www.revportcardiol.org
Revista
Portuguesa
de
Cardiologia
Portuguese
Journal
of
Cardiology
REVIEW
ARTICLE
Heart
disease
and
pregnancy:
State
of
the
art
夽
Tatiana
Guimarães
a,∗,
Andreia
Magalhães
a,
Arminda
Veiga
a,
Manuela
Fiuza
a,
Walkíria
Ávila
b,
Fausto
J.
Pinto
aaServic¸odeCardiologia,HospitaldeSantaMaria,CentroHospitalarLisboaNorte,EPE,CentroAcadémicoMedicinade
Lisboa/CentroCardiovasculardaUniversidadedeLisboa,Lisboa,Portugal
bServic¸odeCardiologia,UnidadedeCardiopatiadaGestante,InstitutodoCorac¸ão(InCor)doHospitaldasClínicasdaFaculdade
deMedicinadaUniversidadedeSãoPaulo,SãoPaulo,Brazil
KEYWORDS
Pregnancy; Heartdisease; Heartfailure
Abstract The association between heart disease and pregnancy is increasingly prevalent. Althoughmostwomenwithheartdiseasetoleratethephysiologicalchangesofpregnancy,there areheartconditionsthatmanifestforthefirsttimeduringpregnancyandothersthattotally contraindicateapregnancy.Itisthereforeimportanttoestablishmultidisciplinaryteams dedi-catedtothemanagementofwomenwithheartdiseasewhointendtobecome,orwhoalready are, pregnant.The aimofthisarticleistosystematicallyreviewcurrent knowledgeonthe approachtowomenwithhigh-riskcardiovasculardiseaseduringpregnancy.
PublishedbyElsevierEspa˜na,S.L.U.onbehalfofSociedadePortuguesadeCardiologia.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/4.0/).
PALAVRAS-CHAVE
Gravidez; Cardiopatia;
Insuficiênciacardíaca
Cardiopatiaegravidez---oestadodaarte
Resumo A associac¸ão entrecardiopatia egravidez écada vez maisfrequente. Aindaque a grande maioria das mulheres com doenc¸as cardíacas tolere as alterac¸ões fisiológicas da gravidez,existempatologiascardíacasquesemanifestampelaprimeiravezduranteoestado gravídicoeoutrasquecontraindicamtotalmenteumagravidezpeloriscomaternoquelheestá associado.Destaforma,torna-seprementeacriac¸ãodeequipasmultidisciplinaresdedicadasà abordagemdemulherescomdoenc¸acardíacaquepretendemengravidarouquejáestão grávi-das.Oobjetivodesteartigoésistematizar,combasenoconhecimentoatual,aabordagemde mulherescomdoenc¸acardiovasculardealtoriscoduranteagravidez.
PublicadoporElsevierEspa˜na,S.L.U.emnomedeSociedadePortuguesadeCardiologia.Este ´e umartigoOpenAccesssobumalicenc¸aCCBY-NC-ND(http://creativecommons.org/licenses/ by-nc-nd/4.0/).
夽 Pleasecitethisarticleas:GuimarãesT, MagalhãesA,Veiga A, etal.Cardiopatiaegravidez--- oestado daarte.RevPortCardiol.
2019;38:373---383.
∗Correspondingauthor.
E-mailaddress:[email protected](T.Guimarães).
2174-2049/PublishedbyElsevierEspa˜na,S.L.U.onbehalfofSociedadePortuguesadeCardiologia.Thisisanopenaccessarticleunderthe CCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
The spectrum and prevalence of heart disease in
preg-nancyvariesconsiderablybetweencountries.Accordingto
the most recent information, 1-4% of all pregnancies in
industrialized countries are complicated by
cardiovascu-lar disease (CVD).1 This incidence has increased, due to
womenbecomingpregnantatolderages,thehigher
preva-lence of cardiovascular risk factors (smoking, diabetes,
obesityand hypertension)in women ofchild-bearing age,
andthegrowingnumberofwomenwithcorrectedcongenital
heartdisease(CHD)whoreachadulthood.Inastudywhich
included13Canadiancardiologycenters,CHDaccountedfor
80%ofallheartdiseaseinpregnancy,2whileinaregistryat
theHeartInstituteoftheUniversityofSãoPaulo,Brazil,that
included1000pregnantwomenwithheartdiseasefollowed
for10years,themostcommonetiologywasrheumaticheart
disease,foundin55%ofcases.3
Cardiomyopathiesarerare inpregnancy, although they
arean importantcause of complications,peripartum
car-diomyopathy(PPCM)beingresponsibleforthemostserious
adverseevents.4
Studies suggest that pregnancy-related mortality has
increased in recent decades, with a growing number of
deathsattributabletoCVD,5whichiscurrentlytheleading
causeofmaternaldeathinWesterncountries.6
Hemodynamicadaptationstopregnancy
Importantadaptations tothe cardiovascularsystem occur
inresponsetopregnancytomeettheincreasingmetabolic
needs of both mother and fetus (Table 1). Non-adaptive
hemodynamic changes can lead to maternal and fetal
morbidity.7Failureofnormaladaptationscanleadto
decom-pensationofexistingheartdisease,theonsetofsymptoms,
orthe firstmanifestationsof previously unknowndisease,
andhence pregnancy is often considered a natural stress
test.
