Review
article
Ischemia
modi
fied
albumin
in
perinatology
Asl
ı
Yarc
ı
Gursoy
a,*
,
Gamze
S.
Caglar
a,
Selda
Demirtas
baUfukUniversityFacultyofMedicine,ObstetricsandGynecologyDepartment,Ankara,Turkey bUfukUniversityFacultyofMedicine,BiochemistryDepartment,Ankara,Turkey
ARTICLE INFO
Articlehistory: Received6April2016
Receivedinrevisedform20October2016 Accepted19December2016
Keywords:
Ischemiamodifiedalbumin Perinatology
ABSTRACT
Ischemia modifiedalbumin is anovel markerof ischemiagenerated due tohypooxygenationand
increasedhydroxylfreeradicalsinlowpH.Themoleculehasbeenlicencedforclinicaluseasanearly
markerforacutecoronarysyndromeincardiology.Sincepresenceofischemiamighthaveseriousand
sometimesdevastatingeffectsinperinatology,variousresearcheshaveevaluateditsvalueindifferent
clinicalconditions.ThisnarrativereviewaimstosummarizetheliteratureconcerningthevalueofIMAin
perinatologyandguideforfurtherresearch.
©2016ElsevierIrelandLtd.Allrightsreserved.
Contents
Introduction ... 183
AssayprinciplesofIMA ... 183
Samplingandstorage ... 183
Albumin,theprominentfactoraffectingIMAlevels ... 183
MaternallevelsofIMA ... 183
IMAlevelsinnon-complicatedpregnancy ... 183
IMAlevelsincomplicatedpregnancies ... 185
Earlypregnancyloss... 185
Recurrentpregnancyloss ... 185
Gestationaldiabetesmellitus ... 185
Mothersbearingsmall-for-gestational-age(SGA)fetuses ... 185
Preeclampsia ... 186
Routeofanesthesiaatdelivery ... 186
UmbilicalcordlevelsofIMA ... 186
Non-complicatedpregnancies ... 186
Routeofdeliveryandanesthesia ... 186
ThedemographicfactorseffectingIMAlevelsinuncomplicatedpregnancies ... 186
Complicatedpregnancies ... 186
Gestationaldiabetesmellitus ... 186
Intrauterinegrowthrestriction ... 186
Complicateddelivery ... 187
Neonatalcomplications ... 187
Conclusions ... 187
Conflictofinterest ... 187
Condensation ... 187
References ... 187
*Correspondingauthorat:UfukUniversityFacultyofMedicine,Departmentof ObstetricsandGynecology,MevlanaBulvarı(KonyaYolu),No:86 88,06520Balgat/ Ankara,Turkey.
E-mailaddress:asliyarci@gmail.com(A.YarcıGursoy).
http://dx.doi.org/10.1016/j.ejogrb.2016.12.022
0301-2115/©2016ElsevierIrelandLtd.Allrightsreserved.
ContentslistsavailableatScienceDirect
European
Journal
of
Obstetrics
&
Gynecology
and
Reproductive
Biology
Introduction
Albuministhemostabundantproteininhumanplasma,which actsasabufferingagentfortoxicmolecules.TheN-terminusof albuminmoleculebindsmetals,inadditiontonucleicacid,lipids andotherproteins.Thestructureofalbuminmoleculeisaltered graduallyin the presence of ischemia. The cascade starts with hypo-oxygenationaccompaniedbyloweredpH.Whenhydroxyl freeradicalsaregenerated,theN-terminusofalbuminmoleculeis damaged.Alteredalbuminisunabletobinddivalentmetalsand release the boundforms [1] called ischemiamodified albumin (IMA)[2].
Themoleculeismostlystudiedincardiologicevents,elevated beforenecrosis,atearlystagesofischemia.IMAisproposedtobe anefficientendogenousresponsetoischemia,preventing myocar-dialdamageorlimitingtheextentofmyocytenecrosis[3].IMAis approvedbyUSFoodandDrugAdministration(USFDA)foruseas anearlymarkerinrulingoutacutecoronarysyndromeinlow-risk patientsbytheAlbuminCobaltBinding(ACB)assay[3].Butalso, IMAlevelshavebeenshowntoincreaseinpathologicalconditions otherthanmyocardialischemiasuchaspulmonaryembolism[4], poorglycemiccontrolinTypeIIdiabetesmellitus[5],trauma[6], acute decompensated heart failure [7] and acute blood loss inducedischemia[8].Ontheotherhand,IMAlevelshavebeen shown todecreasein clinical conditions withincreasedlactate concentrationssuchassepsis,muscleischemiaandrenalfailure
[9,10].AccumulatingevidenceindicatingIMAasavaluablemarker ofischemia,boostinterestforresearchersinperinatology(Table1). This review summarizes the results of the electronic research performedinPubMed,Scopus,andGoogleScholar.Alldatabases wereassesseduptoApril2016.Thedatabasesweresearchedfor keywords‘ischemiamodifiedalbuminANDmaternalORfetalOR cordbloodORpreeclampsiaORintrauterinegrowthretardation OR gestational diabetes OR abortion OR pregnancy loss OR anesthesia OR delivery OR neonate OR pregnancy’ concerning thevalueoflevelsineveryaspectofperinatology.
AssayprinciplesofIMA
TheprincipleformeasuringIMAlevelsreliesonthemodi fica-tionofthealbuminatthepresenceofoxygenradicals[11,12].In normal conditions, cobalt is bound to albumin with minimal circulatingfreelevels[1].Butmodifiedalbuminduetoradicals,is unable to bind cobalt and unbound amount of cobalt enables measurement of IMA levels indirectly. The reactant used for measurementoffreecobaltlevelsis,dithiothreitol,whichresults indevelopmentofcolourinaspectrumrangingbetween470and 500nm[2].Therearetwotestsavailable,oneofwhichismanual
[13] and the otherautomated commercialassay (Cobas Fara1/ Albumin Cobalt Binding1 Test and Roche Cobas Mira1 Plus)
[13,14].Themanualassaygivesthemeasurementsinabsorbance units(A.U.,ABSU)whilethecommercialassaygivestheresultsin arbitraryunits(kUI 1)[2].Otherthanthese,quantitativesandwich enzymeimmunoassaytechnique(ELISA)isanotherbutrarelyused method[15].
