Ebook A practical guide to fetal echocardiography normal and abnormal hearts (3E): Part 1

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APracticalGuidetoFetal
Echocardiography
NormalandAbnormalHearts
THIRDEDITION


APracticalGuidetoFetal
Echocardiography
NormalandAbnormalHearts
THIRDEDITION

AlfredAbuhamad,MD
ProfessorofObstetrics&Gynecology
ProfessorofRadiology
Chairman,DepartmentofObstetrics&
Gynecology
ViceDeanforClinicalAffairs
EasternVirginiaMedicalSchool

Norfolk,Virginia

RabihChaoui,MD
ProfessorofObstetrics&Gynecology
PrenatalDiagnosisandHumanGeneticsCenter
Berlin,Germany



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Abuhamad,Alfred,author.
Apracticalguidetofetalechocardiography:normalandabnormalhearts/
AlfredAbuhamad,RabihChaoui.—3rdedition.
p.;cm.
Includesbibliographicalreferencesandindex.
ISBN978-1-4511-7605-6
eISBN978-1-4963-2640-9
I.Chaoui,Rabih,author.II.Title.
[DNLM:1.FetalHeart—ultrasonography.2.HeartDefects,Congenital—
ultrasonography.3.Ultrasonography,Prenatal—methods.WQ209]
RG628.3.E34
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Thisbookisdedicatedtoallpregnantwomenwhofacethegutwrenchingdiagnosisoffetalcongenitalheartdisease.Maythe
knowledgeinthisbookprovidesforaccuratediagnosis,
compassionatecounselingandoptimalmanagement.

Wealsodedicatethisbooktoourparentsfortheirunwavering
supportandcommitmenttoexcellencethroughouttheyears,andto
Sharon,SamiandNicoleKathleen,AminandElla,
Withunconditionallove.


I

t is with great pleasure that we introduce this third edition of A Practical
GuidetoFetalEchocardiography:NormalandAbnormalHearts,aproduct
ofintenseworkandcollaborationontheimportantandrapidlyevolvingfieldof
fetal cardiology. Given the major success that the second edition of this book
received,andinkeepingwiththeprogressinfetalcardiacimaging,wedecided
towritethisthirdeditioninordertocontinuetoprovidethemostup-to-dateand
comprehensivereferenceonthissubject.
Westrivedtoensurethatthisthirdeditioniswritteninthesameeasy-to-read
style and illustrated with the most informative figures as the second edition.
Furthermore, as compared to the second edition, this third edition represents a
substantiveexpansiononthesubjectwithmajorchapterrevisionsandadditions
of several new relevant topics. In order to maintain the widely successful
systematicandmethodicalapproachofthesecondeditionofthisbook,wechose
the difficult path of writing and illustrating this third edition in its entirety
withoutoutsidecollaboration.
Thebookisdividedintotwomainparts,withpartonecoveringthetechnical
aspects of the cardiac exam and part two covering fetal cardiac abnormalities.
Thefirstpartofthebookistotallyrevampedtoincludeseveralnewchapterson
the following topics: risk factors for cardiac defects, national and international
guidelinesforfetalcardiacscreeningandfetalechocardiography,optimizingthe
cardiacexamination,cardiacembryology,thethree-vessel-tracheaview,andthe
venous system. An updated chapter on the genetics of cardiac malformations
introduces the role of novel technologies in genetic screening and diagnosis.
Otherchaptersinpartoneunderwentmajorrevisions,includingcolorandpulsed
Dopplerandtheuseofthree-dimensionalultrasoundinfetalechocardiography.
A comprehensive chapter on cardiac function completes the first part of the
book.
Detaileddiscussiononfetalcardiacmalformationsispresentedinthesecond
part of the book in a uniform format that includes the definition, spectrum of