Bloodvolume increasesconsiderablyduring pregnancy,
rapidly between six and 20 weeks, and less markedly
between20weeksandterm,withameanoverallincrease
of around 50%.8 Increased erythropoietin production
sti-mulates erythropoiesis, which can rise by over 40% in a
pregnantwomanwithoutnutritionaldeficiencies.9However,
theincrease inplasma volumeisgreater thanthat ofred
bloodcellmass, resultinginhemodilution, whichleads to
physiologicalanemiaofpregnancy.Hemoglobinlevelsaslow
as11g/dlareconsideredphysiological.7Cardiacoutput(CO)
risesbyaround50%,initiallyduemainlytoincreasedsystolic
volumeandthen toincreasedheart rate(HR) inthethird
trimester.Peripheralvascularresistance (PVR)fallsduring
pregnancy, leading to reductions in systolic and diastolic
bloodpressure(BP).BPislowestduringthesecondtrimester
(5-10mmHgbelowinitiallevels),althoughthesteepestBP
fallsoccurbetweensixandeightweeksofpregnancy.10 As
pregnancy-relatedchangesin BPoccur veryearly,BP
lev-elslaterinthe pregnancyshouldbecomparedwiththose
beforepregnancy, ratherthanwith thoserecordedin the
firstweeks.7 Duringthethirdtrimester, BPreturnsto
pre-conceptionlevels.
COreachesapeakinlaborandimmediatelyafter
deliv-ery,withanincreaseof60-80%.Thisisduetovariousfactors,
particularly higher HR, increasedpreload associated with
uterinecontractions(for eachuterinecontraction 300-500
mlofbloodentersthesystemiccirculation),andelevation
of circulating catecholamines.11 It is extremely important
tomaintainbloodvolumeatthisstageandcareshouldbe
takentoavoidexcessivebloodloss,whichcoulddrastically
reducepreload.Thisisthestageatwhichthereisgreatest
riskofdecompensationofheartdisease.
Diagnosisofcardiovasculardiseaseinpregnancy
Acomplete medicalhistory isessential, focusingon
char-acterization of the symptoms and signs associated with
the physiological changes of pregnancy. Healthy pregnant
women may present exertional dyspnea, fatigueand
pal-pitations.Onphysical examination,lowerlimb edemaand
jugular venous distension are common findings. On
car-diac auscultation, afterthe first trimester thefirst sound
islouder,andaejectionsystolicflowmurmur,athirdsound
andanatrioventriculardiastolicflowmurmur areheard in
90%, 80% and 20% of cases, respectively.7 However, chest
pain,new-onsetdyspnea,symptomatichypotension,
unex-plainedtachycardia,palpitationsassociatedwithsyncope,
andcyanosisshouldbealwaysconsideredwarningsigns.
Dif-ferential diagnosis should be based ona detailedclinical
history,withadditionalexaminationsbeingordered
accord-ingtoclinicalsuspicion,weighingtheirriskandbenefitand
interpretingtheresultsintheclinicalcontext,asshownin
Table2.12
Thenegativepredictivevalueofnatriureticpeptidesis
maintainedduringpregnancy,andtheyhavebeenshownto
help exclude heart disease in pregnantwomen. However,
changes inB-type natriureticpeptide levelsin pregnancy,
andtheirprognosticimpactinpregnantwomenwithheart
disease,remainthesubjectofdebate.13
Themajorityofpregnantwomenhaveanormal
electro-cardiogram (ECG),but elevation of the diaphragm by the
pregnant uteruscan lead toleftaxis deviation of 15-20◦.
Other possible non-pathological electrocardiographic
find-ingsaretransientST-segmentandT-wavechanges,presence
ofaQwaveandinvertedTwavesinDIII,anattenuatedQ
waveinaVF,andinvertedTwavesinV1,V2and,
occasion-ally,V3.14
Transthoracic echocardiography (TTE) is the gold
standard for assessing cardiac function during pregnancy.
Non-pathological findings in a pregnant woman include
mild dilatation of all four chambers(which may be more
markedintherightatriumandventricle),transienttrivial
mitralregurgitation(MR),physiologicalpulmonary and
tri-cuspidregurgitation(TR),7andincreasesinCOandleftand
rightventricularmass.15 Aorticregurgitation(AR)isalways
pathological.16 Transesophageal echocardiography can be
useful for the characterization of CHD and when aortic
dissection or prosthetic valve dysfunction are suspected,
particularlyfordiagnosingvegetationsandthrombi.
If examinations involving ionizing radiation are called
for, this decision requires careful consideration, because
eventhoughthepriorityisthemother’shealth,theeffects
Table1 Physiologicalchangesinpregnancy(adaptedfromSanghavietal.7).
Pregnancy Labor
1sttrimester 2ndtrimester 3rdtrimester
Hemodynamic CO ↑ ↑↑ ↑↑ ↑↑↑↑
PVR ↓ ↓↓ ↓↓
HR ↑ ↑↑ ↑↑↑ ↑↑↑↑
BP ↑ ↑ ↔ (pain)
Neurohormonal ↑Sympatheticactivity
↑Estrogen/progesterone/relaxin
RAAS Plasmavolume ↑↑ ↑↑↑ ↑↑↑↑ ↑↑↑↑↑
RBCmass ↑ ↑↑ ↑↑ (autotransfusion) Structural changes LVmass ↑ ↑ ↑ Cardiacchamber size
↑Atriaandventricles Aorta ↑Distensibility
↑:increased;↓:decreased;↔:nochange;BP:bloodpressure;CO:cardiacoutput;HR:heartrate;LV:leftventricular;PVR:peripheral vascularresistance;RAAS:renin-angiotensin-aldosteronesystem;RBC;redbloodcell.