Samplingandstorage
Serumratherthanplasmasampleshouldbeused.Theserum sample should be drawn into a non-heparinized closed tube, centrifuged within 1h, and stored at +4C before running to instrument[16].Thedurationoftimefrombloodwithdrawalto instrumentresultmustbelessthan5h[16].Incaseofstoragefor longerdurations, the specimens should be keptat 20C and thawedat+4C[16].Thestorageofbloodspecimensat26Cor centrifugationjustpriortotheanalysis,resultwithdecreasedIMA
valuesmeasuredwithACBassay.Also,thetestreagentsshouldbe keptinrefrigerator(+4C)andareknowntobestablefor12days afterreagenttwo(DTTconcentrate)reconstitution[16].
Albumin,theprominentfactoraffectingIMAlevels
For more accurate results, total albumin levels should be between3and5.5g/dL.Thealbuminconcentrationofthesample might effect ACB assay results in opposite direction [1,11]. Especiallyincaseswithlowalbuminlevels(<3.5g/dL)thechange inIMAresultsisstronger[1].Thisdeterminationespeciallygains importancewhileworking onspecialpopulationssuchas new-bornsandpregnantwomenwhosenormalalbuminvalueranges arelowerthannormaladultpopulation[17,18].Inthesampleswith albuminlevelsrangingbetween0and6g/dL,IMAvalueschanged up to37–48% from thebaseline with each 1g/dLalteration of albumin[11].ThenegativecorrelationbetweenalbuminandIMA levelshasledtogenerationofadjustmentformulasfor interfer-enceonserumIMAassay.TheformulasuggestedbyLeeetal.[19]
is “albumin-adjusted IMA index”, defined as: serum albumin concentration(g/dL)23+IMA (U/mL)–100. Another formula is based on median albumin levels of the target population as: (individual serum albuminconcentration/median albumin con-centrationofthepopulation)IMA[20](Lippietal.).Others[21]
suggestedIMA/Albuminratioforalteredalbuminlevels. MaternallevelsofIMA
IMAlevelsinnon-complicatedpregnancy
TheimpactofpregnancyonIMAlevelshavebeenevaluatedin three prospective studies.Thefirst reportwas held in2007 by Prefumoetal.[22].FirsttrimesterlevelsofIMAin66singleton pregnanciesat11–13thweeksofgestationwerecomparedwith26 non-pregnantcontrols[22].ThemedianIMAlevelinthepregnant group (115.14kU/L)was significantly higher (p<0.001) than in non-pregnantcontrols(73.71kU/l). Theauthorssuggested preg-nancyasthefirstphysiologicalconditionwithsupraphysiological IMAlevels[22].Others[15]alsoreportedsignificantlyhigherIMA levels in healthy pregnant subjects compared to non-pregnant controls (median values: 173.2 vs 118.8ng/mL, respectively, p<0.05). The firstexplanation forhigh IMAlevelsin pregnant womenmightbethehypoxicintrauterineenvironmentassociated withearlyhumanplacentationduetopluggingofspiralarteriesby extravilloustrophoblastcells[23].Secondly,theincreasedlevels ofIMAinthelatefirsttrimestermightbearesultofradicaloxygen speciesincreasedduetoriseinoxygenconcentrationsinducedby maternalbloodcirculationintheintervillousspace[24].Therefore, thehighIMAlevelsinfirst trimestermight beacompensatory outcomeforneutralizationofoxidativestressratherthanaresult ofit.
Onthecontrary,anotherstudy[25]aboutIMAreportedmean levelsof0.460.12ABSUinthefirsttrimester(<14weeks,n=24), 0.580.11ABSUinthesecondtrimester(14–28weeks,n=34)and 0.610.11 ABSUinthethirdtrimester (>28weeks,n=35).This study documented gradually increasing IMA levels throughout pregnancy whichis stilllower thancontrols(n=23,0.670.08 ABSU)(p=0.001).Thelimitationofthisstudywassamplingwhich mightdecreasethereliabilityoftheresults.
ThereferencevaluesforIMAlevelsinpregnancystillneedsto bevalidatedin furtherlargepopulationbasedstudies.Butuntil then,theresultsfromthefirststudyreportedbyPrefumoetal. cannot be disregarded [22]. As previously mentioned, FDA approvedIMAfor diagnosisofmyocardialischemiawith deter-mined cut off values of>95kU/L withACB assay. However,the studybyPrefumoetal.[22],reportedhigherIMAlevelsin84%of
Table1
SummaryofthestudiesevaluatingvalueofIMAinperinatology.
Author Studypopulation Sample/IMA
Units
Conclusion Pregnancy
Prefumoetal.
[22]
Healthywomenwithsingletonpregnancies(n=66) Non-pregnantcontrols(n=26)
MaternalIMA (kU/I)
IMAlevelsaresupra-physiologicinearlynormalpregnancy Guvenetal. [25] Pregnantwomen 1sttrim.(n=24) 2ndtrim.(n=34) 3rdtrim.(n=35)
Non-pregnanthealthywomen(n=23)
MaternalIMA (ABSU)
SerumIMAincreasesinpregnancy
Early Pregnancy Loss Cengizetal.
[15]
Healthypregnantwomen(n=60)
Pregnantwomenwithabsentfetalcardiacactivity(n=60) Non-pregnanthealthywomen(n=60)
MaternalIMA (ng/mL) MaternalIMA (ng/mL) (Adjusted)
SignificantlyhigherIMAconcentrationsinearlypregnancy loss
AnIMAthresholdof>163ng/mLispredictorforearly pregnancylossinfirsttrimester(sensitivityof75%, specificityof55%)
Özdemiretal.
[26]
2ormoreunexplained1sttrimestermiscarriages(n=43) Healthypregnantwomenin1sttrimester(n=42)
Maternal) IMA(ABSU) (Adjusted
SignificantlyhigherIMAlevelsinwomenwithrecurrent pregnancyloss
Gestational Diabetes Mellitus
Maetal.[30] Gestationaldiabetesmellitus(n=40) Normalglucosetolerance(n=30)
MaternalIMA (U/L)
HigherserumIMAlevelsingestationaldiabetesmellitus Topalogluetal.
