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REVIEWwww.
nature.
com/clinicalpractice/nephMechanismsofDisease:pre-eclampsiaMarinaNoris*,NorbertoPericoandGiuseppeRemuzziThisarticleofferstheopportunitytoearnoneCategory1credittowardstheAMAPhysician'sRecognitionAward.
INTRODUCTIONPre-eclampsiaisasyndromethatisusuallydefinedastheonsetofhypertensionandproteinuriaafter20weeksofgestationinprevi-ouslynormotensivenon-proteinuricpreg-nantwomen.
1Ifleftuntreated,pre-eclampsiacanprogresstoaconvulsivestateknownaseclampsia.
2Pre-eclampsiaisaleadingcauseofmaternalandfetalmorbidityandmortality.
3,4IntheWesternworld,itaffectsbetween2and7%ofallpregnancies,buttheincidenceinothergeographicareaswithdifferentethnicorsocialcharacteristicscanbeuptothreetimesgreater.
5,6Aworldwideincidenceof8,370,000casesperyearhasbeenestimated.
5,6Indevelopingcoun-tries,suchasColombia,42%ofmaternaldeathsareattributedtothisdisorder,whichisalsothemajorreasonforprematuredelivery.
7Theinci-denceofeclampsiaisalsohighindevelopingcountries(1.
6and12per1,000livebirths,respectively,inColombiaandIndia).
8RISKFACTORSPre-eclampsiaisprimarilyregardedasadiseaseoffirstpregnancy,althoughtheprotectiveeffectofmultiparityissaidtobelostwithchangeofpartner.
9Thissupportsthehypothesisthatriskisreducedwithrepeatedexposurestospecificantigensfromthesamepartner;however,recentevidencefromtheMedicalBirthRegistryofNorwayindicatesthattheprotectiveeffectofpreviouspregnancywiththesamepartnerisconfoundedbythetimeintervalbetweenbirths.
10Thesedata,obtainedfrom>1.
8millionbirthsover31years,showedthatwhenthebirthintervalwas>10years,amultiparouswomanhadthesameriskofdevelopingpre-eclampsiaasaprimiparouswoman.
Ithas,however,beensuggestedthatthis'birth-intervalhypothesis'isnotwellfounded.
11Asystematicreviewof>1,000controlledstudiespublishedfrom1966to2002foundthatPre-eclampsia,asyndromeofpregnantwomen,isoneoftheleadingcausesofmaternalandfetalmorbidityandmortality.
Despiteactiveresearch,theetiologyofthisdisorderremainsanenigma.
Recentworkhas,however,providedpromisingexplanationsforthecausationofthedisorderandsomeofitsphenotypes.
Evidenceindicatesthatthesymptomsofhypertensionandproteinuria,uponwhichthediagnosisofpre-eclampsiaisbased,haveseveralunderlyingcauses.
Nevertheless,thetreatmentofpre-eclampsiahasnotchangedsignificantlyinover50years.
Thisreviewdescribesthemostrecentinsightsintothepathophysiologyofpre-eclampsiafrombothbasicandclinicalresearch,andattemptstoprovideaunifyinghypothesistoreconciletheabnormalitiesatthefeto–placentallevelandtheclinicalfeaturesofthematernalsyndrome.
Thenovelfindingsoutlinedinthisreviewprovidearationaleforpotentialfutureprophylacticandtherapeuticinterventionsforpre-eclampsia.
KEYWORDSnitricoxide,oxygenradicals,pathophysiology,pre-eclampsia,vascularendothelialgrowthfactorMNorisisHeadoftheLaboratoryofImmunologyandGeneticsofTransplantationandRareDiseases,NPericoisHeadoftheLaboratoryofAdvancedDevelopmentofDrugsattheClinicalResearchCenterforRareDiseasesandGRemuzziisDirectoroftheClinicalResearchCenterforRareDiseases,atMarioNegriInstituteforPharmacologicalResearch,Bergamo,Italy.