Table 2 Peripartal acute dyspnea: differential diagnosis of acute peripartum cardiomyopathy (adapted from Bauersachs etal.1,2). Peripartum car-diomyopathy Pre-existingheart disease Pregnancy-associated myocardial infarction Pulmonary and/or amniotic embolism Myocarditis
History Morefrequent afterdelivery Morefrequentin the2ndtrimester Retrosternalchest pain,abdominal discomfort, nausea Pleuriticchest pain Infection
Biomarkers ElevatedNPs ElevatedNPs Elevatedtroponin Elevated D-dimers, troponin,NPs Elevatedtroponin, possiblyelevated NPs Echocardiography LVand/orRV dysfunction Evidenceof pre-existing structuralvalve diseaseor congenitaldefect Regional akine-sis/hypokinesis RVdysfunction andelevated pressure; McConnell’s sign Regionalor general hypokinesis
Additionaltests ConsiderMRI ConsiderMRI and/orgenetic testing Coronary angiography CTorV/Q scan;consider angiography MRI Consider myocardialbiopsy
CT:computedtomography;LV:leftventricular;MRI:magneticresonanceimaging;NPs:natriureticpeptides;RV:rightventricular;V/Q: ventilation/perfusion.
dosetowhichthefetus,whichisprotectedbytheuterus,
is exposed tends to be lower than that received by the
mother,although the fetus is more sensitive. The effects
depend on the radiation dose and on gestational age; if
possible the exam should be postponed until after the
first 12 weeks of pregnancy, the period of major
organo-genesis. There is noevidence that doses of <50 mGy are
associated with increased risk of miscarriage,
congeni-tal malformation, growth restriction or mental problems
(https://emergency.cdc.gov/radiation/prenatalphysician.asp).
Thedosetowhichafetus isexposedfromachestX-rayis
<0.01mGy,butevenso,anX-rayshouldonlybeperformed
if no other examination can clarify the etiology of the
mother’ssymptoms.Computedtomographyisrarelyusedfor
diagnosisofCVDinpregnancyand,giventhehighradiation
doses required, is not recommended. An exception can
be made if the mother’s survival is at stake (Table 2).
Cardiac magnetic resonance imaging (MRI) appears to be
safe for both mother and fetus17 and can be useful for
characterizing complex heart disease and disease of the
aorta.Therisktothefetusfromexposuretogadoliniumis
notknownandgadoliniumcontrastshouldthereforenotbe
used.14
Stresstesting,eitherexerciseorpharmacological,should
also be avoided in pregnancy due to the risk of
hypox-emia, fetal bradycardia and even fetal loss, caused by
reduced placental blood flow. Pre-conception stress
chronotropicandbloodpressureresponsetoexertion,and
exertion-inducedarrhythmiasinthemonitoringofpatients
withCHDandasymptomaticvalvedisease.14Stress
echocar-diographycan beuseful for pre-conception assessment of
myocardialcontractilereserveinwomenwithpreviousPPCM
and recovery of left ventricular ejection fraction (LVEF),
other cardiomyopathies with slightly impaired LVEF, valve
disease,andCHD.
Riskstratificationofpregnantwomenwith cardiovasculardisease
Assessmentoftherisk ofpregnancyinwomenwithknown
CVDshouldbeindividualizedandideallyperformedbefore
pregnancy,includingadjustmentstomedicationsuchas
sus-pendingcontraindicateddrugsandintroducingalternatives.
Several scores have been created to stratify the risk of
cardiovascularcomplications inpregnancy, the most
com-monly used of which is the Cardiac Disease in Pregnancy
(CARPREG)riskscore.18TheEuropeanSocietyofCardiology
(ESC)guidelinesrecommendassessmentoftheriskof
car-diovascularcomplicationsbasedontheclassificationofthe
WorldHealthOrganization(WHO), asthis includes
predic-tors that arenot incorporated in the CARPREG and other
riskscores(Tables3and4).14
Typeofdeliveryincardiovasculardisease
Thetypeofdeliveryshouldbedecidedandscheduledbya
multidisciplinary team.The preferredmode of delivery is
vaginal,withadeliveryplanindividualizedtothepatient,
herdisease, and her hemodynamic profile. Cesarean
sec-tion,although controversial,is indicatedfor patientswith
conditions in WHO risk group IV, under oral
anticoagula-tionin pre-term labor, withdecompensated heart failure
(HF),or forobstetricindications.14 Tocolyticbeta-agonists
shouldnotbeusedinmitralstenosis(MS)sincebyinducing
Table3 ModifiedWorldHealthOrganizationclassification ofmaternal cardiovascular risk: principles (adapted from Regitz-Zagroseketal.14).
Risk class
Riskofpregnancybymedicalcondition I Nodetectableincreasedriskofmaternal
mortalityandno/mildincreaseinmorbidity. II Smallincreasedriskofmaternalmortalityor
moderateincreaseinmorbidity.
III Significantlyincreasedriskofmaternalmortality orseveremorbidity.Expertcounselingrequired.If pregnancyisdecidedupon,intensivespecialist cardiacandobstetricmonitoringisneeded throughoutpregnancy,childbirthandthe puerperium.
