Respiratorydistress syndrome (RDS) isoneof themostcommoncausesofneonatal respiratory failure andneonataldeath.TheunderlyingpathogenesisofRDS involvesdevel-opmentalimmaturityofthelungs,leadingtoinadequatepul-monarysurfactant(PS)production.Itwaspreviouslybelievedthat RDSmainly occurs in premature infants (1); however,withtheapplicationofantenatalcorticosteroidsanddeliveryroomPS,typicalandsevereRDSinprematureinfantsisnowrarelydiagnosed.GreaterawarenessofRDShasledtoamorefrequentdiagnosisintermneonates(2-5).However,therea-sonsfor theoccurrenceofRDSin termneonatesarediffer-entfromthoseinprematureinfants,andremainunclear.ThisstudyaimedtoinvestigatethecauseofRDSinfull-termneo-natesbyaretrospectivecase-controlstudy,andthusprovideausefulreferenceforitsdiagnosisandtreatment.

MATERIAL AND METHODS

ThisinvestigationwasapprovedbytheethicscommitteeoftheBeijingMilitaryGeneralHospital.Inthisretrospectivecase-control

study, theproportionof thecasegroup(RDSpatients)andcontrolgroup(RDS-freepatients)was1:2.Thefollowinginformationwasrecorded: mode of delivery, birth asphyxia, premature rupture ofmembranes(PROM),maternalageatpregnancy,pregnancyhyper-tensiondisease,gestationalglucoseintoleranceordiabetes,sex,birthweight,acordaroundtheneckwithcompression,oligohydramnios,meconiumstainingofamnioticfluid,severefetaldistress,andpla-centalabruption.

FromJanuary2008toDecember2010,atotalof205full-termnewbornswithRDSwhowereadmittedtotheDepartmentofNeo-natology&NeonatalIntensiveCareUnit(NICU)(thelargestNICUin theworldwith350beds; thereareabout8,000newborninfantsadmitted to thisNICUwithinoneyear) atBayiChildrensHospi-tal,affiliatedwiththeBeijingMilitaryGeneralHospitaloftheBei-jingMilitaryCommand,wereassignedtothisstudy.ThediagnosisoftermneonatalRDSmetthefollowingcriteria(2-5): (1)full-termneonates(gestationalage37weeks);(2)acuteonset;(3)anacute,explicitperinataltriggeringinsult,suchassevereperinatalacquiredinfection, severe birth asphyxia, meconium aspiration syndrome,or delivery by selective cesarean section; (4) representative clini-calmanifestations,includingprogressiverespiratorydistressoccur-ringshortlyafterbirth,tachypnea,expiratorygrunting,nasalflaring,

Background: Respiratory distress syndrome (RDS) is a commoncriticaldisease in termneonates,but reasonsfor theoccurrenceofRDSremainsunclear.Aims:ThisstudyaimedtoinvestigatethecauseofRDSinfull-termneonatesbyaretrospectivecase-controlstudy.Study Design:Case-controlstudy.Methods:Among thepatientsadmitted toBayiChildrensHospitalbetweenJanuary2008andDecember2010,a totalof205 full-termneonateswithRDSwereassignedtothestudygroup,and410full-termneonateswithoutRDSwereassignedtothecontrolgroup.Clinicalin-formation,includingthepresenceorabsenceofprematureruptureofmembranes(PROM),genderoftheneonates,modeofdelivery,birthweight,andanyconditionssufferedbytheneonateswererecorded.Results:Theresultsoflogisticregressionanalysisshowedthatthefollowingcauseswerecloselycorrelatedwith termneonatalRDS:

selectivecesareansection(OR:8.737;95%CI:5.232-14.588),severebirthasphyxia(OR:6.988;95%CI:2.990-16.333),smallgestationalage(OR:6.222;95%CI:2.001-8.993),maternal-fetalinfection(OR:5.337;95%CI:1.999-8.233),PROM(OR:3.380;95%CI:1.986-5.754),malesex(OR:2.641;95%CI:1.721-4.053),gestationalglu-coseintoleranceordiabetes(OR:2.415;95%CI:1.721-4.053),andlowbirthweight(OR:2.323;95%CI:1.329-4.060).Conclusion: Several high-risk factors, such as selective cesareansection,severebirthasphyxia,maternal-fetalinfection,PROM,andmalesexarecloselycorrelatedwithfull-termneonatalRDS.ThesecouldprovideasignificantreferenceforthediagnosisandtreatmentoftermneonatalRDS.(Balkan Med J2014;31:64-68).Key Words: Full-term, high-risk factors, neonate, respiratory dis-tresssyndrome