Correspondence*TransplantResearchCenter"ChiaraCucchiDeAlessandri&GilbertoCrespi",MarioNegriInstituteforPharmacologicalResearch,ViaCamozzi3,24020Ranica,Bergamo,Italynoris@marionegri.
itReceived27April2005Accepted25August2005www.
nature.
com/clinicalpracticedoi:10.
1038/ncpneph0035REVIEWCRITERIAWesearchedPubMedforarticlespublishedbetween1970and2005.
Thekeywordsusedwere"pre-eclampsia","gestationalhypertension","clinicalfeatures","pathophysiology"and"treatment".
Wealsosearchedthebibliographiesofthearticlesretrievedforfurtherrelevantreferences.
Becauseofthelargenumberofarticlesidentified,thedecisiononwhichtoincludewasbasedonpersonaljudgment.
Moreover,asthediagnosticcriteriaforpre-eclampsiawererefinedin2000bytheNationalHighBloodPressureEducationProgramWorkingGroup,1thisreviewfocusesonstudiespublishedduringthepast5years.
SUMMARYCME98NATURECLINICALPRACTICENEPHROLOGYDECEMBER2005VOL1NO2NaturePublishingGroup2005REVIEWDECEMBER2005VOL1NO2NORISETAL.
NATURECLINICALPRACTICENEPHROLOGY99www.
nature.
com/clinicalpractice/nephaprevioushistoryofpre-eclampsia,multiplepregnancy,nulliparity,pre-existingdiabetes,highBMIbeforepregnancy,maternalage≥40years,renaldisease,hypertension,≥10yearssincepreviouspregnancyandpresenceofanti-phospholipidantibodiesallincreasedawoman'sriskofdevelopingpre-eclampsia.
12Increasesinriskofmorethanninefold,sevenfoldandthreefold,respectively,weredocumentedforantiphospholipidantibodies,previoushistoryofpre-eclampsiaanddiabetes.
Basedonthisevidence,guidelinesforriskassessmentofpre-eclampsiahaverecentlybeenissued.
13Otherriskfactorsforpre-eclampsiaareinsulinresistanceinconcertwithobesity14,15andthrombophilia.
16Indevelopingcountries,protein-calorieundernutritionhasbeenidentifiedasanimportantriskfactor;17however,anegativecorrelationbetweencalciumintakeandincidenceofpre-eclampsiahasrecentlybeendetectedinGuatemala,ColombiaandIndia.
7Thisfindingissupportedbytheobservationthatcalciumsupple-mentationisbeneficialtowomenathighriskofgestationalhypertension,andincommunitieswithlowdietarycalciumintake.
18–20GeneticfactorsThepreciseroleofgeneticfactorsinthedevelop-mentofpre-eclampsiaisunclear,andnospecificcontributorygenehasbeenidentified.
Theinheri-tancepatternofthediseasehasbeendescribedasMendelian(autosomalrecessiveandauto-somaldominantwithincompletepenetrance),polygenic/multifactorialandmitochondrial.
Smallstudies21–24haveindicatedanassociationbetweenpre-eclampsiaandpolymorphismsofgenesthatcontrolbloodpressure,coagulationoroxygen-free-radicalmetabolism—suchasrenin,angiotensinogen,endothelialnitricoxidesynthase(eNOS),FACTORVLEIDEN,METHYLTETRAHYDROFOLATEorlipoproteinlipase—butthishasnotbeenconfirmed.
25Linkageanalysishasidentifiedthreepotentiallocilinkedtosusceptibilitytopre-eclampsia:2p13,2p25and9p13.
26,27Notably,theselociaccountforonlyasmallpercentageofcases(otherstudiesfailedtoconfirmtheassociations).
28,29Afourthlocusforpre-eclampsiawassubsequentlyidenti-fiedon10q22.