[45]
GestationalDiabetesMellitus(n=29) Healthypregnantsubjects(n=20)
CordBlood IMA(ABSU)
HighercordbloodIMAlevelsininfantsfromdiabetic mothers
SmallFor Gestational Age
Rossietal.[34] PregnancieswithAGAfetuses(n=65) PregnancieswithSGAfetuses(n=16) 1sttrimester
2ndtrimester Postpartum
MaternalIMA (ABSU)
HigherfirsttrimesterIMAlevelsinpregnancieswithSGA
Güvendag Guvenetal.
[47]
OligohydramniosandIUGR AbnormalDopplerindices(n=20) NormalDopplerindices(n=20)
CordBlood IMA (ABSU)
HighercordbloodIMAlevelsinintrauterinegrowth restrictedinfantswithabnormalDopplerindicescompared tonormalDopplerindices
Iacovidouetal.
[43]
AGAFetuses(n=110)
AsymmetricIUGRfetuses(n=57)
CordBlood IMA(IU/mL)
NodifferenceincordbloodIMAlevels
HighercordbloodIMAlevelsinfetusesbornfrom multigravidasandC/Sdeliveries
Preeclampsia Dsouzaetal.
[21]
Pregnantwomenwithpreeclampsia(n=50) Mild(n=32)
Severe(n=18)
Healthypregnantwomen(n=50)
MaternalIMA (ABSU)
HigherserumIMAlevelsinpreeclampsia
Gafsouetal.
[38]
Pregnantwithpreeclampsia(n=20) Healthypregnant(n=19) Non-pregnanthealthy(n=22) MaternalIMA (kU/L) Maternal IMA/Albumin (kU/g)
HigherIMA/albuminratioinpregnantsubjectscomparedto non-pregnantsubjects
HigherIMA/Albuminratioinpregnantsubjectswith preeclampsia
Papageorghiou etal.[40]
Pregnantsubjectswithpre-termpreeclampsia(n=19) Controlswithnormalpregnancyoutcome(n=69)
MaternalIMA (kU/L)
HigherfirsttrimesterserumIMAconcentrationsinwomen whosubsequentlydevelopedpreeclampsia
VanRijnetal.
[35]
Patientswithpreeclampsia(n=12) Healthypregnant(n=12) Non-pregnant(n=12)
MaternalIMA (U/mL)
HigherIMAlevelsinnormalpregnantcontrolscompared withnonpregnantcontrols.
NodifferenceinIMAlevelsbetweenpreeclampsiacasesand normalpregnantcontrols.
Ustunetal.[39] Pregnantwomenwithpreeclampsia(n=36) Mild(n=18)
Severe(n=18)
Normotensivepregnantwomen(n=18)
MaternalIMA (ABSU)
HigherIMAlevelsinthemild/severepreeclampsia IMAcut-off0.31ABSUispredictiveforpreeclampsia (sensitivity80%,specificity77.8%)
Dahiyaetal.
[31]
Womenwithpreeclampsia(n=30) Healthypregnantwomen(n=30)
Cordblood IMA(ABSU)
HigherIMAlevelsinnewbornsborntomotherswith preeclampsia
the healthy pregnant subjects. Therefore, it is mandatory to evaluate IMA levels cautiously for diagnosis of myocardial ischemia in pregnancy since false positive results seem to be possible.
IMAlevelsincomplicatedpregnancies Earlypregnancyloss
Thewomenwhowereadmittedforterminationofpregnancy (absence of fetal cardiac activity or absence of fetal pole on ultrasonography)(n=60)was foundtohavesignificantlyhigher IMA concentrations than healthy pregnant women (n=60) (median values 206.5 vs 173.2ng/mL, respectively; p<0.05)
[15].SerumIMAconcentrationsweremeasuredusinga quantita-tivesandwichenzymeimmunoassaytechnique[Humanischemia modifiedalbumin(IMA)ELISAKit, Cusabio,Wuhan,China].The authors concluded that, increased IMA levels in unhealthy pregnanciesmightreflectincreasedoxidativestress[15]. Recurrentpregnancyloss
AnotherstudyevaluatedIMAlevelsinsubjectswithrecurrent pregnancyloss(RPL)(>2)inearlyfirsttrimester(n=42)comparing withhealthypregnancies(n=43)inthefirsttrimester.Theauthors concluded that these subjects, had lower albumin levels than controlsubjectsandbothIMAandadjustedIMAvalues[20](Lippi et al) were higher in this group of patients (1.110.08 vs 0.880.10ABSU,p<0.001and 1.090.09 vs 0.880.11 ABSU; p<0.001)[26].ThehigherlevelsofIMAandadjustedIMAincases withRPLmightbeduetodefectiveplacentation[27]resultingwith a more ischemic environment. The sampling at the time of miscarriage might have caused bias as it is impossible to discriminatewhetherthereportedhighIMAlevelsisassociated with the history of recurrent pregnancy loss or the current miscarriage[15].
Gestationaldiabetesmellitus
IMAhasbeenacceptedtobeanovelmarkerofoxidativestress related withischemia [28,29].IMA is higher inType Idiabetic subjectscomparedtocontrols,especiallywhenketoasidosisexists. Thereducedlevelsafterinsulintherapysupportsthecorrelation betweenoxidativestressandIMAlevels[30].IMAlevelsarehigher inTypeIIdiabeticsubjectsexplainedbychronichypoxiaprovoked mainlybyhyperglycemiaandoxidativestressandIMAmightbe morethanacardiacmarkerinsuchsubjects[5].IMAlevelsdonot riseinTypeIIdiabeticsubjectsatthetimeofdiagnosiswithout vascular complications [31] but increase in cases withdiabetic retinopathy, positively associated with the severity of the condition[32].
Similarly, gestational diabetes mellitus (GDM) has been reportedtobeaccompaniedbyincreasedoxidativestressproducts and reduced antioxidant enzyme activity [33]. Ma et al. [30], measuredIMAlevelsbetween26–28thweeksofpregnancyin40 pregnant women with GDM (25 treated with continuous subcutaneous insulin infusion and 15 treated with medical nutritiontherapy)and30pregnantwomenwithnormalglucose tolerance.IMAlevelsweresignificantlyhigherintheGDMgroup. TheeffectoftherapeuticinterventionforGDMonIMAlevelswas alsoanalyzed.Afterintervention,eitherwithmedicalnutritionor withinsulininfusion,IMAlevelsinGDMsubjectswerereduced. The decline in IMA levels were slightly higher with insulin treatmentthandiettherapy.Also,apositivecorrelationbetween fastingplasmaglucose andIMAlevelswasreportedwhichwas supported by the previous study designed in Type II diabetic subjects[5].
