Physiology of Pregnancy - GLOWM

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PhysiologyofPregnancy|GLOWM
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Thischaptershouldbecitedasfollows:
Barclay,M,Glob.libr.women'smed.,
(ISSN:17562228)2009DOI10.3843/GLOWM.10103
Thischapterwaslastupdated:
May2009
PhysiologyofPregnancy
MelL.Barclay,MD
AssociateProfessor,DivisionofMaternalFetalMedicine,DepartmentofObstetricsandGynecology,University
ofMichiganSchoolofMedicine,AnnArbor,Michigan,USA
INTRODUCTION
MODELSOFPREGNANCYASAPHYSIOLOGICALLYADAPTEDSTATE
METABOLICCHANGES
WEIGHTGAIN
NUTRITION
PLASMALEVELSOFNUTRIENTS
CARBOHYDRATEMETABOLISM
ALTERATIONSINTHECARDIOVASCULARSYSTEM
SALTANDWATER
THEGASTROINTESTINALSYSTEM
SKINCHANGES
SUMMARY
REFERENCES
INTRODUCTION
Pregnancyinthehumanfemaleisanunusualstateinwhichvirtuallyallmaternalsystemsaredramatically
alteredtopermitthesustenanceandgrowthoftheintrauterineconceptus.Inveryrealways,thematernal
organismislifeadapted.
Althoughpregnancyisuniqueinmanyways,itisparticularlysoinbeinglimitedintime.Pregnancyisa
temporarystatewithadefinitepointofonsetandanequallydefinitetermination.Thedurationofpregnancy
inhumans,markedfromthefirstdayofthelastmenstrualperiod,isclassically280days.Recentstudies,
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however,usingcomputerizeddaycountingtechniques,showanaveragedurationof284.2days.1Table1
showsthemeanvaluesandstatisticaldispersionofgestationaldurationaswellasanumberofother
gestationalmilestones.
Table1.Meanobservedintervalstodeliverydateforlastmenstrualperiod(LMP)andobstetricmilestones*
Milestone
Meanintervalto
Standard
delivery(days) deviations(days)
KnownLMP
284.2
14.6
Quickening
156.3
18.0
Fetalheartaudible
136.2
17.0
Uterusatumbilicus
140.8
14.9
*Datafrom418patients.
(AndersenHF,JohnsonTR,FloraJD,BarclayM:Gestationalageassessment:II.Predictionfromcombined
clinicalobservations.AmJObstetGynecol140(7):770,1981)
Thechangesbroughtaboutinthematernalorganismbythestateofpregnancyareimportant,becausein
manyinstancestheymimicpathophysiologicresponsestodisease.Iftheconstellationofchangesoccurring
normallyinpregnancyaremisinterpretedassignsofdiseaseprocesses,thegravidorpuerperalwomanmay
besubjectedtodiagnosticandtherapeuticinterventionsthatarenotonlyunnecessarybutmayalsobe
dangeroustomotherandfetus.
Becausesomanysystemspecificchangesoccurinthecourseofpregnancy,itisdifficulttodevelopatotal
physiologicoverview.Thereare,however,anumberofwelldescribedadaptivephysiologicstatesthat
producechangesinhumansystemssimilartothoseseeninpregnancy.Theseadaptivestatesmaybeusedas
modelsorconstructstohelpintegratethediversealterationsinphysiologicsystemsthatoccurduringthe
courseofnormalgestation.Amongthephysiologicstatesthatproduceadaptivechangessimilartothoseseen
inpregnancyarethepresenceofamoderatesizedarteriovenousfistula,acclimationtoincreased
environmentalorinternalheating,andadjustmentstoincreasinglevelsofcirculatingprogesterone.
MODELSOFPREGNANCYASAPHYSIOLOGICALLYADAPTED
STATE
ModelI:PregnancyasanArteriovenousFistula
2
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In1938,Burwellandassociates2suggestedthattherearestrongsimilaritiesbetweenthephysiologic
alterationsseeninnormalpregnancyandthoseseeninpatientswithlargearteriovenousfistulas.Patientson
chronicrenaldialysiswhohaveperipheralshuntsconstructedforpurposesofdialysistypicallyhaveflow
ratesintheirshuntsofapproximately600ml/minute.3Becauseuteroplacentalflowratesatterm(nearly
600ml/minute4)areessentiallythesameasthoseintheartificiallyproducedshunts,itisnotsurprisingthat
therearesimilaritiesbetweenthecardiovascularchangesintheshuntedpatientsandcardiovascular
alterationsinthepregnantwoman,particularlyassheapproachesterm.
Inbothofthesecircumstancesthereisevidenceofincreasedperipheralcirculation,decreasedperipheral
resistance,increasedheartrate,increasedcardiacoutput,andincreasedplasmavolume.Thisparticular
modelcanbeusedtoexplainanumberofotherchangesrelatednotdirectlytotheshuntingmechanismbut
tosecondarychangesproducedbyincreasedperipheralcirculation,suchasincreasedrenalplasmaflowand
thephysiologicalterationsassociatedwithincreasedrenalperfusion.
ModelII:PregnancyasaStateofHeatAdaptation
Abramsandassociatesandothers5, 6haveshownthatthereisaconsiderabletemperaturegradientbetween
themotherandfetus.Aortictemperaturemeasurementsmadeinthepregnanteweindicatethatthefetal
coretemperatureexceedsthatofthemotherby0.5C,whichisasignificantamount.Thermodynamicsand
thephysicsofheattransfersuggestthatbecauseofthistemperaturedifference,theflowofheatfromthe
fetustothemotherisrelativelyconstant.Asaresult,thematernalorganismmustadjusther
thermoregulatorysystemtopermitincreasedheatlosstotheenvironment.Asidefromphysical
considerations,theneedformaternalthermoregulatoryadjustmentsissuggestedbytheobservationthat
homeothermicmammalsfunctionwithinaverynarrowrangeofinternaltemperatures.Extremesineither
directionproducesignificantalterationsinthefunctionoffundamentalsystemsresponsibleforthe
maintenanceoflife.
Responsesofthehomeothermicmammaltointernalandenvironmentalheatingproducesimilarphysiologic
alterations.Theseincludeincreasedrespiratoryrate,increasedcardiacoutput,increasedheartrate,
expansionofplasmavolume,increasedperipheralcirculation,andanumberofotherchangessimilarto
thoseseeninnormalhumangestation.