IV Extremelyhighriskofmaternalmortalityor severemorbidity;pregnancycontraindicated.If pregnancyoccursterminationshouldbe discussed.Ifpregnancycontinues,careasfor classIII.
tachycardia, they reduce left ventricular (LV) filling time
andconsequentlyincreaseleftatrialpressure.Alternatively,
atosiban,anoxytocinantagonist,canbeused.
Corticoste-roids arecontraindicated inpatients withdecompensated
heartdiseaseduetotheriskofpulmonarycongestion,
pul-monaryedema(PE)andcardiogenicshock.
Infectiveendocarditis
TheESC19andtheAmericanCollegeofCardiology/American
HeartAssociation(ACC/AHA)20donotrecommendantibiotic
prophylaxis during vaginalor cesarean delivery.However,
in the Brazilian Society of Cardiology guidelines
prophy-laxisagainstinfectiveendocarditisisindicatedinhigh-risk
patients,with2gampicillinassociatedwith1.5mg/kg
gen-tamicinonehourbeforebirth.Inallergicpatients,penicillin
shouldbereplacedby1gvancomycin.21
Valvularheartdisease
Stenotic andleft-sided valvelesions areat higherrisk of
decompensation in pregnancy than regurgitant and
right-sided lesions. Valve stenosis restricts increases in CO,
raising transvalvular gradients and pressures upstream of
thelesion,andisthereforelesswelltoleratedinpregnancy
thanregurgitation,sinceregurgitantvolumediminisheswith
systemic vasodilation and consequent reduced afterload.
Mechanicalheart valvesareassociatedwithspecific
prob-lems(seebelow).
Althoughmostwomenwithlessseverevalvedisease
tol-erate pregnancy well, some valve lesions are considered
prohibitive:severeMS,severesymptomaticaorticstenosis
(AS),andanyvalvediseaseassociatedwithLVdysfunction
(LVD) and/or pulmonary hypertension (PH). Women with
these conditions should receive pre-conception
counsel-ingandshouldbetreatedbeforepregnancy.Hemodynamic
changesinpregnancycanleadtoincreasedmitraland
aor-ticvalvegradientsonTTE,leadingtooverestimationofthe
severityofthevalvelesion,22andsostenosisshouldbe
quan-tifiedbyvalveareaassessedusingplanimetry,orbypressure
half-timeforMSorbythecontinuityequationforAS.23,24For
womenwhoremainstableduringpregnancy,termdeliveryis
recommended.Vaginaldeliverywithgoodpainmanagement
isthepreferredmethodformostwomenwithvalvedisease.
Someexpertssuggest acesareansection forpatientswith
severeAS.14
Mitralstenosis
MS is the most commonvalvedisease in women of
child-bearingage,andin90%ofcasesisofrheumaticetiology.The
hemodynamic changes associated with pregnancy (higher
HR, CO, plasma volumeand red blood cellmass) lead to
increasedleftatrialpressureandPE.ManypatientswithMS
become symptomatic for the first time during pregnancy.
The most common complications are reduced functional
capacity,arrhythmias(mostoftenatrialfibrillation[AF])and
PE.ThesearerelatedtomitralvalveareaandNYHAclass24
and occurmore often inthe second andthird trimesters,
Table4 ModifiedWorldHealthOrganizationclassificationofmaternalcardiovascularrisk:application(adaptedfrom Regitz-Zagroseketal.14).
ConditionsinwhichpregnancyriskisWHOI
Uncomplicated,smallormild: pulmonarystenosis
patentductusarteriosus mitralvalveprolapse
Successfullyrepairedsimplelesions(atrialorventricularseptaldefect,patentductusarteriosus,anomalouspulmonary venousdrainage)
Atrialorventricularectopicbeats,isolated
ConditionsinwhichpregnancyriskisWHOIIorIII
WHOII(ifotherwisewellanduncomplicated) Unoperatedatrialorventricularseptaldefect RepairedtetralogyofFallot
Mostarrhythmias
WHOII-III(dependingonindividual) Mildleftventricularimpairment Hypertrophiccardiomyopathy
NativeortissuevalveheartdiseasenotconsideredWHOIorIV Marfansyndromewithoutaorticdilatation
Aorta<45mminaorticdiseaseassociatedwithbicuspidaorticvalve Repairedcoarctation
WHOIII
Mechanicalvalve Systemicrightventricle Fontancirculation
Cyanoticheartdisease(unrepaired) Othercomplexcongenitalheartdisease
Aorticdilatationof40-45mminMarfansyndrome
Aorticdilatationof45-50mminaorticdiseaseassociatedwithbicuspidaorticvalve
ConditionsinwhichpregnancyriskisWHOIV(pregnancycontraindicated)
Pulmonaryarterialhypertensionofanycause
Severesystemicventriculardysfunction(LVEF<30%,NYHAIII-IV)
Previousperipartumcardiomyopathywithanyresidualimpairmentofleftventricularfunction Severemitralstenosis,severesymptomaticaorticstenosis
Marfansyndromewithaortadilated>45mm
Aorticdilatationof>50mminaorticdiseaseassociatedwithbicuspidaorticvalve Nativeseverecoarctation
LVEF: left ventricularejection fraction;NYHA: NewYork HeartAssociation functional class; WHO: WorldHealth Organizationrisk classification.
symptoms occur, the patient should be started on
beta-blockers,toprolongventricularfillingtimeandreduceleft
atrialpressure,and,ifnecessary,diureticstorelieve
conges-tion. Anticoagulation is indicated in the presence of AF,
atrial thrombi or a history of thromboembolism.