Mothersbearingsmall-for-gestational-age(SGA)fetuses
ThestudyconcerningfirsttrimestermaternalIMAlevelsin11– 14thweeksofgestationresultingwithSGAfetusesdocumented higherIMAlevelsthanmotherswhogavebirthtoappropriatefor
Table1(Continued)
Author Studypopulation Sample/IMA
Units
Conclusion Mehmetoglu
etal.[48]
Neonatesborntopreeclampticmothers(n=30) Neonatesborntonormotensivemothers(n=20)
CordBlood IMA(ABSU) NeonateIMA (ABSU)
NodifferenceincordbloodIMAlevels
HigherIMAlevelsinneonatevenousbloodinthe preeclampsiagroup
IMAweresignificantlydecreasedafterdeliveryinboth groups.
Delivery Caglaretal.
[42,44]
Cesareansectionduetofetaldistress(FD)(n=40) Electiverepeatcesareansection(n=76) Noncomplicatedvaginaldelivery(n=85)
MaternalIMA (ABSU) Cordblood IMA(ABSU)
LowermaternalandumbilicalcordIMAlevelsinvaginal deliveriescomparedwithFDorpreviousCSgroups. SimilarcordbloodIMAvaluesinFDgroupcomparedto previousCSgroup
Gugliuccietal.
[49]
Normaltermdeliveries(n=12)
Complicatedorpretermdeliveries(n=14) Healthyadults(n=30)
MaternalIMA (ABSU) Cordblood IMA(ABSU)
CordbloodIMAlevelsofcomplicateddeliveriesare50% higher
IMAvaluesweremorethan300%higherincasesofsevere fetalhypoxia.
Anesthesia
Omuretal.[41] Healthypregnantwomen(n=51) Generalanesthesia(n=28) Epiduralanesthesia(n=21) MaternalIMA (ABSU) Cordblood IMA(ABSU)
HigherIMAlevelsingeneralanesthesia
HigherIMAlevelsandIMA/albuminratiosat30minof surgerycomparedwiththeimmediatepreoperativeperiod ingeneralanesthesia
Caglaretal.
[42,44]
Uncomplicatedtermpregnancies(n=72) Generalanesthesia(n=35) Spinalanesthesia(n=37) MaternalIMA (ABSU) Cordblood IMA(ABSU)
HighermaternalandfetalIMAlevelsingeneralanesthesia IMAlevelsincreaseastimefromincisiontodelivery lengthens,.
gestational age fetuses. The authors emphasized that an early reflection of early placental changes occurring before clinical manifestationsofSGAandpresenceofasubclinicalbutexcessive oxidativestresswhich startsinthefirsttrimestermight bethe possibleexplanationfortheseresults[34].Inanotherstudy,IMA levelsofwomenwithSGAfetuses(<5thcentile)atthirdtrimester ofpregnancywerenotdifferentfromwomenwithappropriatefor gestationalagefetuses[35].SGAnewbornsarea heterogeneous groupconsistingoffetuseswithfetalgrowthrestriction(FGR)due toplacentalinsufficiencyandthosewhoareconstitutionallysmall. Fromthecriticalpointofview,reachingaconclusiononhigher IMAlevelsin SGAgroup,might bemisleadingand theauthors wouldratheranalyzeIMAlevelsinsubgroupsasSGAorFGRto reachmoreaccurateconclusions.
Preeclampsia
Defectiveendovasculartrophoblasticinvasionandinadequate remodelingoftheuterinespiralarteriesisknowntobeassociated withthedevelopmentofpre-eclampsiaandhypoxia[36,37].IMA levelinsuchcases,isexpectedtobehigher thancontrols.IMA levelsin pregnant subjects(n=12)(107.3U/mL; 95% CI,102.5– 112.01) werehigher than non-pregnant (n=12)(94.5U/mL; CI, 89.4–99.6;p=0.015)butIMAlevelsinpreeclampsiasubjectswere notdifferentfromhealthypregnantsubjects(n=12)(109.7U/mL; CI, 102.2–117.2; p=0.65) [35]. On the contrary, IMA and IMA/ albuminratiowerehigherinpregnantsubjectswithpreeclampsia (n=20)(116.912.3kU/l),comparedtohealthypregnant(n=19) (98.498.4kU/L) suggesting IMA as a biological marker for preeclampsia[38].Supportingthesedata,in thestudyofUstun et al. IMA levels were significantly higher in subjects with preeclampsia(n=54) comparedtocontrols (n=18).IMAwitha cutoff valueof 0.31 ABSU was found toidentify women with preeclampsiawithasensitivityof80%andspecificityof77.8%[39]. Alsothestudygroupwasdividedintotwosubgroupsasmildand severe preeclampsia and IMA levels in women with severe preeclampsiawerehigherthanwomenwithmild preeclampsia suggestingthatIMAlevelsatthetimeofdiagnosisofpreeclampsia werecorrelatedwiththeseverityofthedisease[39],whichneeds tobeconfirmedbyfurtherresearch.
Fromanotherpointofview,maternalIMAlevelswerefoundto bepredictiveforpreeclampsia.Pregnantwomenwho subsequent-lydevelopedpreeclampsiahadsignificantlyhigherIMAlevelsin thefirst trimester of pregnancy compared to healthypregnant subjects (median 126.5 kU/L, interquartile range (IQR) 114.33– 134.36kU/L vs median 115.01kU/L, IQR 102.29–124.81kU/L, p=0.02) [40]. Increment in IMAlevels far before the clinically apparentdisease,wassupposedtobeapotentialearlymarkerof abnormal placentation. However, the authors did not mention aboutthesensitivity,specificityandpredictivevalueofIMAlevels in the first trimester. Although the authors [40] suggest the differenceinIMAlevelsismostlikelytheconsequenceofincreased trophoblasthypoxia,IMAasa markerofabnormalplacentation needstobeproven.