ModelIII:PregnancyasaHyperprogestationalState
Withtheonsetofnormalgestation,allmaternalsystemsaresubjectedtoincreasinglevelsofcirculating
progesterone.Atfirstthecorpusluteumofpregnancy,andlatertheplacenta,producelargeamountsofthis
hormone.Atterm,serumlevelsmaybeashighas2.5timesthoseconsiderednormalinthemenstruating
woman.
Increasedbasalbodytemperatureandchangesinthesmoothmuscledynamicsoftheuterus,thevascular
system,theurinarysystem,thegastrointestinalsystem,andtherespiratorysysteminpregnancyhaveoften
beenexplainedonthebasisofincreasinglevelsofserumprogesterone.Themechanismproposedtoexplain
manyofthesechangesrelatestotheeffectofprogesteroneontheelectrochemicalgradientatthecell
membraneofindividualsmoothmusclefibers.7 Accordingtothishypothesis,progesteroneactsto
hyperpolarizethecellmembrane,depressingtherestingelectricalpotentialatthemembranetoalevelbelow
thatofthenormalactivationthreshold.Thiseffectivelyputsthemuscleatrest,becausemuchgreaterlevels
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ofstimulationarerequiredtoproducedepolarizationandsubsequentmusclecontraction.Decreasedtone
andoveralldecreaseincontractileactivityisseeninmostofthestructuresthatdependonsmoothmusclefor
theiraction.Thisincludestheuterus,gut,respiratorysystem,ureters,andperipheralvascularsystem.
Volumeexpansionoftheintravascularspace,decreasedperipheralresistance,increasedheartrate,anda
numberofotheralterationsassociatedwiththepregnantstatecouldtheoreticallybeexplainedonthebasis
ofprogesterone'seffectonsmoothmuscle.
Overall,itseemsunlikelythatasinglemodelcanbeinvokedtoexplainthevariedchangesthattakeplacein
thehumanfemaleduringthecourseofgestation.Itismorelikelythatallofthesemechanismscontribute,
alongwithotherfactorsstillunidentified,tothemyriadchangesthatconstitutethephysiologicalterations
associatedwiththenormalhumangestation.Eachmodel,nonetheless,helpsthecliniciantoanticipateand
integratethechangesinmanyofthealteredsystems.Theconstructsdescribedpermitthealterationsin
individualsystemstobefusedintoamorecoherentoverview.
METABOLICCHANGES
Basalmetabolicstudiescarriedoutinthe1920sand1930sbySandifordandWheeler8andRoweandBoyd9
demonstratedthatpregnancyischaracterizedbyincreasedmetabolicactivityasmeasuredbythebasal
metabolicrate.Inthesestudies,doneonasmallgroupofwomenthroughoutgestation,theyfoundthatthe
basalmetabolicrateincreasedbyapproximately20%asthepregnancyapproachedterm.Thistrendis
picturedinFigure1.Theresearchershypothesizedthatthisincreaseinmetabolicactivityprimarily
representedincreasedfetalandplacentalmetabolicwork,withonlyasmallfractionbeingattributableto
increasedmaternalmetabolicactivity.Atterm,theproductsofgestationwereestimatedtoberesponsible
forapproximately13%ofthe20%increaseintotalmetabolicactivity.Moremodernstudies10, 11using
oxygenconsumptionmeasuresandindirectcalorimetryestimatetheenergyoutputofanaveragesized
pregnantwomanat36weeks'gestationtobeapproximately98W(8443243kJ/day).Thiscompareswith
anenergyoutputofapproximately81W(6971172kJ/day)forasimilarsized,nonpregnant,nonlactating
woman.Althoughthemorerecentstudiesuseddifferentmethodologies,theyallsupporttheresultsofthe
earlierwork.
(http://resources.ama.uk.com/glowm_www/graphics/figures/v2/0130/001f.gif)Fig.1.Metabolic
requirementsforoxygenduringthecourseofnormalpregnancyin11normalpregnantwomen.(Basedon
dataofEmersonK,SaxenaGN,PoindexterEL,etal:Caloriccostofnormalpregnancy.ObstetGynecol
40(6):786,1972).
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Duringthecourseofnormalpregnancy,basalbodytemperatureiselevated.Theincreasedmetabolicactivity
manifestedearlyinthegestation,alongwiththeeffectsofprogesterone,mayberesponsibleforthis
phenomenon.
WEIGHTGAIN
Weightgain,oneofthehallmarksofpregnancy,hasbeenextensivelystudiedasitrelatestothewellbeingof
thefetusandinfant.Optimalweightgaininpregnancyhasbeenthesubjectofconsiderablediscussion,and
attitudesregardingwhatisappropriatehavechangedwithtime,eveninrecenthistory.Currently,atotal
weightgainof1012kgisthoughttobeappropriate.Thepartitioningofthisweightgainanditsdistribution
areillustratedinTable2andFigure2.
Table2.Averagecomponentsofweightgaininpregnancyandcumulativegainattheendofeachtrimester
(kg)
Component
II
III
Fetus
1.0
3.4
Placenta
0.3
0.6
Amnioticfluid
0.4
1.0
Fetaltotal
1.7
5.0
Uterus
0.3
0.8
1.0
Breasts
0.1
0.3
0.5
Bloodvolume
0.3
1.3
1.5
1.5
0.7
2.4
4.5
Extracellularfluid
Maternaltotal
(AfterPitkinR,KaminetskyH,NewtonMetal:Maternalnutrition.Aselectivereviewofclinicaltopics.
ObstetGynecol40(6):773,1972)
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(http://resources.ama.uk.com/glowm_www/graphics/figures/v2/0130/002f.gif)Fig.2.Maternalweightgain
innormalpregnancydividedintermsofindividuallyidentifiablecomponents.(HyttenFE,LeitchI:The
PhysiologyofNormalPregnancy.Oxford,BlackwellScientificPublications,1964)
ThetotalmaternalweightgainindicatedinTable2isthatportionthatcanbeexplainedintermsof
measurableelementsandislessthanthe1012kgincreasedescribedasoptimal.Thedifferenceisusually
ascribedtofatstorageinmaternaltissues.