Copyright Trakya University Faculty of Medicine Balkan Med J2014;31:64-682014

High-riskFactorsofRespiratoryDistressSyndromeinTermNeonates:ARetrospectiveCase-controlStudy

1DepartmentofNeonatology,NICU,BayiChildrensHospitalAffiliatedtoBeijingMilitaryGeneralHospital,Beijing,China2DepartmentofNeonatology,MaternalandChildHealthCareHospitalofHefei,HefeiCity,China

JingLiu1,NaYang1,2,YingLiu1

Original Article |64

AddressforCorrespondence:Dr.JingLiu,DepartmentofNeonatology,NICU,BayiChildrensHospitalAffiliatedtoBeijingMilitaryGeneralHospital,Beijing,China.Phone:+8613301195869e-mail:liujingbj@live.cnReceived: 10.02.2013 Accepted: 24.07.2013 DOI: 10.5152/balkanmedj.2014.8733Available at www.balkanmedicaljournal.org

subcostalretractions,cyanosis,andreducedorabsentbreathsounds,andseveredyspnearequiringcontinuouspositivepressure ventilato-rysupportforatleast72hours;(5)typicalchestX-rayfindings,suchashypoexpansion,diffuse,finegranulardensities,airbronchogramsign,ground-glassopacity,blurredcardiacborders,orwhitelungs;and (6) arterial blood gas analysis showing hypoxia, hypercapnia,andanoxygentension/fractionofinspiredoxygenratio(PaO

2/FiO

2)

26.7kPa.Atotalof410full-termneonateswithjaundicewhowereadmittedtothesamehospitaloverthesameperiodwereincludedascontrols.Thosewithjaundicecausedbyinfectiousdiseases,suchassepticemiaandbacterialpneumonia,wereexcluded.

Additionally,theotherdiagnosticcriteriausedinthisstudywereasfollowing:severebirthasphyxiawasdiagnosedaccordingtothe Expertsconsensuson thecriteriafor thediagnosisandgradingof

Factors Casegroup(205) Controlgroup(410) 2 p-value

Pregnancyage 1.529 0.216 35ys 20(9.8%) 28(6.8%)

neonatal asphyxia inChina, i.e.ApgarScore7at1 to5minutesafter birthwith umbilical arterial pH

DISCUSSION

Theresultsofthisstudyshowthatselectivecesareansec-tion,severebirthasphyxia,PROM,malesex,andgestationalglucose intolerance or diabetes are themain risk factors ofRDSinfull-termneonates. It iswell-knownthat thefactorssmall for gestational age, low birthweight, and gestationalglucoseintoleranceordiabetesplayaroleinthemechanismsofRDS.Therefore,wefocusedontheotherhigh-riskfactors.

SelectivecesareansectionisoneofthemostimportantriskfactorsofRDSintermneonates.Thereasonsforthisareasfollows(8-14). 1-Thereislessactivityofamiloride-sensitivesodiumchannels inalveolarepithelialcellsfollowingcesar-eansection,leadingtoreducedfluidclearance.2-Leadingtorelativeprematurebirth.Whenacesareansectionisperformedearly,theincidenceofRDSincreasesinfull-termneonates.Inourstudy,31.7%ofinfantswereintheRDSgroupatgesta-tionalage38weeks,while itwasonly15.1%innon-RDSneonates.

Severebirthasphyxiaandmaternal-fetalinfectionaretheimportantcausesoftermneonatalRDS(5).Thismaybebe-causeofthefollowingtworeasons:1-acutelunginjurycausedbyseverebirthasphyxiaormaternal-fetalinfectiondecreasesthesynthesisandsecretionofPS;and2-hypoxiaormaternal-fetalinfectioninhibitstheactivityofPSandevenleadstoitsinactivation. Moreover, severe asphyxia and maternal-fetalinfectioncanincreasemortalityandextendthelengthofhos-pitalstayofRDSpatients;thus,itisimportantforustopayattentiontothemanagementofthesepatients.