Pregnancyisadynamicstatewithchangingreferencevaluesof many parameters including albumin. Also superimposed pre-eclampsiais characterizedwithsignificantchanges in hemody-namicsandbloodparameters.Asthereversecorrelationbetween IMAandalbuminhasbeenrevealedbymanyauthors,theIMA levels evaluated in this special population (pregnant women, pregnantwomenwithpreeclampsia)mightneedadjustmentand correctionaccording toalbuminconcentrations, for more clear conclusions.Additionally,smallnumberofcases,differentunitsfor IMAanddifferentforms ofthedisease(earlyvs late)mightbe otherpossibleexplanationsforconflictingresultsofthestudies.So weinferthatfurtherstudieswithlargernumberofsubjectsshould bedesignedtoreachmoreclearconclusionsinwhichcorrectedor
adjustedvaluesofIMAisusedsincesuggestinganearlymarkerfor abnormalplacentationleadingtopreeclampsiahasgreat impor-tanceinobstetricpractice.
Routeofanesthesiaatdelivery
Effect of routeof anesthesia onmaternal IMAlevels during cesareansectionhasalsobeenevaluatedbytwo studies.Ömür etal.[41]reportedthatmaternalIMAlevelssignificantlyincreased at30thminuteduringcesareansectionundergeneralanesthesia while there was not a significant alteration in the regional anesthesiagroup.Thedifferencebetweentworoutesofanesthesia mightbeduetobettersuppressionofoxidativestressbyregional anesthesia compared togeneral anesthesia. Our previousstudy supportshighermaternalIMAlevelsingeneralanesthesiagroup comparedtoregionalanesthesia[42].Althoughoxygensaturation levelswererelativelyhighinbothgroups(medianvalues99–100 for both groups), a significant difference in oxygen saturation levelsatdifferenttimepoints(1,2,5and10thminutes)between regionalandgeneral anesthesiagroups mightbeacontributing factorforhigherIMAlevelsingeneralanesthesiagroup. UmbilicalcordlevelsofIMA
Non-complicatedpregnancies Routeofdeliveryandanesthesia
ThecordbloodIMAlevelshavebeenshowntobehigherin fetusesdeliveredbyelectivecesareansectioncomparedto non-complicated vaginal delivery [43,44]. Also, impact of route of anesthesiaoncordbloodIMAlevelshasbeenevaluatedbytwo studiesresultingwithconflictingoutcomes.Thefirststudy[41]
reportedthattherouteofanesthesia didnothavea significant impactoncordbloodIMAlevelswhilethesecond[42]reported significantlyincreasedcordbloodIMAlevelsinneonatesdelivered under general anesthesia. The increment in IMAlevels suggest oxidativestressingeneralanesthesiagroup.
ThedemographicfactorseffectingIMAlevelsinuncomplicated pregnancies
Gestationalageandgenderofthefetushasbeenshowntohave noeffectonthecordbloodIMAlevels[43].Intwostudies,cord bloodIMAlevelswerepositivelycorrelatedwithfetalbirthweight
[42,43]. However, the positive correlation between maternal gravidityandparityseemtobeanunexpectedincidentalfinding
[42,43].
Complicatedpregnancies Gestationaldiabetesmellitus
ThelevelsofIMAwerefoundtobestatisticallyhigherincord blood of fetuses born to gestational diabetic mothers (n=29) compared to control subjects (n=20) [45]. The presence of a potentialoxidativestressininfantsborntodiabeticmothersneeds tobeelucidatedbyfurtherresearch.
Intrauterinegrowthrestriction
Previously, an imbalance between oxidative stress markers (TOS; Totaloxidant status)andantioxidantcapacity (TAS: Total antioxidantstatus)hasbeenshowninfetuseswithIUGRresulting withincreased oxidativestressindex [46].IMA asa markerof oxidativestress,hasalsobeenevaluatedintwostudiesinIUGR fetuses.
InthefirststudyIMAlevelsincordbloodoffetuseswhohad IUGR (n=57,<3rd percentile) were found to be similar with appropriateforgestationalagefetuses(n=110)(115.54 (111.97– 119.12)IU/mL vs 112.44 (109.95–114.92) IU/mL; p>0.05) [43].
Heterogeneityoftherouteofbirth(vaginal/cesareansection)and route of anesthesia in cesarean sections were the possible interferingfactorsforIMAlevels,asmentionedpreviously[42].
Inanotherstudy[47],theoxidativestressmarkersincluding IMA(0.407(0.364–0.496)vs0.235(0.120–0.361)ABSU;p<0.001) incordbloodofIUGRfetuseswithabnormalDopplerindices(a decreaseof>2SDinmiddlecerebralarterypulsatilityindicesoran elevation of>2SD umbilical artery pulsatility indices) (n=20) performedinthelastsixhourspriortodeliveryatbetween33and 41weeks’gestation,werefoundtobesignificantlyelevatedand neededintensivecareunitsubmissioncomparedtoSGAfetuses withnormalDopplermeasurements(n=20)Besides,antioxidant markerswerefoundtobesignificantlylowerinIUGRgroup.Small samplesizeofthesestudiesenablestodrawfinalconclusions. Complicateddelivery
Two reports [31,48] documented higher IMA levels in cord bloodoffetusesborntowomenwithpreeclampsiacomparedto healthypregnantsubjects.Thefirstauthor[31]reportedsigni fi-cantlyelevatedcordbloodIMAlevelsinsubjectswith preeclamp-sia (0.8350.02 vs 0.3250.01 ABSU, p<0.001) compared to controls.Intheotherstudy[48]atday7,IMAlevelsofneonates frommotherswithpreeclampsia(n=20)weresignificantlyhigher thanneonatesofhealthypregnantsubjects(n=30)(0.530.27vs 0.290.17ABSU,respectively,p<0.001)[48].Likewise,IMAhas beenalsoevaluatedincordbloodofneonatesfromcomplicated deliveries [49]. The cord blood IMA levels in neonates from complicateddeliveries(n=14)wassignificantlyhigher(50%)than cordblood fromuncomplicated deliveries (n=12) classifiedby normalorlowApgarscores[49].