Weightgaininpregnancyisnegligibleinthefirsttrimester,ascanbeseeninTable2andFigure2.Inthe
secondandthirdtrimesters,weightgainismuchmoreappreciableand,accordingtotheworkofHyttenand
Leitch,12averagesapproximately0.410.45kg/week(0.91.0pounds/week)innormalpregnanciesin
primigravidas.
NUTRITION
StudiescarriedoutinThirdWorldcountriesindicatethatmaternalmalnutritionmayinterfere,atleast
epidemiologically,withappropriateintrauterinenutrition.Womenwhoweremarginallynourishedbefore
pregnancydeliverahigherproportionofprematureandlowbirthweightinfants.Feedingprogramsin
Guatemala,Colombia,andotheremergingnationshaveprovidedinformationthatsuggeststhattheproper
nourishmentofthepregnantwomanmaybeofconsiderablebenefittoherfetus.13
NutritionalauthoritiesintheUnitedStatesandmuchoftheWesternWorldhaveestablishedsuggested
programsforappropriatenutritioninpregnancy.Basically,pregnantwomenrequirecaloriesadditionalto
thenormaldailyrequirement.Theserecommendations,althoughvariablefromcountrytocountry,also
suggesttheadditionofprotein,iron,andothermineralandvitaminsupplementstoprovidethenecessary
materialsforfetalandmaternalwelfareduringthecourseofgestation.Althoughcommonsenseindicates
thatappropriatenutritionisimportantformaximizingthepossibilityofhealthyoffspring,Hyttenand
Leitch12andothers14havepointedoutthatitisdifficulttofocusonnutritionaloneasafactorinthegrowth
anddevelopmentofnormalbabies.Womenwhoareappropriatelynourishedduringthecourseofpregnancy
arealsousuallybetterhoused,bettereducated,andhavegreateraccesstothemedicalantepartumcarethat
seemstobeassociatedwithimprovedpregnancyoutcomes.Antepartumnutrition,however,continuestobe
anareaofgreatinterestbecausethefeedingofpregnantwomenisasimpleinterventionthatmayhavea
significantimpactontheoutcomeofreproduction.ThecurrentrecommendationsproposedbytheFoodand
NutritionBoardoftheUSNationalScienceFoundationarelistedinTable3.
Table3.Recommendeddietaryallowances(Revisedin2005)*
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Nutrient
Fornonpregnantwoman Forpregnantwoman
Protein
45g/day
+30g/day
Calories
2100
+300
Calcium
1000mg/day
Nosupplementation
Iron
18mg/day
+9mg/day
Folicacid
400g/day
+200g/day
Ascorbicacid 75mg/day
+10mg/day
*FoodandNutritionBoard,InstituteofMedicine.Dietaryreferenceintakesforenergy,carbohydrate,fiber,
fat,fattyacids,cholesterol,protein,andaminoacids.Washington,DC,NationalAcademiesPress,2005.
CaloricRequirements
Maternalmassincreasesbyapproximately20%duringthecourseofnormalgestation.Thisincreaseinmass
andthemetabolicneedsofthefetusrequireadditionalcaloriesabovetherecommendeddailyallowance.In
1989,theFoodandNutritionBoardoftheNationalAcademyofSciencessuggestedthat300additional
caloriesbeaddedtothedietofpregnantwomentocompensatefortheadditionalneedsoffetalgrowthand
increasedmaternalmetabolism.14Inpregnantadolescents,orthosestillintheiractivegrowthphase,
additionalcaloriesbeyondthisrecommendationarerequiredtosustainneedsrelatedtomaternalgrowth.
Thebasalcalorielevelsforanywomancanbedeterminedfromtablesthattakeheightandbodyhabitusinto
consideration.Apregnantwomanofaveragesizerequiresapproximately2200calories/day(Table3).
ProteinRequirements
Onthebasisofnitrogenbalancestudies,theFoodandNutritionBoardhasrecommendedthatanextra30g
ofproteinbesuppliedtopregnantwomeninadditiontothebasicrequirementbasedonageandsize.14In
theaveragesizedwoman,thisconstitutesatotaldailyproteinrationof4446g/day(0.88g/kg/day)plus
the30gramsupplement(Table3).
IronandMineralRequirements
Ironsupplementationisrecommendedinpregnancybyvirtuallyallnutritionalauthorities.The
requirementsofthefetusandplacentaandincreasedmaternalredcellproductionrequireapproximately
500mgofelementalironduringthecourseofanormalpregnancy.15Thisexceedswhatmostwomenhavein
termsofphysiologicironstores.TheFoodandNutritionBoardrecommends27mg/dayofsupplemental
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ironduringthecourseofpregnancy.Thisamountisusuallypresentinprenatalvitamins.Ifthematernaldiet
islikelytohavebeendeficientinironbeforepregnancy,ironstoresmaybesignificantlylessthannormal,
andadditionalironsupplementationshouldbeconsidered.
FolicacidisacoenzymeessentialinpurineandpyrimidinemetabolismandinthesynthesisofDNA.Clinical
evidenceoffolicaciddeficiencyisusuallyfirstevidentintissuesthathaverapidcellturnover,notablyin
hematopoiesis.Megaloblasticanemiaofpregnancyasaresultofinadequateintakeoffolicacidisnotarare
causeofanemiainpregnantwomenintheUnitedStates.Prenatalmultivitaminswithfolicacidoftencontain
1mgoffolate,whichexceedstherecommendedsupplement.
PLASMALEVELSOFNUTRIENTS
Changesinnutrientsandrelatedmaterialsintheplasmaofpregnantwomensuggestfundamentalalterations
inthemannerinwhichtheyhandlethesematerials.Totalproteinlevelsfallinpregnancytolevelsabout
1000mg/dllessthanthoseobservedinthenonpregnantwoman.Muchofthisdecreaseisinthealbumin
fraction,whichisimportantintermsofitseffectonthecolloidosmoticpressure.Loweringofthecolloid
osmoticpressureallowswatertoflowfromtheplasmaintocellsorfromvesselsintotheextracellularspace.
Globulinsshowarelativelysmallincreaseinserumconcentrationduringthecourseofnormalpregnancy.