Thisstudyisthefirsttoshowthatmalesexisariskfac-torfortermneonatalRDS.TherelativeriskofRDSis2.641times higher formales than females. It is believed that thefemalefetallungproducessurfactantearlieringestationthanthemale fetal lung.The reasons for this findingmay be asfollows(15-18). 1-Androgensdelaylungfibroblastsecretionoffibroblast-pneumocytefactor,whichcandelaythedevelop-mentof alveolar type II cells and reduce the releaseofPS.2-Androgens slow fetal lungdevelopment by adjusting thesignalingpathwaysofepidermalgrowthfactorandtransform-inggrowthfactor-beta.3-EstrogenpromotesthesynthesisofPS,includingphospholipids,lecithin,andsurfactantproteinsAandB.4-EstrogenalsoimprovesfetallungdevelopmentbyincreasingthenumberofalveolartypeIIcellsandbyincreas-ingtheformationoflamellatedbodies.

TheresultsofthisstudydemonstratethatPROMisalsoanimportantriskfactorfortermneonatalRDS.Wehypothesizethat thereareseveralreasonswhythismaybethecase(10,19). 1-PROMleadstomaternal-fetalinfection;thisoccursinnearly1/3ofpatientswithPROM(20). IntrauterineinfectionandchorioamnionitiscausedbyPROMcanresultindirectin-jury to the fetal lungs andalveolar type II cells, decreasingthesynthesisor releaseofsurfactant.2-Fetal-neonatal lunginflammationincreasesthepermeabilityofthealveolar-capil-

larymembranetobothfluidandsolutes.Thisresultsinplasmaproteinsenteringthealveolarhypophase,whichfurtherinhib-itsthefunctionofsurfactant.3-PROMleadstorelativelypre-maturebirth.TheORofaneonatebornat38weeksgestationsufferingRDSversusaneonatebornat>38weeks is6.222(95%CI:2.001-8.993).Therefore,relativeprematurebirthisoneoftheimportantreasonswhyRDSisrelatedtoPROM.Similartobirthasphyxiaandmaternal-fetalinfection,PROMcanalsoincreasemortalityandextendthelengthofhospitalstayofRDSpatients;thus,itisalsoimportanttopayattentiontothemanagementofRDSpatientswithPROM.

Inconclusion,theresultsofthepresentinvestigationshowthatselectivecesareansection,severebirthasphyxia,PROM,malesex,gestationalglucoseintoleranceordiabetes,lowbirthweight,smallforgestationalageandmaternal-fetalinfectionare high-risk factors for developingRDS in term neonates.Thesefindingshaveimportantclinicalimplicationsforthedi-agnosisandtreatmentoftermneonatalRDS.

Ethics Committee Approval:EthicscommitteeapprovalwasreceivedforthisstudyfromtheethicscommitteeoftheBeijingMilitaryGeneralHospital.

Informed Consent:Writteninformedconsentwasobtainedfrompatientsparentswhoparticipatedinthisstudy.

Peer-review:Externallypeer-reviewed.

Author contributions:Concept-L.J.;Design-L.J.;Supervision-L.J.;Resource-Y.N.;Materials-L.J.,Y.N.,L.Y.;DataCollection&/orProcessing-Y.N.,L.Y.;Analysis&/orInterpretation-L.J.,Y.N.;LiteratureSearch-Y.N.,L.Y.;Writing-L.J.;CriticalReviews-L.J.

Acknowledgements:WeappreciateMissGuang-PeiGao,whohaspol-ishedthispaperforuscarefully.

Conflict of Interest:Noconflictofinterestwasdeclaredbytheauthors.

Financial Disclosure: This work was supported by China PostdoctoralScience Foundation (20080431405&200801041) and CJP-Kelisu ResearchFunding(cjp2011005).