disease and incidence, the use of gray scale, color Doppler, three-dimensional,
and early gestation ultrasound in the diagnosis of each cardiac abnormality
followedbythedifferentialdiagnosis,andprognosisandoutcome.Newcolored
schematics, drawings, and figures illustrate cardiac anomalies and the book
reliesontheliberaluseoftablesoutliningcommonanddifferentiatingfeatures
ofvariouscardiacmalformations.Acomprehensivesectiononreferenceranges
of cardiac measurements is presented in a graphic and tabular format in the
appendix.
Congenitalheartdiseaseisthemostcommoncongenitalmalformationwitha
significant impact on neonatal morbidity and mortality. Prenatal diagnosis of
congenitalheartdiseasehasbeensuboptimalovertheyearsowinginlargepart
to the complexity of cardiac anatomy and the inherent difficulty of the
ultrasound examinationof thefetal heart. Wefeelthat thisthirdeditionof this
bookprovidesacomprehensivereferencetothepractitionersinvolvedincardiac
imaging, and we sincerely hope that this book enhances the detection rate of
congenitalheartdisease,whichshouldtranslateintoimprovedoutcomeforour
smallestpatients.
This book would not have been a reality without the support of several
people,firstandforemost,ourfamilieswhounselfishlyallowedustospendlong
evenings and weekends away from them in completing this task, the artistic
talentsofMs.PatriciaGastwhoperformedallthesuperbdrawingsinthisbook
inanefficientandaccuratemanner,Dr.ElenaSinkovskaya(forDr.Abuhamad)
and Dr. Kai-Sven Heling (for Dr. Chaoui) for the collegiality and close
cooperationthroughouttheyears,Drs.AnnaKlassenandCorneliaTennstedfor
providing us with figures of anatomic specimens on the normal and abnormal
hearts, and the professional editorial and production teams at Lippincott
WilliamsandWilkins.
Inclosing,wecontinuetooweagreatdebtofgratitudetotwogiantsinthe
field of ultrasound, Dr. John Hobbins (for Dr. Abuhamad) and Dr. Rainer

Bollmann(forDr.Chaoui)whogaveusourultrasoundrootsandprovidedlonglastingmentorshipandguidance.
AlfredAbuhamad,MD
RabihChaoui,MD


1CongenitalHeartDisease:Incidence,RiskFactors,
andPreventionStrategies
2GuidelinesforthePerformanceofthe
SonographicScreeningandEchocardiography
ExaminationoftheFetalHeart
3EmbryologyoftheHeart
4GeneticAspectsofCongenitalHeartDiseases
5CardiacAnatomy
6FetalSitus
7CardiacChambers:TheFour-Chamberand
Short-AxisViews
8TheGreatVessels:Axial,Oblique,andSagittal
Views
9TheThree-Vessel-TracheaViewandUpper
Mediastinum
10SystematicEvaluationoftheVenousSystem


11OptimizationoftheTwo-DimensionalGrayscale
ImageinFetalCardiacExamination
12ColorDopplerinFetalEchocardiography
13PulsedDopplerinFetalEchocardiography
14FetalCardiacFunction
15Three-andFour-DimensionalUltrasoundofthe
FetalHeart

16FetalCardiacExaminationinEarlyGestation
17FetalCardiacMeasurementsandReference
Ranges
18Atrial,Ventricular,andAtrioventricularSeptal
Defects
19UniventricularAtrioventricularConnection,
DoubleInletVentricle,andTricuspidAtresia
withVentricularSeptalDefect
20EbsteinAnomaly,TricuspidValveDysplasia,and
TricuspidRegurgitation
21AorticStenosisandBicuspidAorticValve
22HypoplasticLeftHeartSyndromeandCritical
AorticStenosis
23CoarctationoftheAortaandInterruptedAortic


Arch
24PulmonaryStenosis,PulmonaryAtresiawith
IntactVentricularSeptum,andDuctus
ArteriosusConstriction
25TetralogyofFallot,PulmonaryAtresiawith
VentricularSeptalDefect,andAbsentPulmonary
ValveSyndrome
26CommonArterialTrunk
27DoubleOutletRightVentricle
28CompleteandCongenitallyCorrected
TranspositionoftheGreatArteries
29RightAorticArch,DoubleAorticArch,and
AberrantSubclavianArtery
30FetalHeterotaxyandSitusInversus