Maximalallelesharingbetweenpre-eclampticsistersatthislocuswasobservedformaternal-derivedbutnotpaternal-derivedalleles,30indicatingmatrilinealinheritance.
TheSTOX1geneinthe10q22locuscontainsfivedifferentmissensemutations.
STOX1isidenticalinaffectedsisters,co-segregateswiththepre-eclampticphenotypeandisinheritedmatrilineally.
31Arolehasbeenproposedforthegeneproduct(aDNA-bindingprotein)incontrollingpolyploidizationofextravilloustrophoblasts,althoughitsprecisebiologicalfunctionhasnotbeenclarified.
31InalargestudybytheBritishGeneticsofPre-eclampsiaConsortium,657womenaffectedbypre-eclampsiaandtheirfamiliesweregenotypedatsitesof28single-nucleotidepolymorphismsinseveralgenes,includingthoseinvolvedinangiotensinactivity(angiotensinogenandangiotensinIItype1receptor[AT1])andoxida-tivestress(methylenetetrahydrofolatereduc-tase).
32Noneofthegeneticvariantstestedwerefoundtoconferahighriskofdiseasedevelop-ment,indicatingthatalterationsofangiotensinactivityandoxidativestressarenotprimecausesofpre-eclampsia.
DIAGNOSISANDCLINICALFEATURESThecardinalfeaturesofpre-eclampsiaarehypertensionandproteinuria.
Inthepast,hyper-tensionindicativeofpre-eclampsiawasdefinedasanelevationof>30mmHgsystolicpressureor>15mmHgdiastolicpressureabovethepatient'sbaselinebloodpressure.
Thisdefinitionprovedtobeapoorindicatorofoutcome33and,in2000,thecriteriawererefinedbytheNationalHighBloodPressureEducationProgram(NHBPEP)WorkingGroup.
1Sincethen,therehasbeenconsiderableagreementbetweeninternationalworkinggroups.
34Thecriteriadefinehyper-tensionasasystolicbloodpressure≥140mmHgoradiastoliclevel(Korotkoff5)≥90mmHgontwoormoreoccasionsatleast4–6h(butnotmorethan7days)apartafter20weeksofgesta-tioninawomanwithpreviouslynormalbloodpressure.
Nevertheless,theNHBPEPworkinggroupreport1alsostatedthecollectiveopinionthat30mmHgsystolicand15mmHgdiastolicincreases,evenatvalues140mmHg,diastolicbloodpressure>90mmHg1Proteinuria:urinaryproteinexcretion>300mg/day;preservationofpodocytefootprocessesinthepresenceofsubstantialproteinuria137Decreasedplasmavolume:contractedby30–40%comparedwithnormalpregnancy138Edema:interstitialfluidretention;multifactorial138(observedin>50%ofnormalgravidas)Decreasedrenalbloodflow:renalperfusionlessthaninnormalpregnantwomen101Increasedplasmauricacid:secondarytoreduceduricacidrenalclearance139Increasedaminotransferasesandlactatedehydrogenase:hepatocellularnecrosiswithleakageofliverenzymesintomaternalblood140Cerebraledema:duetohypertensionandvascularautoregulatorydysfunction141Thrombocytopenia:plateletcount/=15mmHginassociationwithproteinuriaAmJObstetGynecol183:787–79234BrownMAetal.
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AmJObstetGynecol193:3–4AcknowledgmentsWeareindebtedtoProfessorFranklinHEpstein(SeniorPhysician,RenalDivision,DepartmentofMedicine,BethIsraelDeaconessMedicalCenter,Boston)andWilliamApplebaum(ProfessorofMedicine,HarvardMedicalSchool,Boston)fortheircriticalreadingofthemanuscriptandinsightfuldiscussion.
WealsothankDrPrudenceHill(DepartmentofAnatomicalPathology,StVincent'sHospital,Melbourne)forhercriticalreading.