Levelsoffibrinogen,animportantproteininnormalbloodcoagulation,aswellasfactorsVII,VIII,IX,andX,
areappreciablyincreasedinthepregnantstate.Theincreasedconcentrationoffibrinogen(approximately
50%),isthoughttoberesponsibleforthecommonlyobservedincreaseinerythrocytesedimentationrate.
Lipidconcentrationintheserumismarkedlyincreasedinpregnancy(Fig.3).Triglycerides,phospholipids,
cholesterol,andfreefattyacidsincreasemarkedlyinamount.Theincreaseinserumcholesterolseemsto
occurregardlessofthedietaryhabitsofthegravidavegetariansshowthesameincreaseasthosewhoeat
meat.16, 17
(http://resources.ama.uk.com/glowm_www/graphics/figures/v2/0130/003f.gif)Fig.
3.Relativechangesintheplasmaconcentrationofvariouslipidsduringthe
courseofpregnancy.Thenormalornonpregnantlevelisexpressedas100%.
(HyttenF,ChamberlainG:ClinicalPhysiologyinObstetrics.Boston,Blackwell
ScientificPublications,1980)
CARBOHYDRATEMETABOLISM
Carbohydratemetabolismisalteredinthecourseofnormalpregnancy,andthepregnantstatehasbeen
characterizedasdiabetogenic.Previouslyundiscovereddiabetesmaybeunmaskedduringthecourseof
pregnancy,orawomanmaydevelopdiabeticlevelsofbloodglucoseasaresponsetopregnancy.
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Inthefastingstate,glucoseistransferredtothefetusfromthematernalcirculation,producingadecreasein
maternalserumglucoselevels.Themajoreffectsofpregnancyonglucosemetabolismarerelatedtothefact
thatthefetuswithdrawsglucosefromthematernalcirculation.InastudybyBleicherandcolleagues,18
averageplasmaglucosevaluesinantepartumwomen(75.2mg/dlstandarderrorofthemean[SEM]=
2.8mg/dl)weresignificantlylowerthanthoseinpostpartumwomen(92.5mg/dlSEM=2.7mg/dl).This
phenomenonisthoughttooccurbecausethefetususesglucosealmostexclusivelyasitsmetabolicfuel.The
rateofdeliveryofglucosetothefetalcirculationisthoughttobecontrolledbythedifferenceinserum
concentrationsbetweenmaternalandfetalserumlevels.Glucosealsoseemstobetransferredacrossthe
placentabymeansoffacilitateddiffusion.Placentaltransferofglucoseandothermaterialsrelatedto
carbohydratehandlinginpregnancyispicturedinFigure4..
(http://resources.ama.uk.com/glowm_www/graphics/figures/v2/0130/004f.gif)Fig.4.Aschematic
representationofmaternalfetalnutrientandhormoneexchangeacrosstheplacentainpregnancy.
Glucose,aminoacids,andketonesmovefreelyintothefetalcirculation,whereasinsulin,glucagon,and
freefattyacids(FFA)donot.Maternalhyperglycemiaandketosisarethusreflectedinthefetalcirculation.
(FeligP:Bodyfuelmetabolismanddiabetesmellitusinpregnancy.MedClinNorthAm61(1):43,1977)
Glucoseutilizationstudiesdemonstratethatthefetususesglucoseatarateof6mg/kg/minuteatterm.This
rateisquitehighcomparedwiththatinthenormaladult,whichisapproximately2.5mg/kg/minute.In
additiontoglucose,aminoacidsarefreelytransportedacrosstheplacentaintothefetalcirculation.This
transferproducesmaternalhypoaminoacidemia,particularlyofalanine,animportantprecursorofglucose
ingluconeogenesis.Withthefallinserumglucoselevels,thereisanassociateddecreaseinplasmainsulin,
producingwhatFelig19hasreferredtoasanacceleratedandexaggeratedresponsetostarvation.Thisisone
explanationoftheelevationinfreefattyacidsandtriglyceridesseeninthemother.
Inpregnancy,feedingproduceshyperglycemia,anincreaseinseruminsulinlevels,andhypertriglyceridemia.
Thereisalsoadiminishedresponsetoinsulin.Thediminishedresponsetoinsulin,whichmaybemediated
hormonally,producesaberrationsinbloodsugartestingusingbothoralandintravenousloadingwith
glucose.Adjustednormsarethereforenecessarytodiagnosediabetesinpregnancy.Bleicherandothers17 ,
18, 19havehypothesizedthatthesechangesarerelatedandthatthepurposeofthesechangesinthe
carbohydratemetabolismofthemotheristheprotectionoffetaltissuesfromfluctuationsinglucoseby
switchingthematernaltissuesovertofreefattyacidandtriglyceridemetabolism.Theplacentalproduction
oflactogen,asubstanceknowntohavelipolyticproperties,isthoughttoexplainthesephenomena.Theanti
insulineffectsofplacentallactogenseemtoprovideadditionalevidenceforthishypothesis.Thecomplexities
ofcarbohydratemetabolisminpregnancy,althoughpartiallyelucidated,continuetobeconfusingand
requirefurtherinvestigation.
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ALTERATIONSINTHECARDIOVASCULARSYSTEM
Regardlessoftheetiologicfactorsinthemanychangesthatoccurinthephysiologyofthepregnantwoman,
thesystemthatundergoessomeofthemostsignificantalterationsisthecardiovascularsystem.Thechanges
inthissystemarequiteprofoundandbegintooccuralmostatthetimeofconception.Lindhard's
observationsin1915thatthecardiacoutputisincreasedinpregnancyformedthebasisformuchofthework
subsequentlydoneindelineatingthemultiplechangesthatoccurincirculatoryphysiologyinthepregnant
woman.20
AnatomicAlterations
Thepositionoftheheartinthechestchangesduringthecourseofnormalpregnancy.Itisrotatedslightly,
anditsapexdeviatestotheleft.Thus,onphysicalexaminationofthechestofthepregnantwoman,thepoint
ofmaximumintensityofthecardiacactionisoftenlateraltothemidclavicularlineandinthefourthrather
thanthefifthintercostalspace.