Percuta-neous mitral commissurotomy should be considered only
when, despite medicaltreatment, the patientremains in
NYHA classIII/IV,and preferablynot untilafter 20 weeks
gestation. Cardiac surgery should be reserved for
life-threatening situations in which all other measures have
failed.14
Mitralregurgitation
The most common causes of MR in pregnant women are
rheumaticvalvedisease,MVPandCHD.ReducedPVRandBP
duringpregnancyexplainwhywomenwithmild,moderate
orevensevereMRbutwithoutLVdilatationordysfunction
toleratepregnancywell.However,increasedplasmavolume
andCOcanleadtoHForarrhythmias,particularlyincasesof
severeMRandinpatientswithLVdilatationordysfunction.22
Aorticstenosis
Bicuspidaortic valveisthemain causeofASin womenof
child-bearingage,andisfrequentlyassociatedwithaortic
dilatationandcoarctation,whichfurtherincreasestherisk
inpregnancy. MildtomoderateAS is generallywell
toler-ated, unlike severe AS, which is associated with angina,
tachyarrhythmiasandPE.UnlikeMS,thereis noeffective
pharmacologicaltherapyforAS.Pulmonarycongestioncan
berelievedwithdiuretics,althoughtheseshouldbeavoided
as much as possible due to the risk of hypotension and
symptomsofHF,syncopeorangina,percutaneousorsurgical
interventionisindicated.23
Aorticregurgitation
LikeAS, themostcommoncauseofARinyoungwomenis
bicuspidaorticvalve.WomenwithsevereARandpreserved
systolicfunctionusuallytoleratepregnancywell.However,
severe AR associated with LVD due to increased CO and
plasmavolumeis poorlytolerated. Symptomaticpregnant
womenshouldreceiveHFtherapy.22
Pulmonarystenosis
Isolated pulmonary stenosis is more common when there
are congenital abnormalities of the pulmonary valve.
Even in women with severe pulmonary stenosis, cardiac
complications (HF and low CO) during pregnancy are
rare,but if present theycan betreated by percutaneous
valvuloplasty, with good results at any gestational age.26
Non-cardiac complications have been reported, including
hypertensive disorders, prematurity and thromboembolic
complications.27
Tricuspidregurgitation
The causes of primary, non-trivial, TR in young women
includeCHD(forexampleEbstein’sanomaly,which,
depend-ingonitscomplexity,canaffecttheprognosis),rheumatic
valvedisease,andinfectiveendocarditis.TRisusuallywell
toleratedduringpregnancy.However,insurgicallycorrected
oruncorrectedCHDinwhichthetricuspidistheonly
atrio-ventricularvalve, thevalvebecomesregurgitantandmay
beassociatedwith ventriculardilatation and dysfunction,
whichincreasesthepregnancyrisk.28
Prostheticvalves
When a woman who may become pregnant has a native
valvereplaced,therisksandbenefitsofabiologicalvalve
(riskofstructuraldeteriorationandlessdurability,with90%
likelihoodofreinterventionforvalvereplacementafter15
years,29 butwithnoneed for anticoagulation) needtobe
weighedagainstthoseofamechanicalvalve(greater
dura-bility and better hemodynamic profile, but higher risk of
thromboembolism and consequent need for lifelong
anti-coagulation).Pregnancyisusuallywelltoleratedinwomen
withbiologicalvalves;maternalcardiovascularriskdepends
on valve and ventricular function to a similar extent to
nativevalvedisease.Monitoringofthepregnancyissimilar
tothatfornativevalvedisease.Theriskofvalvethrombosis,
bleedingandfetalcomplicationsishigherwithmechanical
valves.
Aretrospective studypublishedin 2015of 84pregnant
women with valve disease (23 of whom had prosthetic
valves)demonstratedthatpregnancyinwomenwith
pros-theticvalveswasassociated withhighmaternal and fetal
morbidity.30 2015 also saw publication of data on the
outcomes of pregnancy in women with prosthetic valves
fromtheESC’sRegistry OfPregnancy AndCardiac Disease
(ROPAC).31Thisregistryincluded212patientswith
mechan-icalvalves,134 withbiologicalvalves and2620 without a
prostheticvalve.Maternalmortalitywas1.5%inthegroup
withprostheticvalvesand0.2%inwomenwithout(p=0.025).
Valve thrombosis occurred in 10 women with mechanical
valves,andbleedingcomplicationswerealsomorecommon
inthisgroup(23%vs.5%bothinwomenwithbiologicalvalves
and in thosewithout a prosthetic valve, p<0.001).
Event-freesurvivalwas78%inwomenwithout prostheticvalves,
79%inthosewithbiologicalvalvesandonly58%inthosewith
mechanicalvalves(p=0.001).Furthermore,fetaloutcomes
ofmotherswithmechanicalvalveswasworse,with
signif-icantly higherincidences of miscarriage,deathand lower
birthweight.Manyspecialiststhereforeprefertoreplacethe
nativevalvewithabiologicalvalveinwomenwhowishto
becomepregnant,notonlybecauseofthelowerassociated
risk,butalsobecausestudieshavedemonstratedthat
preg-nancy does notaffect degenerationofbiological valves,32
andbecausetheypermitpercutaneousvalve-in-valve
treat-ment,whichislikelytoberequiredforintermediate-and
high-riskpatientsinthefuture.