ThedifferenceinIMA(300%)wasremarkableinneonatesborn with severe hypoxia (Apgar 5). Another study [44], revealed, althoughnotsignificant,higherIMAlevelsinneonateswithfetal distress (persistent late decelerations or recurrent prolonged decelerations) (n=40) compared to elective cesarean section (n=76).TheauthorsreportedanegativecorrelationbetweenIMA levelsand1st minuteApgarscoresbutwith alow rvalue[44]. Therefore,theseresultsneedtobeconfirmedwithfurtherresearch. IMA might be a future potential marker, on its own or as an adjunctiveparameter,inevaluatingfetalischemiainthefuture.
Deprivationofoxygentoafetusmightoccurbefore,duringor afterbirth(perinatalasphyxia).Perinatalasphyxiaispredictedby objectiveparameterssuchasumbilicalarterybloodgasanalysis, fetal scalppHmeasurement and fetalelectronicmonitoring, or subjective parameters such as presence of meconium-stained amnioticfluid,Apgarscoreincombination[50].Increasedlevelsof IMA in cord blood are reported in perinatal asphyxia when comparedtohealthycontrols[51].OthersalsosuggestedthatIMA might be useful for the prediction and diagnosis of perinatal asphyxia[50].
Neonatalcomplications
Up to now there are few studies concerning IMA levels in neonatal complications. The oxidative stress induced during mechanical ventilation [ventilated by 2 different modes of ventilation (SIMV and CPAP), both during ventilation support andaftercessationofventilation]wasevaluatedbyIMA,TACand TOSlevelsinneonates.IMAwasfoundtobesignificantlyhigher duringventilationinbothmodesofventilationfavoringincreased oxidativestress[50].OthersfoundsignificantlyhigherIMAlevels inneonateswithtransienttachypneaofthenewborn(TTN)[52]. Although TTN is usually a self-limited disease, it has been determined by the authors, to cause hypoxia in the newborn. Moreover,rarelysubstantialmorbiditiesmightbeobserved.The authorssuggestthat,IMAasapotentialbiomarkerofhypoxiaanda productofconcurrentoxidativestress,mightbeusedtodiagnose
the degree of hypoxia caused by TTN but also severity of the process.Being thefirstprospective controlledstudyconcerning IMAlevelsinpredictionandseverityofTTN,theseresultsneedto beconfirmedwithfurtherstudiestoconcludeonthesubject.
In another study [53] which included preterm infantswith necrotizingenterocolitisofdifferentstages,IMAwasevaluatedasa markerconcerningdiagnosisandseverityofthedisease.Infants with 32 weeks of gestation, 1500g of birth weight were enrolledinthestudyandneonateswithtrueNECweredefinedas thestudygroup(n=37),whileneonateswithoutNEC(n=36)were defined as the control group. Blood samples were taken for evaluation of CRP, IL-6, and IMAwere collectedat thetime of diagnosis(firstday),thethirdday,andseventhdaysinstudygroup whilebloodsampleswerecollectedatthethirddayoflifeinthe control group. Twenty patients (54%) had stage-II NEC and 17 patients(46%)had stage-IIINECinthestudygroup.The serum levels ofIMA, CRP, and IL-6 determinedat thefirst dayof the diagnosisinthestudygroup(P<0.001)weresignificantlyhigher thancontrolgroup.Moreover,althoughtherewasnotasignificant differencebetweenIL-6andCRPlevelsinneonateswithstage–II and stage-III diseasewhen compared atthreetime points,IMA levelsweresignificantlyhigherinneonateswithstage-IIIdisease compared to ones with stage-II disease for all time points suggesting that IMA might be a superior marker relative CRP andIL-6inbothissuesbothdiagnosisandseverityofNEC.
AgroupofauthorsalsosearchedaboutIMAlevelsinpreterm neonateswithsepsisbeforeandaftertreatment(atthe5thdayof antibiotherapy) [54]. The study revealed that IMA levels were significantlyhigherinsubjectswithsepsisbeforethetreatment compared toafterthetreatmentand controlgroupvalues. The authorsconcludedthatIMAlevelsmightbeusefulinlate-onset neonatalsepsis bothatthetimeofdiagnosisand alsoafterthe therapy.
Conclusions
Consequently, maternalIMAlevelshavebeenrevealedtobe higher in pregnancies complicated with preeclampsia, diabetes mellitus and IUGR. Although in these studies p values are reassuringatp<0.05,mostoftheassociationshaveoverlapping 95% confidence interval and standart deviations. In addition, interpretationofstatisticalsignificanceshouldbeunder consider-ation ofsmallsample sizes.Thestrikingpointisincreasedcord blood IMA levels in intrauterine hypoxic conditions and birth asphyxia. The long-term consequences of ischemia determined high cord blood IMA levels necessitates follow-up of these neonates. Although the accumulated data concerning value of IMAisstillscarcetoconcludeaboutitsuseinperinatologypractice, thisareaofreserchseemstodeservefurtherinvestigation.
Conflictofinterest
The authors declare that no actual or potential conflict of interestinrelationtothisarticleexists.
Condensation
Ischemiamodifiedalbumin,anovelmarkerofischemia,might be a promising marker in perinatology practice but further researchisneeded.
References
[1]GazeDC,CromptonL,CollinsonP.Ischemia-modifiedalbuminconcentrations shouldbeinterpretedwith cautioninpatients withlow serumalbumin concentrations.MedPrincPract2006;15(4):322–4.
[2]Dominguez-Rodriguez A, Abreu-Gonzalez P. Current role of ischemia-modifiedalbumininroutineclinicalpractice.Biomarkers2010;15(8):655–62. [3]LippiG, MontagnanaM,GuidiGC.Albumincobaltbindingandischemia modifiedalbumingeneration:anendogenousresponsetoischemia?IntJ Cardiol2006;108:410–1.
[4]TurediS,GunduzA,MenteseA,KarahanSC,YilmazSE,ErogluO,etal.Valueof ischemia-modifiedalbumininthediagnosisofpulmonaryembolism.AmJ EmergMed2007;25(7):770–3.
[5]PiwowarA,Knapik-KordeckaM,WarwasM.Ischemia-modifiedalbuminlevel intype2diabetesmellitus–preliminaryreport.DisMarkers2008;24(6):311–7. [6]CanM,DemirtasS,PolatO,YıldızA.Theevaluationoftheischemiceffectson albumincobaltbindingassay(ACB)inthepatientswhoexposuredtotrauma. EmergMedJ2006;23(7)537–92006.