Becauseofthesechangesinpositionandslightlyincreasedcardiacvolume(7080ml),theareaofrelative
dullnessovertheprecordiumisincreased,asisthecardiacshadowonxrayexamination.Lateralxrayfilms
ofthepregnantwoman'sthoraxmay,infact,showfindingssuggestiveofatrialdilation,whichissuggestiveof
stenoticmitralvalvulardisease.ThesealterationsinmorphologyarepicturedinFigure5.Thechangesin
heartposition,increasedoutput,andincreasedbloodvolumeareprobablyresponsibleforthesystolicflow
typemurmurthatiscommoninpregnancy.
(http://resources.ama.uk.com/glowm_www/graphics/figures/v2/0130/005f.gif)Fig.5.
Morphologicchangesintheheartandlungs.Thefigureshowsthealterations
producedbypregnancy.Leftaxisdeviation,changesintheelectrocardiogram,and
alterationsinphysicalfindingsarecommonconcomitantsofnormalpregnancy.
(BonicaJ:PrinciplesandPracticeofObstetricAnalgesiaandAnesthesia.
Philadelphia,FADavis,1967)
ElectrocardiographicChanges
Thesechangesincardiacposition,presumablybroughtaboutbysomeofthefunctionalchangesin
cardiodynamics,inducecertainchangesintheelectrocardiographic(ECG)findingsassociatedwith
pregnancy.Aswouldbeanticipated,ECGfindingsaresuggestiveofleftaxisdeviationofapproximately15
degrees.TheremaybedecreasedvoltageintheQRScomplexes,aswellasalterationsinTandPwaves.Ina
numberofnormalpregnantwomen,theremaybeflatteningorinversionofTwavesinleadIII,aswellas
depressionoftheSTsegmentinlimbandchestleads.Thesefindings,whicharesuggestiveofmyocardial
ischemia,havebeenreportedtooccurinasmanyas14%ofnormalpregnantwomeninwhomnoneofthe
otherdemonstrableconcomitantsoftruemyocardialdiseaseareseen.Whenthisfindingoccursina
pregnantwoman,ittendstorecurinsubsequentpregnancies.Cardiacarrhythmias,particularlythoseof
supraventricularorigin,arealsorelativelycommoninpregnancybutarenotgenerallyproductiveof
symptomssignificantenoughtorequiretherapy.21, 22
AlterationsinCardiodynamics
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Beginningearlyinpregnancy,cardiacoutputincreasessignificantlytomaximumlevelsataround2024
weeks(Fig.6)andmaintainsthatleveluntilafterdelivery.Itisgenerallyacceptedthatinthecourseof
pregnancythecardiacoutputincreasestolevels3035%inexcessofthatinthenonpregnantwoman.Recent
workbyClappandCapeless23hasdemonstratedthatthisincreaseincardiacoutputmaybeenhancedin
subsequentpregnancies.Strokevolumeandenddiastolicvolumearealteredinasimilarmanner.Systemic
vascularresistanceisalsosignificantlyaltered.
(http://resources.ama.uk.com/glowm_www/graphics/figures/v2/0130/006f.gif)Fig.6.Changesin
cardiovasculardynamicsduringthecourseofprimiparousandsubsequentpregnancies(afterClappAFIII,
CapeleasE:AmJCardiol80:14691473,1997)
Thefactorsresponsibleforthechangeincardiacoutputarenotcompletelyunderstoodbutarethoughttobe
relatedtooneorseveralofthemechanismsnotedintheintroductoryremarksinthischapteror,morelikely,
tosomecombinationofallthesefactors.Almostallofthetheoriesusedtoexplaintheobservedchanges
implicateeitherneurohumoralfactors,suchasestrogenandprogesterone,ortheplacentalcirculationacting
asanarteriovenousfistula.Maternalheartrateisincreasedinpregnancy,consistentwithafunctional
arteriovenousfistulatheincreaseaveragesapproximately15beats/minute.Figure7demonstratesthe
increaseinheartrateaspregnancyprogresses.
(http://resources.ama.uk.com/glowm_www/graphics/figures/v2/0130/007f.gif)Fig.7.Changesinmaternal
heartrateduringthecourseofgestation.Aprogressiveincreaseisshownaspregnancyapproachesterm.
(ClappJ:Maternalheartrateinpregnancy.AmJObstetGynecol152(3):251252,1985)
Clinicalsymptomsandfindingsmayberelatedtothesealterationsinnormalcardiovasculardynamics.The
pregnantwomanhaslessmeasurablecardiacoutput,aswellasdecreaseduterineperfusion,wheninthe
supineposition.Thesupinehypotensivesyndrome,whichischaracterizedbyhypotension,tachycardia,
diaphoresis,anddiscomfort,maybecomemagnifiedbytheeffectsofaconductionanestheticthatincreases
venouspoolingandfurtherreducesvenousreturntotheheart.Bypositioningthepatienttoproduce
leftwarddeviationoftheuterus,suchposturalchangesinvitalsignsmaybeavoidedandtheneedfor
vasopressorsobviated.ThecasereportsofO'ConnorandSevarino,24aswellasDePaceandcolleagues,25
suggestthatanappreciationofthisposturerelatedeffectmaybeimportantinthesuccessful
cardiopulmonaryresuscitationofpregnantwomenwhohavesustainedacardiacarrest.
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Rapidchangesinbodypositionmayproducesyncopeorlightheadednessbecauseofdecreasedperipheral
resistanceinthelowerextremities.Theseeffectsmaybefurtherintensifiedwhenwarmenvironmental
conditionscontributetoperipheralvasodilatation.Theoriesrelatingtotheeffectsofchangesin
cardiovasculardynamicsonthemetabolicheatproductionofthefetusandotherproductsofconceptionare
notablyabsentfrommostdiscussionsofthesephenomena,althoughsignificantfetalheatproductionis
demonstrableinmammaliangestations.
IntravascularVolumeChanges
Largeexpansionoftheintravascularvolume,particularlyplasmavolume,isoneofthehallmarksofnormal
pregnancy.Plasmavolumeincreasestoasignificantextentearlyinpregnancy.Maternalbloodvolume
expansionof40%isnotunusualinsingletonpregnancyandmaybeevengreaterinmultiplegestations.This
expansioninbloodvolumeisduetoanincreaseinplasmavolumeof4555%andanincreaseinredcellmass
of2030%.