Anticoagulation
Pregnancy is a prothrombotic state, due not only to the
venousstasiswithwhichitisassociated,butalsoto
hyperco-agulabilityresultingfromincreasinglevelsofthrombogenic
factorsthroughoutpregnancy.33However,thematernaland
fetal complications associatedwith different
anticoagula-tionregimens,andthelackofrandomizedclinicaltrialsand
consistentguidelines,meanthatmanagementof
anticoag-ulationduringpregnancyisproblematic.22
Warfarin,avitamin Kantagonist,crossesthe placenta,
anditsuseinthefirst6-12weeksofpregnancyisassociated
with fetal complications, including warfarin embryopathy
(1-30%)andmiscarriage(15-56%),22andahigherincidence
of miscarriage and fetal intracranial bleeding throughout
pregnancy,30 the incidence of which varies in different
studies.34,35 However, when maintained throughout
preg-nancy, it offers the best thromboembolic protection in
womenwithmechanicalvalves.Althoughtheyincludedfew
patients,studieshaveshown thattherisk offetaltoxicity
islowerwhentherapeuticanticoagulationisachievedwith
warfarindoses≤5mg/dayratherthanwithhigherdoses.36,37
On thebasisof thesefindings,theESCandACC/AHA
con-sidervitaminKantagonistssafe,recommendingwarfarin<5
mg/day (or phenprocoumon <3 mg/day or acenocoumarol
<2 mg/day) throughout pregnancy (ESC: class IIa
recom-mendation, levelof evidenceC; AHA/ACC:classIIa, level
B).14,38 When the dose needed toachieve the target INR
is higher than those above, vitamin K antagonists should
be replaced by continuous low molecular weight heparin
(LMWH) or unfractionated heparin (UFH) during the first
trimester,thecriticalstageoforganogenesis.However,this
approachisdebatable,becauseotherstudieshave
demon-stratedthatwarfarinisassociatedwithfetalmortalityeven
atlowdoses.39
The AHA/ACC recommend aspirin 75-100 mg/day in
association with warfarin during the second and third
UFH does not cross the placenta and thus has no
direct effect on the fetus. Subcutaneous administration
is not effective, and is not therefore recommended due
tothe risk of thromboemboliccomplications,40 but
intra-venousUFHisthemostappropriateformofanticoagulation
pre- and post-birth due to its rapid onset of action and
elimination.
Like UFH, LMWHdoes not cross the placenta, but has
a better safety profile (greater bioavailability and longer
half-life,andlowerriskofbleedingandofheparin-induced
thrombocytopenia).40 However, its efficacy during
preg-nancyisdebatable.Somestudieshaveshownsimilarefficacy
to that of warfarin in women with mechanical valves if
administered at thecorrect dosage (twice dailybased on
themother’sbodyweight)andwithanti-Xalevelsmeasured
4-6hoursafteradministration,foratargetvalueof0.8-1.2
U/ml.35 However, a study of 15 pregnant women
receiv-ing full-dose LMWH (1 mg/kg±20% subcutaneously twice
daily)showedthatfactoranti-Xalevelswere
subtherapeu-ticinover50%ofcasesandthatlevelsvariedconsiderably
betweenadministrations.41
Warfarin should be suspended at least a week before
delivery,inahospitalenvironment,andshouldbeswitched
to LMWH or UFH. If warfarin is replaced by LMWH, the
latter should be suspended 36 hours before delivery and
UFH started. In turn, UFH should only be suspended 4-6
hoursbeforethebirthandresumed6-8hoursafterwardsif
hemostasisisensured.Themanagementofwarfarintherapy
variesbetween centersbut itshouldberesumed48hours
afterchildbirth.
Use oftheneworalanticoagulantsisincreasingin
non-pregnant women. The US Food and Drug Administration
recently gave rivaroxaban a class C recommendation in
pregnancy, but there have as yet been no reports on its
use.42
Complexcongenitalheartdisease
CHDaccountsfor80%of heartdiseaseinpregnantwomen
in the Western world.43 Some categories of CHD, such as
Fontancirculation,systemicrightventricleanduncorrected
cyanoticCHD,areassociatedwithhighmaternalandfetal
risk. In patients withFontan circulation, 10% of
pregnan-ciesareassociatedwithmaternalcomplications, themost
common of which are arrhythmias, and there may also
bethromboemboliccomplicationsandworseningofHF.44,45
There is agreement that Fontan patients with impaired
ventricular function, severe atrioventricular regurgitation
andenteropathyshouldbecounseledagainstpregnancy.14
Women withasystemic right ventricle(following Mustard
orSenning surgeryorwithcongenitallycorrected
transpo-sition of the great vessels) have a similar risk of cardiac
complications(10-30%),andshouldbeassessedbefore
preg-nancy.Pregnancyshouldbediscouragedinthepresenceof
severerightventriculardysfunctionorTR.14Inuncorrected
cyanotic CHD without PH, 32% of pregnancies are
associ-ated withcomplications, mostoften HF. Fetaloutcome is
directly relatedtothe mother’soxygen saturationat rest
(≤85% saturation is associated with fetal survival of only
12%).46
Pulmonaryhypertension
PHisassociatedwithhighmaternalmortality,butadvances
in pulmonary vasodilator therapy have raised hopes of
improvements in prognosis.47 Among types of PH, the
best prognosis is seen with idiopathic PH under specific
therapy,for whichmortalityis9%.48 Inthisgroup,women
withvasoreactivePH whoarestableunder calcium
chan-nelblockertherapyhavearelativelygoodprognosisduring
pregnancy.49
DespiteimprovementsinprognosisforwomenwithPHin
recentdecades,thisconditionis stillassociatedwithhigh
mortality, and is categorizedas risk level IV in the WHO
classification.Nocriteriahave beenagreedforidentifying
women with lower risk during pregnancy, and all women
diagnosedwithPHareadvisednottobecomepregnant.14If
awomandecidestocontinuewiththepregnancy,sheshould
be referred to a center specializing in PH and followed
byamultidisciplinaryteam.Pulmonaryvasodilatortherapy
in use before pregnancy should be continued, except for
endothelinreceptorantagonists(bosentan,macitentanand
ambrisentan),whichareteratogenicandshouldbereplaced
bysildenafiland/orprostacyclinderivatives.
