedroleinrhinitisduringpregnancy,reservedfor themostseverecases,whichincludepregnantwomenwith OSASsecondarytogestationalrhinitisandfailureof contin-uous positiveairway pressure(CPAP) or other therapeutic methods.7

Conclusion

Bothgestationalrhinitisandthe‘‘rhinitisduringpregnancy’’ arerelatively commonconditionsthathavegained impor-tance in recent years, not only due to the discovery of association with maternal OSAS and possible unfavorable outcomestothefetus,butalsoduetotheimportantimpact onthepregnant woman’s qualitylife.7,41 _Boththe

otorhi-nolaryngologistandtheobstetricianshouldbealertforan early diagnosis and adequate treatment, considering the safetyprofile andcurrent evidence of available measures andmedications.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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