Therapidincreaseinplasmavolume,depictedinFigure8,outstripsthemanufactureofnewredcellsand
mayproduceavirtualanemiainearlypregnancy.Theincreaseinplasmavolumewithoutaconcomitantly
rapidproductionofredcellmassismanifestedinanapparentdropinthehemoglobinconcentration,
hematocrit,andredbloodcellcount.Thisplasmaexpansionrequiresthatthedefinitionofanemiain
pregnancybealteredsothatapregnantwomanisnotconsideredanemicinmostcentersuntilthe
hemoglobinfallsbelow10g/dl.26Theredcellmassincreasesinthecourseofpregnancyby2030%,or
approximately250500mlofpackedredcells.
(http://resources.ama.uk.com/glowm_www/graphics/figures/v2/0130/008f.gif)Fig.8.Expansionofplasma
volume,totalbloodvolume,andredcellvolumeinthecourseofnormalgestation.Therapidexpansionof
plasmavolumeexceedstherateofredcellproductionearlyingestation,producingadecreasein
hemoglobinandhematocritconcentration.(BonicaJ:PrinciplesandPracticeofObstetricAnalgesiaand
Anesthesia.Philadelphia,FADavis,1967)
Thereasonsforthisplasmavolumeexpansionareprobablynumerous,andallsuggestedmajorcausative
factors,includingtheeffectsofhormonallevelchanges,thedecreaseinperipheralresistanceproducedby
theplacentalanduterineshuntingmechanisms,andheatadaptivemechanisms,arelikelyinvolvedtosome
extent.Theroleofincreasedcardiacoutputinthegenesisofthesechangesisalsosomewhatspeculativein
thatitispresentlyuncertainhowplasmavolumeexpansionistemporallyrelatedtoincreasedcardiacoutput.
Toexplainthisphenomenon,Longo 27 hasproposedasetofmechanismsthatintegratetheeffectsofvarious
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pregnancyhormones,includingestrogenandprogesterone,aswellastheknowneffectsofpregnancyonthe
reninangiotensinsystemandhumanplacentallactogen,coupledwiththechangespresumablybroughtabout
bytheincreaseduterineandplacentalcirculationflowratesaspregnancyapproachesterm.
Thechangesinbloodvolumeandplasmavolumeareassociatedwithchangesinthedistributionofcardiac
output.Astheuterinecontentsincreaseinsizeandrequirementsforoxygenandnutrientmaterialsgrow,
thereisanincreaseinthevolumeofuterinearterybloodflow.ThestudiesofRomneyandcolleagues4
indicatethattheincreaseinuterineperfusionisassociatedwiththeincreasingsizeoftheproductsof
conception.Theflowratesintheuterineandplacentalcirculationapproximateroughly10ml/minuteper
100goffetaltissue.Theassociationbetweenthemassoftheconceptusanduterinebloodflowintermsof
gestationalageisdisplayedinFigure9.
(http://resources.ama.uk.com/glowm_www/graphics/figures/v2/0130/009f.gif)Fig.9.Uterinebloodflowat
variousstagesofgestation.Theflowincreasessignificantlywiththedurationofpregnancy.(HyttenF,
ChamberlainG:ClinicalPhysiologyinObstetrics.Boston,BlackwellScientificPublications,1980)
AlterationsinFormedElementsoftheBlood
Normalpregnancyischaracterizedbyleukocytosis.Thisincreaseinwhitecellcountismostlydueto
increasednumbersofpolymorphonuclearleukocytes,whichincreaseinnumberfromthetimeoffertilization
untilthetimeoflabor.AstudybyGriffinandBeck26indicates,asdoesolderliterature,28thatleukocyte
countsincreasesignificantlyfromtheirpreviouslyelevatedlevelinpregnancyataround35weeksof
gestationandcontinuetoriseuntilthetimeofparturition.Atthetimeofdeliveryinthisstudy,theleukocyte
countswereinexcessof14,000103cells/ml(standarddeviation=1.62103cells/ml).Perhapsbecause
oftherapidproductionofnewcells,asmallnumberofmyelocytesormetamyelocytesarenormallypresent
inthepregnantwoman'speripheralcirculation.
Lymphocyteandmonocytenumbersarenotalteredsignificantlyduringthecourseofpregnancy,but
eosinophillevelsarereportedtodecreasesharplyduringlaboranddelivery.Basophillevelsmaybereduced
inpregnancy.
Plateletsareanimportantelementinthecoagulationprocesstheirlevelsdecreaseslightlyduringthecourse
ofpregnancy.Thisdecreasemaybeafunctionoftheincreaseinplasmavolumeandisnotreportedtobe
associatedwithanysignificantchangeinplateletfunction.
AlterationsinVenousPressure
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Thestateofpregnancy,eitherthroughtheeffectsofprogesteroneontheveinsoftheperipheryorviathe
shuntingmechanismsofplacentalcirculation,increasesthevenouscapacitance.Thisismoremarkedinthe
lowerextremities,wheredependentedemaisseeninasmanyas30%ofpregnantwomenatsometime
duringthegestationalperiod.Venouspressureabovetheleveloftheumbilicusisgenerallynormal,whereas
thatbelowtheleveloftheumbilicusiselevated.ThesechangesareportrayedinFigure10.
(http://resources.ama.uk.com/glowm_www/graphics/figures/v2/0130/010f.gif)Fig.10.Venouspressure
changesassociatedwithpregnancyinfemoralandantecubitalveins.(BonicaJ:PrinciplesandPracticeof
ObstetricAnalgesiaandAnesthesia.Philadelphia,FADavis,1967)
Theclinicaleffectsofthiselevationinvenouspressurearethoughttoberesponsibleforthepedaland
pretibialedemaseeninmanypregnancies,particularlyapproachingparturition.Theincreasedseverityof
varicositiesofthelowerextremitiesandofthevulvaandvagina,aswellashemorrhoids,maybeatleast
partiallyexplainedbythiseffect.Obstructionofthevenousreturntotherightheartasaresultofuterine
compressionofthevenacavaproducingsupinehypotensivesyndromehasbeenmentionedasacauseof
hypotensionfollowingtheadministrationofconductionanesthesiaspinal,epidural,andcaudalanesthesia
producesympatheticblockade,whichincreasesthevenouscapacitancetoevengreaterlevelsthanthat
alreadyproducedbytheeffectsofprogesteroneonthesmoothmuscleofthevessels.