Peripartumcardiomyopathy
In2010,theESC’sworkinggrouponPPCMproposeda
simpli-fieddefinitionofthisentity,asanidiopathiccardiomyopathy
frequentlymanifested byHF secondarytoLV systolic
dys-function (LVEF <45%) towards the end of pregnancyor in
themonthsfollowingdelivery,wherenoothercauseofHF
is found.50 As there is as yet no specific examination for
diagnosing PPCM, it is a diagnosis of exclusion and must
be differentiated from existing heart failure
decompen-satedbythehemodynamic changesunderlying pregnancy.
Whatlittleepidemiologicalinformationisavailableonthis
entitycomesmainly fromNigeria,SouthAfricaandHaiti,
where itsincidence is higher, andthe US, where its
inci-denceis increasing.51 In2017, Sliwa etal.publisheddata
gatheredbetween2012and2016 intheEURObservational
ResearchProgramme52 demonstrating thatPPCMoccursin
women from all over the world, with different ethnic
origins and socioeconomic conditions, but with very
sim-ilar forms of presentation and course. Risk factors that
have been identified are African-Americandescent, older
maternalage,multifetalpregnanciesandhypertensive
dis-orders during pregnancy.51 Although its etiology remains
unknown,variousmechanismshavebeensuggested,suchas
lowseleniumlevels,reactivationoflatentviralinfections,
stress-activatedcytokines,inflammation,autoimmune
reac-tions, pathological response to hemodynamic stress and
unbalanced oxidative stress.53 Recently a new potentially
causal factor has been described, cleavage of prolactin
to produce a 16-kDa N-terminal prolactin fragment (16K
PRL), mediated by oxidative stress.54 The antiangiogenic
effectof16K PRLand ofsoluble fms-like tyrosine
kinase-1(sFlt-1), levelsof which are alsohigh in this condition,
canchangethebalanceof angiogenesis,leadingto
vascu-lar damage and hence HF.53 The high incidence of PPCM
in Africans and a family history in 16% of cases have
Initial assessment
PPCM without hemodynamic instability Probable PPCM with hemodynamic instability
Hemodynamic assessment Diagnosis
12-lead ECG
Blood tests including natriuretic peptides Echocardiography, lung ultrasound Additional tests to exclude differential diagnoses SBP <90 mmHg; HR >130 bpm or <45 bpm
RR >25/min; SpO2 <90% Blood lactate >2.0 mmol/l; ScvO2 <60% Altered mental state; cold skin; oliguria (<0.5 ml/kg/min)
Optimize preload
Volume vs. diuretics; vasodilators if SBP >110 mmHg
Optimize oxygenation
Consider non-invasive vs. invasive ventilation (if change in consciousness or persistent hypoxemia)
Add inotropes and/or vasopressors Consider levosimendan 0.1 µ/kg/min for 24 hours
Urgent delivery (cesarean section)
Consider bromocriptine (2.5 mg twice daily)
Consider mechanical circulatory support if refractory cardiopulmonary distress
Recovery? No Heart transplantation Yes Weaning Continue HF therapy (for ≥12 months after recovery of LV function) Consider wearable cardioverter-defibrillator
if LVEF ≤35% Consider delivery HF therapy Hydralazine Nitrates BB (metoprolol) Diuretics (if volume
overload)
HF therapy ACEIs (or ARBs)
BBs Spironolactone Diuretics Ivabradine Consider bromocriptine (2.5 mg twice daily) Antepartum Postpartum
Figure1 Algorithmfor managementofpatientswith peripartumcardiomyopathy(adapted fromBauersachset al.12). ACEIs:
angiotensin-convertingenzymeinhibitors;ARBs:angiotensinreceptorblockers;BBs:beta-blockers;ECG:electrocardiogram;HF: heartfailure;HR:heartrate;IV:invasiveventilation;LV:leftventricular;LVEF:leftventricularejectionfraction;PPCM:peripartum cardiomyopathy;RR: respiratory rate;SBP: systolic bloodpressure;SpO2:peripheral oxygensaturation; SvcO2:centralvenous
oxygensaturation.
documented so far are associated with familial forms of
cardiomyopathy.