31AnomaliesofSystemicandPulmonaryVenous
Connections
32FetalCardiomyopathiesandFetalHeartTumors
33FetalArrhythmias
Appendix:GraphLegends
Index




●INCIDENCEOFCONGENITALHEART
DISEASE
Congenital heart diseases (CHDs) are the most common severe congenital
abnormalities (1). Half of the CHD cases are, however, minor and are easily
correctedbysurgery,theremainderaccountingforoverhalfofthedeathsfrom
congenital abnormalities in childhood (1). Moreover, CHD results in the most
costly hospital admissions for birth defects in the United States (2). The
incidence of CHD is dependent on the age at which the population is initially
examined and the definition of CHD used. Inclusion of a large number of
prematureneonatesinastudymayincreasetheincidenceofCHD.Bothpatent
ductusarteriosusandventricularseptaldefectsarecommoninprematureinfants.
Anincidenceof8to9per1,000livebirthshasbeenreportedinlargepopulation
studies (1). Of all cases of CHD, 46% are diagnosed by the first week of life,
88% by the first year of life, and 98% by the fourth year of life (1). The
incidence of CHD is also influenced by the inclusion of bicuspid aortic valve,
theincidenceofwhichisestimatedat10to20per1,000livebirths(3).Bicuspid
aortic valve may be associated with considerable morbidity and mortality in
affected persons (3). Furthermore, accounting for subtle anomalies such as
persistent left superior vena cava (5–10 per 1,000 live births) and isolated
aneurysmoftheatrialseptum(5–10per1,000livebirths)resultsinanoverall

incidence of CHD approaching 50 per 1,000 live births (4). CHD remains the
mostcommonsevereabnormalityinthenewborn;itsprenataldiagnosisallows
forbetterpregnancycounselingandimprovedneonataloutcome.Table1.1lists
theincidenceofCHDbyvarioussubtypes(5).SeveralriskfactorsforCHDhave


beenidentified,includingfetalandmaternalriskfactors,whicharediscussedin
detailinthefollowingsections.


●FETALRISKFACTORS
ExtracardiacAnatomicAbnormalities
The presence of extracardiac abnormalities in a fetus is frequently associated
withCHDandisthusanindicationforfetalechocardiography.TheriskofCHD
withfetalextracardiacabnormalitiesisincreasedeveninthepresenceofnormal
karyotype (6). The risk of CHD is dependent on the specific type of fetal
malformation. Abnormalities detected in more than one organ system increase
the risk of CHD and also of concomitant chromosomal abnormalities (7).
NonimmunehydropsinthefetusisfrequentlyassociatedwithCHD.Incidence
of abnormal cardiac anatomy is reported in about 10% to 20% of fetuses with
nonimmune hydrops (8, 9). Table 1.2 lists associated extracardiac anomalies
detectedinfetuseswithfetalcardiacanomalies(7).

TABLE
1.1

TypesandIncidenceofHumanCongenital
HeartDisease

Defect

VSD
PDA
ASD
AVSD
PS
AS
CoA
TOF
D-TGA
HRH
Tricuspidatresia

Incidenceper1,000livebirths
3.570
0.799
0.941
0.348
0.729
0.401
0.409
0.421
0.315
0.222
0.079


Ebsteinanomaly
Pulmonaryatresia

0.114

0.132

HLH
Truncus
DORV

0.266
0.107
0.157

SV
TAPVC

0.106
0.094

VSD,ventricularseptaldefect;PDA,patentductusarteriosus;ASD,atrial
septaldefect;AVSD,atrioventricularseptaldefect;PS,pulmonarystenosis;AS,
aorticstenosis;CoA,coarctationoftheaorta;TOF,tetralogyofFallot;D-TGA,
completetranspositionofthegreatarteries;HRH,hypoplasticrightheart;HLH,
hypoplasticleftheart;DORV,doubleoutletrightventricle;SV,singleventricle;
TAPVC,totalanomalouspulmonaryvenousconnection.
ModifiedfromHoffmanJI,KaplanS.Theincidenceofcongenitalheartdisease.
JAmCollCardiol.2002;39:1890–1900,withpermission.