CompetinginterestsTheauthorsdeclaredtheyhavenocompetinginterests.
NaturePublishingGroup2005
nature.
com/clinicalpractice/nephMechanismsofDisease:pre-eclampsiaMarinaNoris*,NorbertoPericoandGiuseppeRemuzziThisarticleofferstheopportunitytoearnoneCategory1credittowardstheAMAPhysician'sRecognitionAward.
INTRODUCTIONPre-eclampsiaisasyndromethatisusuallydefinedastheonsetofhypertensionandproteinuriaafter20weeksofgestationinprevi-ouslynormotensivenon-proteinuricpreg-nantwomen.
1Ifleftuntreated,pre-eclampsiacanprogresstoaconvulsivestateknownaseclampsia.
2Pre-eclampsiaisaleadingcauseofmaternalandfetalmorbidityandmortality.
3,4IntheWesternworld,itaffectsbetween2and7%ofallpregnancies,buttheincidenceinothergeographicareaswithdifferentethnicorsocialcharacteristicscanbeuptothreetimesgreater.
5,6Aworldwideincidenceof8,370,000casesperyearhasbeenestimated.
5,6Indevelopingcoun-tries,suchasColombia,42%ofmaternaldeathsareattributedtothisdisorder,whichisalsothemajorreasonforprematuredelivery.
7Theinci-denceofeclampsiaisalsohighindevelopingcountries(1.
6and12per1,000livebirths,respectively,inColombiaandIndia).
8RISKFACTORSPre-eclampsiaisprimarilyregardedasadiseaseoffirstpregnancy,althoughtheprotectiveeffectofmultiparityissaidtobelostwithchangeofpartner.
9Thissupportsthehypothesisthatriskisreducedwithrepeatedexposurestospecificantigensfromthesamepartner;however,recentevidencefromtheMedicalBirthRegistryofNorwayindicatesthattheprotectiveeffectofpreviouspregnancywiththesamepartnerisconfoundedbythetimeintervalbetweenbirths.
10Thesedata,obtainedfrom>1.
8millionbirthsover31years,showedthatwhenthebirthintervalwas>10years,amultiparouswomanhadthesameriskofdevelopingpre-eclampsiaasaprimiparouswoman.
Ithas,however,beensuggestedthatthis'birth-intervalhypothesis'isnotwellfounded.
11Asystematicreviewof>1,000controlledstudiespublishedfrom1966to2002foundthatPre-eclampsia,asyndromeofpregnantwomen,isoneoftheleadingcausesofmaternalandfetalmorbidityandmortality.
Despiteactiveresearch,theetiologyofthisdisorderremainsanenigma.
Recentworkhas,however,providedpromisingexplanationsforthecausationofthedisorderandsomeofitsphenotypes.
Evidenceindicatesthatthesymptomsofhypertensionandproteinuria,uponwhichthediagnosisofpre-eclampsiaisbased,haveseveralunderlyingcauses.
Nevertheless,thetreatmentofpre-eclampsiahasnotchangedsignificantlyinover50years.
Thisreviewdescribesthemostrecentinsightsintothepathophysiologyofpre-eclampsiafrombothbasicandclinicalresearch,andattemptstoprovideaunifyinghypothesistoreconciletheabnormalitiesatthefeto–placentallevelandtheclinicalfeaturesofthematernalsyndrome.
Thenovelfindingsoutlinedinthisreviewprovidearationaleforpotentialfutureprophylacticandtherapeuticinterventionsforpre-eclampsia.
KEYWORDSnitricoxide,oxygenradicals,pathophysiology,pre-eclampsia,vascularendothelialgrowthfactorMNorisisHeadoftheLaboratoryofImmunologyandGeneticsofTransplantationandRareDiseases,NPericoisHeadoftheLaboratoryofAdvancedDevelopmentofDrugsattheClinicalResearchCenterforRareDiseasesandGRemuzziisDirectoroftheClinicalResearchCenterforRareDiseases,atMarioNegriInstituteforPharmacologicalResearch,Bergamo,Italy.