ThemajorityofpatientsadmittedwithPPCMhavetypical
symptomsandsignsofHF. Differentialdiagnosis shouldbe
madewithotherentitiesincludingmyocarditis,pre-existing
cardiomyopathy,valvediseaseandcongenitalheartdisease.
When presentation is with cardiogenic shock, myocardial
infarctionandpulmonaryembolismshouldimmediatelybe
excluded.12 An ECG should be performed in all patients
suspected of having PPCM, even though there is no
spe-cificelectrocardiographicpattern,duetoitshighnegative
predictive value. N-terminal pro-B-type natriuretic
pep-tide (NT-proBNP)levels are usuallyhigh and can be used
toexclude non-cardiac-related dyspnea, although it does
nothelpdifferentiatePPCMfromother cardiomyopathies.
TTEshould be performed assoon as possible in all cases
of suspected PPCM, to exclude other heart disease and
complicationssuchasapicalthrombus,andtoobtain
prog-nosticinformation.Althoughprognosisismorefavorablein
PPCMthaninothercardiomyopathies,itisassociatedwith
significantmortality(<5-50%)andmorbidity(PE,cardiogenic
shock, arrhythmiasandthromboembolicevents).12
Mortal-ityriskishigherwithadvancedmaternalage,multiparity,
severelyimpairedglobalsystolicfunction,African-American
race and late diagnosis.4 The proportionof patients who
recoverleftventricularfunction(LVEF≥50%)varies
accord-ing to the study (35-70%), but in most cases this occurs
withinsixmonthsofchildbirth.51Recentstudiesshowthat
African-AmericanraceandlowerLVEFandgreaterLV
end-diastolic volumeat diagnosis are associated witha lower
probabilityofrecovery.56Insubsequentpregnancies,women
withpersistentLVDareatgreaterrisk(around50%)of
clin-ical deterioration than those with complete recovery of
recurrenceinanotherpregnancy(cardiacfunctionworsens
in around 20%, in 20-50% of whomthis persistsfollowing
delivery).57
Fromatherapeuticstandpoint,theapproachtoPPCMis
similartothatof othercauses ofacuteHF,taking careto
avoidadverseeffectsonthefetus.Figure1showsaproposed
treatment algorithm, according to the patient’s
hemody-namic stability. In hemodynamically unstable patients a
rapid and systematic approach is essential in order to
provide support and prevent target organ damage. This
is one of the few situations in which an emergency
cesarean section is indicated to treat the mother, with
the aim of starting bromocriptine.58 Regarding inotropic
support, levosimendan is preferred in these patients as
it does not increase myocardial oxygen consumption,
while catecholamines should be avoided. If
levosimen-dan isunavailable, dobutamineis the inotrope of choice,
and noradrenaline should be used as a vasopressor
agent.12 Angiotensin-converting enzymeinhibitors(ACEIs),
angiotensinreceptorblockersandrenininhibitorsare
con-traindicated during pregnancy due to their fetal toxicity.
Alternatively,nitratesandhydralazinecanbeusedtoreduce
pre- and afterload, respectively. After childbirth, ACEIs
can be resumed, preferably captopril and enalapril
dur-ingbreastfeeding.Whilebeta-blockersincreasetheriskof
intrauterinegrowthrestriction,theycanbeusedin
hemo-dynamically stable patients, preferably beta 1 selective
beta-blockerssuchasmetoprololsuccinate.
Mineralocorti-coid receptorantagonists should beavoided in pregnancy
andbreastfeeding.14 Bromocriptine,inassociation withHF
therapy, should be considered in view of its promising
resultsintermsofrecoveryofLVsystolicfunctionand
clin-icalimprovement.59 Ina Germanretrospective registryof
PPCM,treatmentwithbeta-blockers,ACEIsand
bromocrip-tine (2.5 mg twice daily for two weeks followed by 2.5
mgoncedailyforsixweeks)wasassociatedwithfavorable
outcomes.60Anticoagulationwithheparinshouldbestarted
inpatientswithPPCMunderbromocriptineand/orwithLVEF
≤35%(duringpregnancyandforat leasteightweeksafter
delivery).61,62Treatmenttocounteractventricular
remodel-ingshouldbecontinuedforatleast12monthsafterrecovery
ofLVdimensionsandfunction.Althoughthemaincauseof
deathin PPCMis HF, one quarter of deaths occur due to
ventriculararrhythmias,mostinthefirstsixmonths.63The
use of wearable cardioverter-defibrillators for six months
afterdiagnosisofPPCMhasbeenproposedforwomenwith
severeLVdysfunction,asabridgetorecoveryofLVfunction
orplacementofanimplantablecardioverter-defibrillator.63
Conclusions
The association between heart disease and pregnancy is
increasingly prevalent. Pregnancy involves various
adap-tations which are not always tolerated by patients with
existingheartdisease.Assessmentandmonitoringofwomen
withknownorsuspectedheartdiseasewhowishtobecome
pregnantshouldtherefore beginbeforepregnancysothat
theindividual’sriskcanbestratifiedandthemeasurestobe
takencanbescheduled in advance.Detectionof a
devel-oping cardiovascular disorder must also be a priority in
the monitoring of the pregnancy and if one is identified,
thecardiologyteam shouldimmediatelybe involved.It is
increasingly common to have teams dedicated todealing
with cardiac disorders in pregnancy, an approach that is
recommended,sinceitleadstobetterclinicaloutcomes.
Conflicts
of
interest
Theauthorshavenoconflictsofinteresttodeclare.
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