Theincreasedvenouspressurebelowtheleveloftheumbilicusalsosuggeststheuseofalternativepathsfor
venousreturntotheheart,includingtheazygosandhemiazygossystemsandtheparavertebralandepidural
veins.Suchpathways,particularlytheparavertebralandepiduralpathways,mayberesponsibleforthe
decreaseinvolumeofthesubarachnoidspace.Becauseofthischange,smalleramountsofanestheticdrugs
arerequiredfortheinductionofspinalanesthesia.29, 30Thisisanimportantpoint,becauseexcessivelyhigh
levelsofspinalanesthesiamaybeobtainedwithwhatwouldbeausualdosageinanonpregnantwoman.
RespiratoryChanges
Alongwiththechangesinthecardiovascularsystem,numerouschangesoccurinthepulmonaryphysiology
thatreflectchangesinlungperfusionandthemechanismsoflungaction.Aswouldbeexpectedfromthe
increaseinfetalrequirementsforoxygenasitsmassincreases,thechangesinpulmonaryphysiologyreflect
theprocessoffetalgrowth.Thechangesthatoccurasaresultofthatgrowthincludechangesintheprofileof
thematernalchestand,obviously,inthelevelandmovementofthediaphragms,whicharemechanically
interferedwithbythepresenceofthegraviduterusandthedisplacementoftheperitonealcontents.The
circumferenceofthechestinpregnancyincreasesasthesubcostalmarginalangleisincreasedfrom
approximately70degreestomorethan100degreesnearterm,andthetransversediameterofthechest
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increasesbynearly2cm.Althoughtherespiratoryrateinpregnancyisnotappreciablyincreased,the
pregnantwomanexperiencesarelativehyperventilationduringthecourseofpregnancy.Thetidalvolume,
normally450ml/minute,isincreasedto650ml/minute,producingagreatergaseousexchangedespitethe
samefrequencyofinspirationandexpiration.Thesealterationsinfunctionalparametersaredepictedin
Figure11.
(http://resources.ama.uk.com/glowm_www/graphics/figures/v2/0130/011f.gif)
Fig.11.Changesinpulmonaryvolumemeasuresassociatedwithnormal
gestation.(HyttenF,ChamberlainG:ClinicalPhysiologyinObstetrics.
Boston,BlackwellScientificPublications,1980)
Theetiologicfactorsinthechangesinthefunctionalelementsofrespirationareobscurebecausethechanges
seenmaybemediatedbyanynumberofstimulipresentinpregnancy.Increaseddemandforoxygenforthe
growingfetus,theneedforincreasingheattransfertotheexternalenvironment,andtheeffectsof
progesteronemayallplaysomeroleinthegenesisoftheventilatorychangesthattakeplaceinthecourseof
normalgestation.Theprogesteronerelatedargumentisespeciallycogentbecauseithasrecentlybeen
demonstratedinanimalmodelsthatprogesteroneadministeredchronicallyinduceshyperventilationina
dosagerelatedfashion.Factorsrelatedtohyperventilation,suchasincreasedarterialpHanddecreased
PCO2,arealsoalteredintheprogesteronetreatedanimalsinamannersimilartothatseeninthepregnant
humanwoman.31
RenalChanges
Increasedcardiacoutputresultsinanincreasedvolumeofbloodflowtothekidneys.Becauseofthisincrease
inbloodflow,thekidneysareperfusedwithlargeramountsofblood,andthereforewithlargeramountsof
soluteandwatervolume,thanusualthusthekidneysdomorefilteringoftheblood.Thisextrakidney
filteringactionreducesthevaluesofsomecommonlaboratorybloodtestsbloodureanitrogenlevelsare
decreasedmarkedly,asarecreatininelevels.
Morphologicchangesoccurinthekidneysandcollectingsystems.Markedhydronephrosisandhydroureter
oftenarepresentinnormalpregnantwomen.InFried's31seriesofstudiesof109normalpregnantwomen,
theincidenceofhydronephrosisandhydroureterbyultrasonicmeasurementswas93.6%.Inthisstudy,the
rightsidewasmoreprofoundlyaffectedthantheleft.Thesenewdatasupportearlierworkusing
radiographictechniques.Thesechangesarethoughttobeduetotheeffectsofprogesteroneorthe
mechanicalobstructionoftheuretersandrenalpelvesbythegraviduterusormarkedlydistendedovarian
veins.Therightsidedureteralandrenaldilatationmaybeproducedbypressureontherightureteratthe
levelofthepelvicrim.Ontheleftside,theureterisprotectedandpaddedbythepresenceofthesigmoid
colon.Theincreasedvolumeofthecollectingsystemanduretersisthoughttopredisposetoupperurinary
tractinfectionbyincreasingtheurinarydeadspaceandpossiblytheamountofrefluxfromthebladdertothe
ureters.
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Asthepregnancyprogresses,theglomerularfiltrationrateincreases,anditdoessomoresignificantlythan
canbeexplainedbyincreasedcardiacoutputalone.AthertonandGreen32havesuggestedthatthe
mechanismsproducingthisdisparateincreasemayberelatedtoincreasedprolactinordopaminesecretionin
thepregnantwoman.Inmoststudiesusingrats,progesteronehasnothadthiseffect.Withcardiacoutput
increasingby3035%andrenalplasmaflowincreasingbymorethan50%,thetubularreabsorptivecapacity
forseveralsubstancesisexceeded.Thisproducesconditionssuchasglycosuriaandaminoaciduria.11
Althoughvaluesvary,about1215%ofgravidwomenhaveglycosuriaatsometimeduringtheirpregnancy,
oftenshortlyafterthewomaneatsfoodshighinsimplesugars.Lactoseandothersugarsmayalsoappearin
theurineinthecourseofthepregnancy.