[7]ÇavuşogluY,KorkmazŞ,DemirtaşS,GencerE,ŞaşmazH,MutluF,etal. Ischemia-modified albuminlevels inpatients with acutedecompensated heartfailuretreatedwithdobutamineorlevosimendan:IMA-HFstudy.Anatol JCardiol2015;15(8):611–7.
[8]ŞekerR,OguzAK,ÖzdemirS,DemirtaşS,AylıM,MergenK.Theevaluationof IMAasacardiacischemiamarkerinthecasesofhypohemoglobinemiaand hypoxemiaduetobloodloss.TurkBiochem2014;39(2):221–5.
[9]RoyD,QuilesJ,SharmaR,SinhaM,AvanzasP,GazeD,etal.Ischemia-modified albumin concentrationsin patientswith peripheralvasculardisease and exercise-inducedskeletalmuscleischemia.ClinChem2004;50:1656–60. [10]Zapico-MuñizE,Santaló-BelM,Mercé-MuntañolaJ,MontielJA,
Martínez-RubioA,Ordóñez-LlanosJ.Ischemia-modifiedalbuminduringskeletalmuscle ischemia.ClinChem2004;50:1063–52004.
[11]HakligörA,KösemA,SeneşM,YücelD.Effectofalbuminconcentrationand serummatrixonischemia-modifiedalbumin.ClinBiochem2010;43(3):345– 8.
[12]GidenneS,CeppaF,FontanE,PerrierF,BurnatP.Analyticalperformanceofthe albumincobaltbinding(ACB)testonthecobasMIRAplusanalyzer.ClinChem LabMed2004;42(4):455–61.
[13]Bar-OrD,LauE,WinklerJV.Novelassayforcobalt-albuminbindingandits potentialasamarkerformyocardialischemia–apreliminaryreport.JEmerg Med2000;19:311–5.
[14]FaganGJ,WaymentH,MorrisDL,CrosbyPA.Thealbumincobaltbindingtest: analyticalperformanceofanewautomatedchemistryassayforthedetection ofischemiamodifiedalbumin(IMA).JClinLigandAssay2002;25:178–87. [15]CengizH,DagdevirenH,KanawatiA,ÇaypinarSSuzen,YesilA,EkinM,etal.
Ischemia-modified albumin as an oxidative stress biomarker in early pregnancyloss.JMaternalFetalNeonatalMed2015;18(September):1–4. [16]GidenneS,CeppaF,FontanE,PerrierF,BurnatP.Analyticalperformanceofthe
albumincobaltbinding(ACB)testonthecobasMIRAplusanalyzer.ClinChem LabMed2004;42(4):455–61.
[17]SoldinSJ,BrugnaraC,HicksJM.Pediatricreferenceranges.3rded.Washington, DC:AACCPress;1999.
[18]http://perinatology.com/Reference/Reference%20Ranges/Albumin.htm. [19]LeeYW,KimHJ,ChoYH,ShinHB,ChoiTY,LeeYK.Applicationof
albumin-adjustedischemiamodifiedalbuminindexasanearlyscreeningmarkerfor acutecoronarysyndrome.ClinChimActa2007;384(1–2)24–718. [20]LippiG,MontagnanaM,SalvagnoGL,GuidiGC.Standardizationof
ischemia-modifiedalbumintesting:adjustmentforserumalbumin.ClinChemLabMed 2007;45(2):261–2.
[21]D'souzaJM,PaiVR,HarishS,ShriyanC,D'souzaN.IMAandIMARinserumand salivaofpreeclampsia–apreliminarystudy.HypertensPregnancy2014;33 (4):440–8.
[22]PrefumoF,GazeDC,PapageorghiouAT,CollinsonPO,ThilaganathanB.First trimestermaternalserumischaemia-modifiedalbumin:amarkerof hypoxia-ischaemia-driven early trophoblast development. Hum Reprod 2007;22 (7):2029–32.
[23]JauniauxE,HempstockJ,GreenwoldN,etal.Trophoblasticoxidativestressin relationtotemporalandregionaldifferencesinmaternalplacentalbloodflow innormalandabnormalearlypregnancies.AmJPathol2003;162:115–25. [24]JauniauxE,GulbisB,BurtonGJ.Thehumanfirsttrimestergestationalsaclimits
rather than facilitates oxygen transfer to the foetus—a review. Placenta 2003;24(Suppl.A):S86–93.
[25]GuvenS,AlverA,MenteseA,IlhanFC,CalapogluM,UnsalMA.Thenovel ischemia marker ‘ischemia-modified albumin' is increased in normal pregnancies.ActaObstetGynecolScand2009;88(4):479–82.
[26]ÖzdemirS,KıyıcıA,BalciO,GöktepeH,ÇiçeklerH,ÇelikÇ.Assessmentof ischemia-modifiedalbuminlevelinpatientswithrecurrentpregnancyloss duringthefirsttrimester.EurJObstetGynecolReprodBiol2011;155(2):209– 12.
[27]HustinJ,JauniauxE,SchaapsJP.Histologicalstudyofthematerno-embryonic interfaceinspontaneousabortion.Placenta1990;11:477–86.
[28]HjortshojS,KristensenSR,RavkildeJ.Diagnosticvalueofischemiamodified albumininpatientswithsuspectedacutecoronarysyndrome.AmJEmerg Med2010;28:170–6.
[29]MaSG,XuW,WeiCL,WuXJ,HongB,WangZJ,etal.Roleofischemia-modified albuminandtotalhomocysteineinestimatingsymptomaticlacunarinfarction intype2diabeticpatients.ClinBiochem2011;44:1299–303.
[30]MaSG,YuWN,JinY,HongB,HuW.Evaluationofserumischemia-modified albuminlevelsinpregnantwomenwithandwithoutgestational diabetes-mellitus.GynecolEndocrinol2012;28(11):837–40.
[31]DahiyaK,KulshresthaMR,BansalP,GhalautVS,KulshresthaR,DahiyaP,etal. Evaluationofcordbloodischemiamodifiedalbumininnormalpregnancies andpre-eclampsia.HypertensPregnancy2015;34(2):204–8.
