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Preeclampsia,PregnancyInducedHypertension&GestationalDiabetes

Case

  31yearoldwoman6weekspregnant Nosymptoms  Randombloodglucoseinclinicis180  Abnormalglucosetolerancetest  Incidenceinpregnancyisupto3‐10% Whatisit?

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Diagnosis:GestationalDiabetes  Inpregnancymaternalpancreasisletcellshypertrophy

  Conflictbetweenhowmuchglucosegoestothefetusvs.tothemother’sbody.

  Placentalhormone“resistin”inducesinsulinresistanceinmother–shuntingglucosetotheplacenta.

Complicationsofgestationaldiabetes?

 Macrosomia  Shoulderdystocia  IncreasedrateofCsectionandbleedingcomplications

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BigBaby

22yearoldfemale6monthspregnant  PresentstotheERwithheadaches  BloodPressureis160/110  Proteinisnotedinherurine  Shehaslowplatelets  Youareworried–youhadasimilarpatientwhohadseizuresanddied!

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Pre‐eclampsia

  Illnessofpregnancy  PIH,Pre‐eclampsia,Eclampsia  veryhighbloodpressure,seizuresanddeath Morecommoninfirstpregnancy Morecommonintwinbirths

Fairlycommondisease

  2‐8%pregnancies  10%pregnanciesmayhavePIH  Common,mysterious,&cankillyou?Why?

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Hereisaclue

  Getridoftheplacenta–ecclampsiagoesaway

  Placentaisentirelyderivedfrompaternalgenes!

  Invadestheuterus  Thereisabalancethatdeterminesthedegreeofinvasionandcontrolthemothergivesup

RiskFactors

 Multiplegestation–twins,triplets

  HydatidMole  Thesegiveyoualargeplacenta

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Theplacenta

  “Aruthlessparasiticorganexistingsoleyforthemaintenanceandprotectionofthefetus,perhapstoooftentothedisregardofthematernalorganism”

  Page,E.W.1939

SpiralArteries

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Outofbalance!

  Shouldn’tallpartiesagreeonkeepingbothmotherandbabyhappyandhealthy?

Paternalgenes

  Paternalgenesaresharedinthefetusbutnotwiththemother.Interestsliemostlywiththefetus.

  Paternalderivedgenesmightattempttoextractmoreresourcesfrommotherthanmotherwouldliketogiveup

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Maternalgenes

  Promotecontroloverresourcedeliverytoplacenta

  Canwithholdresourcesfromonereproductiveeffortthatcanbedivertedtootherneeds

Implantation

  Inflammation  Implantationandtrophoblastinvasiondoesnotoccurwithoutafight.

 MaternalNK(NaturalKiller)cellscauseinflammationaroundtheearlyplacenta–canresistinvasionandcaninduceabortion

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Crypticmatechoice

  Investmentinpregnancybalancedagainstfuturehealthandinvestmentinotheroffspring

  50%spontaneousabortionrate(earlymiscarriage)

Paternalgenes

 Wouldbeexpectedtoresisteffortstopreventimplantationandtrophoblastinvasion

 Mightbeexpectedtoincreaseresourcedeliverytothefetusatexpenseofmother.

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Trophoblastinvasion

Pregnancyinducedhypertension  Theplacentaisalowpressurevenoussystem  Raisingmaternalarterialpressureincreasedflow.

  600ccbloodperhour  Increasedflowmeansincreasedglucoseandnutrientstothefetus

  Paternallyderivedtrait

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Pre‐eclampsia

 Uterinespiralarteriesresistancetoinvasionofuterusbytrophoblasts

  Trophoblastsinducecytokinesandfreefattyacidproduction‐>increasevascularresistanceinthemother

  Thisraisesherbloodpressure  Canleadtoincreasednutrientdeliverytofetus

Eclampsia

  Processgetsoutofhand–cyokinesdamagemother’sarteriesandorganswithdiffuseinflammation

  Causeshemolysis,thrombosis,seizures,death

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SoundsFarFetched?

 OKletsmakesomepredictions  Ifafatherhasseveralkidswithamother–paternalgenesmightnotbenefitfrominjuringthemothertobenefitafetus.

  Conversely,amothermight“trust”spermfrompartnershehaspreviouschildrenwithandbemorelikelytoallowimplantation

 Domultiplepregnanciesdecreasetherisk?

Multiparity&Preeclampsia

 Nulliparouswomenhavehigherrisk  Previouspregnancydecreasesrisk

  Howdoesthisoccur?

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Malereproductiveproteins

  Antigenstocertainproteinsmightbeneutralizedbyfemaleantibodies

  Increasesthechanceofsuccessfulpregnancy

  Youmightalsopredictchangeinsexualpartnerswouldincreasetherisk…

MHCandpreeclampsia

 Majorhistocompatibilityantigensseemtobeimportantinpregnancy,spontaneousabortion,andpreeclampsia

 MaternalKIR(AA)withfetalHLA‐C

  TrowsdaleJ,MoffettA.NKreceptorinteractionswithMHCclassImoleculesinpregnancy.SeminImmunol(2008),doi:10.1016/j.smim.2008.06.002

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DangerofaOneNightStand!

  Changeinsexualpartnershaseffects:  Increasesriskofpreeclampsia Durationofcohabitationdecreasesrisk

Condomsincreaserisk!

  Exposuretomalespermdecreasesrisk  Barriermethodsincreaserisk Malereproductiveproteinsseemtodecreasethelikelihoodofreproductiveconflictovertime

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Confounder:STDS?

  SpermdonorIVFincreasedtherisk Washedsemen–testsforandremovesSTDs  Autologousspermdonorlesslikelytocausepreeclampsiathanstrangerspermdonors

  SuggeststhatMRPsaffecttoleranceofspermandpossiblyimplantationofembryofromarecognizedmale

 OccursevenwhentheMRPsarenotpresent

MaleorFemaleEffect?

  Increasedsuccessfulimplantationfromlong‐durationpartners

  Isthefemalealteringspermcomposition Oristhespermchanging?  Femaletoleranceofmorefertilizedeggs? Maybeboth?

EsplinMS,FausettMB,FraserA,KerberR,MineauG,CarrilloJ,etal.Paternalandmaternalcomponentsofthepredispositiontopreeclampsia.NEnglJMed2001;344:867–72.

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DangerousMale

  Preeclampsiaspecialists  Certainmaleshavehigherriskofinducingpreeclampsia

  Arethesemalesmorelikelytohavemultiplepartners?

Eggdonation

  InimplantedoocyteIVF‐fetusdoesnotshareanygeneswithmother–rateofpreeclampsiais30%!

  Lackofexpressedmaternalcounteradaptationstopaternalattemptstoincreasebloodpressure.

SalhaO,SharmaV,DadaT,NugentD,RutherfordAJ,TomlinsonAJ,etal.Theinfluenceofdonatedgametesontheincidenceofhypertensivedisordersofpregnancy.HumReprod1999;14:2268–73.

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Summary

  Paternalgenesincreaseresourceextraction Maternalgenesresisttheseeffects  Tugofwar–usuallythesebalanceout  PIH,Ecclampsia,GestationalDiabetesoccurwhensidesareout‐of‐balance.