REFERENCES

1. Koivisto M, Marttila R, Kurkinen-Raty M, Saarela T, Pokela ML,Jouppila P, et al. Changing incidence and outcome of infants withrespiratorydistresssyndromeinthe1990s:apopulation-basedsurvey.Acta Paediatr2004;93:177-84.[CrossRef]

2. FaixRG,ViscardiRM,DiPietroMA,NicksJJ.Adultrespiratorydistresssyndromeinfull-termnewborns.Pediatirics1989;83:971-6.

3. AyachiA,RigourdV,KiefferF,DommerguesMA,VoyerM,MagnyJF. Hyaline membrane disease in full-term neonates. Arch Pediatr 2005;12:156-9.[CrossRef]

4. BouziriA,BenSlimaS,HamdiA,MenifK,BelhadjS,KhaldiA,etal.Acuterespiratorydistresssyndromeininfantsattermandneartermabout23cases.Tunis Med2007;85:874-9.

5. LiuJ,ShiY,DongJY,ZhengT,LiJY,LuLL,etal.Clinicalcharacteristics,diagnosisandmanagementofrespiratorydistresssyndromeinfull-termneonates. Chin Med J (Engl)2010;123:2640-4.

6. Naonatal Professional Committee of Chinese Medical DoctorAssociation. Experts consensus on the criteria for the diagnosis and

Balkan Med J, Vol. 31, No. 1, 2014

67Liuetal.RiskFactorsofRDSinTermNeonates

gradingofneonatalasphyxiainChina.Zhongguo Dangdai Er Ke Za Zhi 2013;15:1

7. Martin RJ, FanaroffAA,WalshMC. Fanaroff &Martins Neonatal-PerinatalMedicine:Diseasesof theFetusand Infant.ElsevierMosbyInc.,9thEdition,Louis,USA,2011:181-187;402-410.

8. GreenoughA.Acute respiratory distress syndrome. In:GreenoughA,MilnerAD, eds.Neonatal RespiratoryDisorders. 2nd edition,Arnold:London;2005:396-398.

9. GreenoughA,RobertonNRC.Acuterespiratorydiseaseinthenewborn,In:Renme JM, Roberton NRC, eds. Textbook of Neonatology. 3rd edition,ChurchillLivingltone:London;1999:481-483.

10. JainL,EatonDC.Physiologyoffetallungfluidclearanceandtheeffectof labor. Semin Perinatol2006;30:34-43.[CrossRef]

11. HansenAK,WisborgK,UldbjergN,HenriksenTB.Riskofrespiratorymorbidityinterminfantsdeliveredbyelectivecaesareansection:cohortstudy.BMJ2008;336:85-7.[CrossRef]

12. TitaATN, Landon MB, Spong CY, Lai Y, Leveno KJ, Varner MW.Timing of elective repeat cesarean delivery at term and neonataloutcomes.N Engl J Med2009;360:111-20.[CrossRef]

13. FarchiS,DiLalloD,PoloA,FrancoF,LucchiniR,DeCurtisM.Timingofrepeatelectivecaesareandeliveryandneonatalrespiratoryoutcomes.Arch Dis Child Fetal Neonatal Ed2010;95:F78.[CrossRef]

14. RobinsonCJ,VillersMS,JohnsonDD,SimpsonKN.Timingofelectiverepeatcesareandeliveryattermandneonataloutcomes:acostanalysis.Am J Obstet Gynecol2010;202:632.e1-e6.

15. NielsenHC,Torday JS. SexDifferences in avian embryo pulmonarysurfactant production:evidence for sex chromosome involvement.Endocrinology1985;117:31-7.[CrossRef]

16. Seaborn T, Simard M, Provost PR. Sex hormone metabolism in lungdevelopmentandmaturation.Trends Endocrinol Metab2010;21:729-38.[CrossRef]

17. NielsenHC.Androgenreceptorsinfluencetheproductionofpulmonarysurfactant in the testicular feminization mouse fetus. J Clin Invest 1985;76:177-81.[CrossRef]

18. BressonE,SeaboornT,CtM,CormierG,ProvostPR,PiedboeufB,etal.Geneexpressionprofileofandrogenmodulatedgenesinthemurinefetaldevelopinglung.Reprod Biol Endocrinol2010;8:2.[CrossRef]

19. YangLC,TaylorDR,KaufmanHH,HumeR,CalhounB.Maternalandfetaloutcomesofspontaneouspretermprematureruptureofmembranes.JAOA2004;104:537-42.

20. Liu J, Feng ZC, Wu J. The Incidence rate of premature rupture ofmembranes and its influence on fetal-neonatal health: a report frommainlandChina.J Trop Pediatr2010;56:36-42.[CrossRef]

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