TABLE AssociatedExtracardiacAnomaliesinFetal
1.2
HeartDefectsaccordingtoOrganSystem
Organsystem
Centralnervoussystem

Genitourinary
Genital
Renal
Skeletal
Respiratory
Gastrointestinal
Craniofacial
TOTAL

%
71.7

25
75
52.3
38.1
47.5
35.7
53.6

ModifiedfromSongMS,HuA,DyamenahalliU,etal.Extracardiaclesionsand
chromosomalabnormalitiesassociatedwithmajorfetalheartdefects:


comparisonofintrauterine,postnatalandpostmortemdiagnoses.Ultrasound
ObstetGynecol.2009;33:552–559,withpermission.

FetalCardiacArrhythmia
The presence of fetal cardiac rhythm disturbances may be associated with an
underlying structural heart disease. The association of CHD with fetal

arrhythmia is dependent on the type of cardiac rhythm disturbances. Overall,
about 1% of fetal cardiac arrhythmias are associated with CHD (8). Fetal
tachycardiaandisolatedextrasystolesarerarelyassociatedwithCHD.Complete
heart block, on the other hand, resulting from abnormal atrioventricular (AV)
node conduction, is associated with structural cardiac abnormalities in about
50%offetuses,withtheremainingpregnanciesassociatedwiththepresenceof
maternal Sjögren antibodies (10, 11). A fetal echocardiogram should be
performed in all fetuses with suspected or confirmed arrhythmias to assess
cardiacstructureandfunction.Thisincludesfetuseswithirregularfetalrhythm,
such as that caused by frequent extrasystoles, as this may be the harbinger of
moremalignantarrhythmiasifitispersistent(12).Infetuseswithlessfrequent
extrasystoles,afetalechocardiogramisreasonabletoperform,especiallyifthe
ectopic beats persist beyond 1 to 2 weeks (13). Diagnosis and management of
fetalcardiacrhythmdisturbancesarediscussedindetailinChapter33.

SuspectedCardiacAnomalyonRoutineUltrasound
A risk factor with one of the highest yields for CHD is the suspicion for the
presence of a cardiac abnormality during routine ultrasound scanning. Fetal
echocardiogram should therefore be performed in all fetuses with a suspected
cardiac abnormality noted on obstetric ultrasound. CHD is confirmed in about
40%to50%ofpregnanciesreferredwiththisfinding(8,9).Inviewofthis,and
the fact that most infants born with CHD are born to pregnancies without risk
factors,ultrasoundevaluationofthefetalheartshouldnotbelimitedtopregnant
motherswithknownriskfactors.Indeed,recentguidelinesofcardiacscreening
have been expanded to include evaluation of the great vessels (14–16). The
valueofroutineultrasoundinthescreeningforCHDisdiscussedinChapter2.

KnownorSuspectedChromosomalorGenetic

Abnormality
Thepresenceofafetalgeneticorchromosomalabnormalityisassociatedwitha
high risk of cardiac and extracardiac defects and thus a fetal echocardiogram
should be performed. Please refer to Chapter 4 for a more comprehensive
discussiononthistopic.