[32]JiaZT,LiuCY,LiH.Changesoftheconcentrationofserumischemiamodified albuminandhighsensitivityC-reactiveproteinintype2diabeticpatientswith retinopathy.ZhonghuaYanKeZaZhi2009;45(9):805–8.
[33]MakedouK,KourtisA,GkiomisiA,ToulisKA,MouzakiM,AnastasilakisAD, etal.Oxidizedlow-densitylipoproteinandadiponectinlevelsinpregnancy. GynecolEndocrinol2011;27(12):1070–3.
[34]RossiA,BortolottiN,VescovoS,RomanelloI,ForzanoL,LonderoAP,etal. Ischemia-modifiedalbumininpregnancy.EurJObstetGynecolReprodBiol 2013;170(2):348–51.
[35]vanRijnBB,FranxA,SikkemaJM,van RijnHJ,BruinseHW,VoorbijHA. Ischemiamodifiedalbumininnormalpregnancyandpreeclampsia.Hypertens Pregnancy2008;27(2):159–67.
[36]KlimanHJ.UteroplacentalbloodflowThestoryofdecidualization, menstrua-tion,andtrophoblastinvasion.AmJPathol2000;157:1759–68.
[37]BrosensJJ,PijnenborgR,BrosensIA.Themyometrialjunctionalzonespiral arteriesinnormalandabnormalpregnancies:areviewoftheliterature.AmJ ObstetGynecol2002;187:1416–23.
[38]GafsouB,LefèvreG,HennacheB,DebargeVHoufflin,Ducloy-BouthorsAS. Maternal serum ischemiamodified albumin: biomarker to distinguish between normal pregnancy andpreeclampsia? Hypertens Pregnancy 2010;29(1):101–11.
[39]UstunY,Engin-UstunY,OzturkO,AlanbayI,YamanH.Ischemia-modified albuminasan oxidativestress markerin preeclampsia.J MaternalFetal NeonatalMed2011;24(3):418–21.
[40]PapageorghiouAT,PrefumoF,LeslieK,GazeDC,CollinsonPO,ThilaganathanB. Defectiveendovasculartrophoblastinvasioninthefirsttrimesterisassociated withincreasedmaternalmaternalserumischemia-modifiedalbumin.Hum Reprod2008;23(4):803–6.
[41]OmürD,HaciveliogluSÖ,OguzalpH,UyanB,KirazHA,DumanC,etal.The effectofanaesthesiatechniqueonmaternalandcordblood ischaemiamo-difiedalbuminlevelsduringcaesareansection:arandomizedcontrolledstudy. JIntMedRes2013;41(4):1111–9.
[42]CaglarGS,ErdogduP,GursoyAY,SekerR,DemirtaşS.Theimpactofrouteof anesthesiaonmaternalandfetalischemiamodifiedalbüminlevelsatcesarean section:aprospectiverandomizedstudy.JPerinatMed2013;41(5):573–9. [43]IacovidouN,BrianaDD,BoutsikouM,LiosiS,BakaS,BoutsikouT,etal.Cord
bloodischemia-modifiedalbuminlevelsinnormalandintrauterinegrowth restrictedpregnancies.MediatorsInflamm2008;2008:523081,doi:http://dx. doi.org/10.1155/2008/523081.
[44]CaglarGS,TasciY,GoktolgaU,OztasE,PabuccuR,OzdemirED,etal.Maternal andumbilicalcordischemia-modifiedalbuminlevelsinnonreassuringfetal heartratetracingsregardingthemodeofdelivery.JMaternalFetalNeonatal Med2013;26(5):528–31.
[45]TopalogluN,YıldırımŞ,TekinM,KaymazN,TütüncülerF,ÖzdemirC,etal. Meanplateletvolumeandischemiamodifiedalbuminlevelsincordbloodof infantsofdiabeticmothers.PediatrNeonatol2014;55(6):455–8.
[46]ToyH,CamuzcuogluH,AriozDT,KurtS,CelikH,AksoyN.Serumprolidase activityandoxidativestressmarkersinpregnancieswithintrauterinegrowth restrictedinfants.JObstetGynaecolRes2009;35(6):1047–53.
[47]GuvendagGuvenES,KarcaaltincabaD,KandemirO,KiykacS,MenteseA.Cord bloodoxidativestressmarkerscorrelatewithumbilicalarterypulsatilityin fetalgrowthrestriction.JMaternalFetalNeonatalMed2013;26(6):576–80. [48]MehmetogluI,KurbanS,TokerA,AnnagürA,AltunhanH,ErbayE,etal.Serum
ischemia-modifiedalbuminandoxidizedLDLincordbloodandserumof neonatesborntopre-eclampticmothers.PediatrInt2015;57(3):422–6. [49]GugliucciA,HermoR,MonroyC,NumaguchiM,KimuraS.Ischemia-modified
albuminlevelsincordblood:acase-controlstudy inuncomplicatedand complicateddeliveries.ClinChimActa2005;362(1–2):155–60.
[50]DursunA,OkumusN,ZencirogluA.Ischemia-modifiedalbumin(IMA):couldit be usefulto predictperinatal asphyxia? JMaternal FetalNeonatal Med 2012;25(11):2401–5.
[51]KumralA,OkyayE,GucluS,GencpinarP,IslekelGH,OguzSS,etal.Cordblood ischemia-modifiedalbumin:isitassociatedwithabnormalDopplerfindingsin complicatedpregnancies and predictive of perinatal asphyxia? J Obstet GynaecolRes2013;39(3):663–71.
[52]OztekınO, KalayS,TaymanC,NamusluM,CelıkHT.Levelsof ischemia-modifiedalbuminintransienttachypneaofthenewborn.AmJPerinatol 2015;30(2):193–8.
[53]YakutI,TaymanC, OztekinO, NamusluM,KaracaF,KosusA. Ischemia-modifiedalbuminmaybeanovelmarkerforthediagnosisandfollow-upof necrotizingenterocolitis.JClinLabAnal2014;28(3):170–7.
[54]YerlikayaFH,KurbanS,MehmetogluI,AnnagurA,AltunhanH,ErbayE,etal. Serumischemia-modifiedalbuminlevelsatdiagnosisandduringtreatmentof late-onsetneonatalsepsis.JMaternFetalNeonatalMed2014;27(17):1723–7.