Correspondence*TransplantResearchCenter"ChiaraCucchiDeAlessandri&GilbertoCrespi",MarioNegriInstituteforPharmacologicalResearch,ViaCamozzi3,24020Ranica,Bergamo,Italynoris@marionegri.
itReceived27April2005Accepted25August2005www.
nature.
com/clinicalpracticedoi:10.
1038/ncpneph0035REVIEWCRITERIAWesearchedPubMedforarticlespublishedbetween1970and2005.
Thekeywordsusedwere"pre-eclampsia","gestationalhypertension","clinicalfeatures","pathophysiology"and"treatment".
Wealsosearchedthebibliographiesofthearticlesretrievedforfurtherrelevantreferences.
Becauseofthelargenumberofarticlesidentified,thedecisiononwhichtoincludewasbasedonpersonaljudgment.
Moreover,asthediagnosticcriteriaforpre-eclampsiawererefinedin2000bytheNationalHighBloodPressureEducationProgramWorkingGroup,1thisreviewfocusesonstudiespublishedduringthepast5years.
SUMMARYCME98NATURECLINICALPRACTICENEPHROLOGYDECEMBER2005VOL1NO2NaturePublishingGroup2005REVIEWDECEMBER2005VOL1NO2NORISETAL.
NATURECLINICALPRACTICENEPHROLOGY99www.
nature.
com/clinicalpractice/nephaprevioushistoryofpre-eclampsia,multiplepregnancy,nulliparity,pre-existingdiabetes,highBMIbeforepregnancy,maternalage≥40years,renaldisease,hypertension,≥10yearssincepreviouspregnancyandpresenceofanti-phospholipidantibodiesallincreasedawoman'sriskofdevelopingpre-eclampsia.
12Increasesinriskofmorethanninefold,sevenfoldandthreefold,respectively,weredocumentedforantiphospholipidantibodies,previoushistoryofpre-eclampsiaanddiabetes.
Basedonthisevidence,guidelinesforriskassessmentofpre-eclampsiahaverecentlybeenissued.
13Otherriskfactorsforpre-eclampsiaareinsulinresistanceinconcertwithobesity14,15andthrombophilia.
16Indevelopingcountries,protein-calorieundernutritionhasbeenidentifiedasanimportantriskfactor;17however,anegativecorrelationbetweencalciumintakeandincidenceofpre-eclampsiahasrecentlybeendetectedinGuatemala,ColombiaandIndia.
7Thisfindingissupportedbytheobservationthatcalciumsupple-mentationisbeneficialtowomenathighriskofgestationalhypertension,andincommunitieswithlowdietarycalciumintake.
18–20GeneticfactorsThepreciseroleofgeneticfactorsinthedevelop-mentofpre-eclampsiaisunclear,andnospecificcontributorygenehasbeenidentified.
Theinheri-tancepatternofthediseasehasbeendescribedasMendelian(autosomalrecessiveandauto-somaldominantwithincompletepenetrance),polygenic/multifactorialandmitochondrial.
Smallstudies21–24haveindicatedanassociationbetweenpre-eclampsiaandpolymorphismsofgenesthatcontrolbloodpressure,coagulationoroxygen-free-radicalmetabolism—suchasrenin,angiotensinogen,endothelialnitricoxidesynthase(eNOS),FACTORVLEIDEN,METHYLTETRAHYDROFOLATEorlipoproteinlipase—butthishasnotbeenconfirmed.
25Linkageanalysishasidentifiedthreepotentiallocilinkedtosusceptibilitytopre-eclampsia:2p13,2p25and9p13.
26,27Notably,theselociaccountforonlyasmallpercentageofcases(otherstudiesfailedtoconfirmtheassociations).
28,29Afourthlocusforpre-eclampsiawassubsequentlyidenti-fiedon10q22.