ThickenedNuchalTranslucency
Measurement of fetal nuchal translucency (NT) thickness in the late first and
early second trimesters of pregnancy is currently established as an effective
method for individual risk assessment of fetal chromosomal abnormalities.
Several reports have noted an association between increased NT and genetic
syndromes and major fetal malformations, including cardiac defects (17–19).
The prevalence of major cardiac defects increases exponentially with fetal NT
thickness, without an obvious predilection to a specific type of CHD (18). An
NT thickness of greater than or equal to 3.5 mm in a chromosomally normal
fetushasbeencorrelatedwithaprevalenceofCHDof23per1,000pregnancies,
aratethatishigherthanpregnancieswithafamilyhistoryofCHD(17,20).In
this setting of an NT that is greater than or equal to 3.5 mm, referral for fetal
echocardiographyisthuswarranted.FindinganNTthicknessofgreaterthanor
equalto3.5mmmayleadtoanearlierdiagnosisofallmajortypesofCHD(21).
Chapter16providesamoredetaileddiscussionontheultrasoundexaminationof
thefetalheartinearlygestation.

MonochorionicPlacentation
The incidence of CHD in fetuses of monochorionic placentation is higher (22,
23)andisestimatedat2%to9%(22,24,25).Twin–twintransfusionsyndrome
(TTTS),acomplication of monochorionic twinplacentation,hasbeenreported
tooccurinabout10%ofcases.TTTShasbeenassociatedwithacquiredcardiac
abnormalities,includingrightventricularoutflowtractobstruction,whichoccurs
inabout10%ofrecipienttwinfetuses(26).TheincreasedriskofCHDinfetuses

of monochorionic placentation is noted even after excluding cardiac effects of
TTTS(23).Inacohortstudyof165setsofmonochorionictwins,theoverallrisk
ofatleastoneofatwinpairhavingastructuralCHDwas9.1%(23).Thisrisk
was 7% for monochorionic–diamniotic twins and 57.1% for at least one twin


member of monochorionic– monoamniotic twins (23). If one twin member is
affected, the risk that the other twin member is also affected is 26.7% (23).A
systemic literature review of 830 fetuses from monochorionic–diamniotic twin
pregnancies confirmed an increased risk of CHD independent of TTTS (22).
Ventricular septal defects were the most common type of CHD in non-TTTS
fetuses,andpulmonarystenosisandatrialseptaldefectsweresignificantlymore
prevalent in fetuses of pregnancies complicated with TTTS (22). Fetal
echocardiogramisthereforerecommendedinallmonochorionictwingestations.


●MATERNALRISKFACTORS
MaternalMetabolicDisease
Maternal metabolic disorders, primarily including pregestational diabetes
mellitusandphenylketonuria,haveasignificanteffectontheincidenceofCHD.
In the presence of maternal metabolic disease, preconception counseling and
tight metabolic control immediately prior to and during organogenesis are
recommendedinordertoreducetheincidenceoffetalCHD.

DiabetesMellitus
The incidence of CHD is fivefold higher in infants of pregestational diabetic
mothers than in controls, with a higher relative risk noted for specific cardiac
defects, including 6.22 for heterotaxy, 4.72 for truncus arteriosus, 2.85 for
transposition of the great arteries, and 18.24 for single-ventricle defects (27).
Poor glycemic control in the first trimester of gestation, as evidenced by an

elevated glycohemoglobin level (HbA1c), has been strongly correlated with an
increased risk of structural defects in infants of diabetic mothers (28, 29).
Althoughsomestudieshaveidentifiedalevelofglycohemoglobinabovewhich
the risk of fetal structural abnormalities is increased (28), other studies have
failed to identify a critical level of glycohemoglobin that provides an optimal
predictivepowerforCHDscreening(30).Therefore,itappearsthatalthoughthe
risk may be highest in those with increased HbA1c levels (>8.5%), all
pregnanciesofpregestationaldiabeticwomenareatsomeincreasedrisk.Given
thisinformation,afetalechocardiogramshouldbeperformedinallwomenwith
pregestational diabetes mellitus. Gestational diabetes, which is diagnosed
beyondthefirsttrimesterofpregnancy,doesnotincreasetheriskofCHDinthe


fetus, and thus a fetal echocardiogram is not indicated for these pregnancies.
Fetalventricularhypertrophyinlategestation(thirdtrimester)isacomplication
ofpoorglycemiccontrolinpregestationalandgestationaldiabeticpregnancies,
andthedegreeofhypertrophyisrelatedtothelevelofglycemiccontrol.Fetal
echocardiogram in the third trimester to assess for ventricular hypertrophy is
thusrecommendedforpregestationalandgestationaldiabeticpregnanciesifthe
HbA1cisgreaterthan6%inthesecondtrimester(31).