SALTANDWATER
Despitetheincreaseinsodiumandwaterpresentedtotheglomerulusinpregnancy,morereabsorptionof
bothoccursthaninthenongravidsituation.Thisimpliesanincreaseintotalbodywaterofapproximately6
8L,aswellasanincreaseinsodiumcontentofnearly950mEq/L.Amongthehormonesthatareincreasedin
theserumduringthecourseofpregnancy,severalhavebeennotedtoproducesodiumloss.Amongtheseare
progesterone(apartialinhibitorofaldosterone),prostaglandins,anddopamine.AthertonandGreen32have
suggestedthatseveralothercirculatinghormonesmayactasantinatriuretics.Amongthese,cortisol,
deoxycortisone,estrogen,humanplacentallactogen,andprolactinmayallhavesomeroleinopposingthe
saltlosingpropertiesofprogesterone.Inaddition,thedecreaseinserumproteinconcentration,the
decreaseinarterialpressure,andtheeffectsofposturalchangesinbloodflowinpregnancymayacttogether
indeterminingthefinalamountofsodiumreabsorptioninthepregnantstate.Thechangesinrenal
physiologyinpregnancy,althoughmanifoldandpresumablyrelatedtootherchangesinmaternal
physiology,remainsomewhatobscureintermsoftheunderlyingmechanismsinpregnancyandwherethese
mechanismsactintheglomerulusandtubule.
THEGASTROINTESTINALSYSTEM
Amongtheotherprofoundchangesthatoccurinthecourseofnormalgestationaremanyalterationsinthe
physiologyofthegastrointestinalsystem.Themostmarkedoftheseareprobablyrelatedtotheglobal
effectsofprogesteroneonthesmoothmuscle,whichmakesupthelargestportionofthegut.Kumar,33and
morerecentlyGillandcolleagues,34havedescribedtheeffectsofprogesteroneonextrauterinesmooth
muscle.Progesteronehastheeffectofproducingadosedependentandreversibleinhibitionoftheelectrical
andmechanicaleventsassociatedwiththecontractionofsmoothmusclefibers.Lawsonandcolleagues35
demonstratedprolongationofgastrointestinaltransittimeinthesecondandthirdtrimestersbutshowedno
statisticaldifferencesfromthenonpregnantstateinthefirsttrimesterorpostpartum.
Depressionofmusculartoneandactionmayexplainthenumerousalterationscommonlyseeninthe
pregnantwomanthesealterationsmayhaveclinicalimplications.Theincreasedoccurrenceofregurgitation
andoftentroublesomepyrosisofpregnancymaybeexplainedbydecreasedtoneatthecardioesophageal
junction,aswellasbyincreasedintraabdominalpressure.Inanimalmodels,Fisherandassociates36
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demonstrateddecreasedactivityofthecircularsmoothmuscleintheloweresophagusinresponsetoboth
estrogenandprogesterone.Decreasedmuscleactionalsoexplainstheincreasedemptyingtimeofthe
stomachandduodenum,aswellasthedelayingallbladderemptying.Constipationmayberelatedtothis
phenomenonaswell,inthatdecreasedcolonicmotilitymayprovidetheopportunityforincreasedwater
removalfromthestool.Thismechanismmayaggravatehemorrhoidsproducedbytheincreasedvenous
pressurebelowthelevelofthegraviduterus.
Themajorclinicalimplicationsoftheseprocessesinthegastrointestinalsystemaremostrelevanttothe
problemsproducedintheadministrationofgeneralanesthesia.Howevertheyaremediated,theeffectsof
pregnancyonthemotilityoftheentiregastrointestinalsystemmakevirtuallyeverypregnantwomanwho
requiresageneralanestheticduringlaborahighriskpatientforaspirationpneumonia.Aspirationofgastric
contentsduringoraftertheadministrationofgeneralanesthesiacontinuestobeanimportantcauseof
maternalmortality.37 Whengeneralanesthesiaisindicated,oftenunderemergentconditions,endotracheal
intubationshouldbeperformed
SKINCHANGES
Pregnancyproducesmanychangesintheskinthat,althoughphysiologic,maycausesomeconcerninthe
pregnantwoman.Amongthesechangesishyperpigmentation,whichoftenoccursintheareolae,theperineal
skin,theanalregion,theinnerthighs,andthelineanigra,whichappearsontheabdominalwall.Melasmaor
chloasmaisablotchy,sharplymarginatedhyperpigmentationthatoccursonthefaceofdarkhairedand
darkcomplexionedwomen.Itismostoftencentrallydistributedontheface.
Vascularspidersoccurinabout67%ofwhitepatientsand11%ofblackpatientsbythetimepregnancyhas
reachedthethirdtrimester.Theselesionsoccurontheneck,throat,face,andarms.Mostofthesefadeafter
theseventhpostpartumweek.Circulatingestrogensinhighlevelsarethoughttoberesponsibleforthe
appearanceoftheselesions.
Palmarerythema,whichisalsocommoninliverdisease,hyperthyroidism,andcollagenvasculardiseases,
appearscommonlyinpregnancy.Approximately67%ofwhitewomenand33%ofblackwomenexperience
palmarerythemaduringthecourseofgestation.Striaearecommonamongwhitewomeninlatepregnancy
butarelesscommoninblackandAsianwomen.Thereseemstobeafamilialtendencyintheoccurrenceof
theselesions.Whentheyoccur,theyfirstappearduringthesixthandseventhmonthsofgestationonthe
abdominalskintheythenoccuronthebreasts,upperarms,lowerback,buttocks,andthighs.Thecauseof
theselesionsisunclear,buttheyhavebeenrelatedtoacombinationofstretchingoftheskinandincreased
levelsofcorticosteroidsandestrogeninpregnancy.38
SUMMARY
Thepregnantstateischaracterizedbyamyriadofalterationsinthenormalphysiologyofthegravidwoman.
Anunderstandingofsomeofthemajormechanismsthatproducethesechangesishelpfulintheanalysisof
symptomsandproblemsthatariseduringthecourseofanormalgestation.Whenassociateddiseaseis
present,understandingofthesealterationsbecomesmoreimportantinthattheymustbedistinguishedfrom
pathophysiologicchangeswroughtbythediseaseprocess.Theinteractionbetweendiseaseandgestational
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physiologymaymaketheappropriatediagnosisandmanagementofthepregnantwomandifficult.Whena
pregnantwomanrequiresmedicalorsurgicaltherapy,theconsultativeservicesofanobstetricianorclinician
trainedinthecomplexitiesofmaternalphysiologyisabsolutelycriticaltothepropermanagementofclinical
problems.
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