Maximalallelesharingbetweenpre-eclampticsistersatthislocuswasobservedformaternal-derivedbutnotpaternal-derivedalleles,30indicatingmatrilinealinheritance.
TheSTOX1geneinthe10q22locuscontainsfivedifferentmissensemutations.
STOX1isidenticalinaffectedsisters,co-segregateswiththepre-eclampticphenotypeandisinheritedmatrilineally.
31Arolehasbeenproposedforthegeneproduct(aDNA-bindingprotein)incontrollingpolyploidizationofextravilloustrophoblasts,althoughitsprecisebiologicalfunctionhasnotbeenclarified.
31InalargestudybytheBritishGeneticsofPre-eclampsiaConsortium,657womenaffectedbypre-eclampsiaandtheirfamiliesweregenotypedatsitesof28single-nucleotidepolymorphismsinseveralgenes,includingthoseinvolvedinangiotensinactivity(angiotensinogenandangiotensinIItype1receptor[AT1])andoxida-tivestress(methylenetetrahydrofolatereduc-tase).
32Noneofthegeneticvariantstestedwerefoundtoconferahighriskofdiseasedevelop-ment,indicatingthatalterationsofangiotensinactivityandoxidativestressarenotprimecausesofpre-eclampsia.
DIAGNOSISANDCLINICALFEATURESThecardinalfeaturesofpre-eclampsiaarehypertensionandproteinuria.
Inthepast,hyper-tensionindicativeofpre-eclampsiawasdefinedasanelevationof>30mmHgsystolicpressureor>15mmHgdiastolicpressureabovethepatient'sbaselinebloodpressure.
Thisdefinitionprovedtobeapoorindicatorofoutcome33and,in2000,thecriteriawererefinedbytheNationalHighBloodPressureEducationProgram(NHBPEP)WorkingGroup.
1Sincethen,therehasbeenconsiderableagreementbetweeninternationalworkinggroups.
34Thecriteriadefinehyper-tensionasasystolicbloodpressure≥140mmHgoradiastoliclevel(Korotkoff5)≥90mmHgontwoormoreoccasionsatleast4–6h(butnotmorethan7days)apartafter20weeksofgesta-tioninawomanwithpreviouslynormalbloodpressure.
Nevertheless,theNHBPEPworkinggroupreport1alsostatedthecollectiveopinionthat30mmHgsystolicand15mmHgdiastolicincreases,evenatvalues140mmHg,diastolicbloodpressure>90mmHg1Proteinuria:urinaryproteinexcretion>300mg/day;preservationofpodocytefootprocessesinthepresenceofsubstantialproteinuria137Decreasedplasmavolume:contractedby30–40%comparedwithnormalpregnancy138Edema:interstitialfluidretention;multifactorial138(observedin>50%ofnormalgravidas)Decreasedrenalbloodflow:renalperfusionlessthaninnormalpregnantwomen101Increasedplasmauricacid:secondarytoreduceduricacidrenalclearance139Increasedaminotransferasesandlactatedehydrogenase:hepatocellularnecrosiswithleakageofliverenzymesintomaternalblood140Cerebraledema:duetohypertensionandvascularautoregulatorydysfunction141Thrombocytopenia:plateletcount/=15mmHginassociationwithproteinuriaAmJObstetGynecol183:787–79234BrownMAetal.
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AmJObstetGynecol193:3–4AcknowledgmentsWeareindebtedtoProfessorFranklinHEpstein(SeniorPhysician,RenalDivision,DepartmentofMedicine,BethIsraelDeaconessMedicalCenter,Boston)andWilliamApplebaum(ProfessorofMedicine,HarvardMedicalSchool,Boston)fortheircriticalreadingofthemanuscriptandinsightfuldiscussion.
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CompetinginterestsTheauthorsdeclaredtheyhavenocompetinginterests.
NaturePublishingGroup2005
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