Phenylketonuria
Another metabolic disorder that is associated with CHD is phenylketonuria.
Women with phenylketonuria should be aware of the association of fetal CHD
withelevatedmaternalphenylalaninelevels(32).This is particularlyimportant
as phenylketonurics usually follow unrestricted dietary regimens in adulthood.
Fetalexposureduringorganogenesistomaternalphenylalaninelevelsexceeding
15mg/dLisassociatedwitha10-to15-foldincreaseinCHD(33).Otherfetal
abnormalities in phenylketonurics include microcephaly and growth restriction
(32).TheriskofCHDinfetuseshasbeenreportedtobe12%ifmaternaldietary

control is not achieved by 10 weeks of gestation (34). With maternal
phenylalanine levels at <6 mg/dL before conception and during early
organogenesis,theriskofCHDwasnotedtobenodifferentfromcontrolsina
largeprospectivestudy(35).Unlessyouhaveevidenceofstrictdietarycontrol
in early gestation with a phenylalanine levels at <10 mg/dL, fetal
echocardiogramisrecommendedinphenylketonurics(13).

MaternalTeratogenExposure(Drug-Related
CongenitalHeartDisease)
Theeffectsofmaternalexposuretodrugsduringcardiogenesishavebeenwidely
studied.Numerous drugshavebeenimplicatedascardiacteratogens.Evidence
suggests that the overall contribution of teratogens to CHD is small (36).
Available literature suggests that maternal use of lithium, anticonvulsants,
ethanol, isotretinoin, indomethacin, angiotensin-converting enzyme (ACE)
inhibitors,andselectiveserotoninreuptakeinhibitors(SSRIs)mayincreasethe
riskofcardiovascularabnormalitiesinthenewborn(Table1.3).


TABLE1.3

Drug-RelatedCongenitalHeartDisease

Drug

Lithium
Hydantoin/Phenytoin
Trimethadione
Sodiumvalproate
Carbamazepine
Ethanol

Retinoicacid
Indomethacin
ACEinhibitors(1st
trimester)
ACEinhibitors(2ndand
3rdtrimesters)
SSRIs(1sttrimester)
SSRIs(2ndand3rd
trimesters)

Frequencyof
association
Rare
Moderate
High
Rare
Rare
High
Moderate
Moderate
Moderate
High
Rare
Moderate

Commoncardiac
abnormalities
Ebsteinabnormality
Mixedabnormalities
Septaldefects

Mixedabnormalities
Mixedabnormalities
Septaldefects
Conotruncalabnormalities
Prematureconstrictionof
ductusarteriosus
Septaldefects
ACEinhibitorfetopathy
Septaldefects
PPHN

ACE,angiotensin-convertingenzyme;SSRIs,selectiveserotoninreuptake
inhibitors;PPHN,persistentpulmonaryhypertensionofthenewborn.

Lithium
Initialretrospectivereportsregardingtheteratogenicriskoflithiumtreatmentin
pregnancy showed a strong association between lithium use and Ebstein
anomaly in the fetus (37). More recent controlled studies, however, have
consistentlyreportedalowerriskofCHDinexposedfetuses.Fourcase-control
studies of Ebstein anomaly involving a total of 208 affected children found no
association with maternal lithium intake in pregnancy (38–40). A cohort study
ontheeffectoflithiumexposureinpregnancyshowednosignificantrisktothe
fetus(41).Thesefindingssuggestthattheteratogenicriskoflithiumexposureis
lower than previously reported, and that the risk–benefit ratio of prescribing


lithiuminpregnancyshouldbeevaluatedinlightofthismodifiedriskestimate.
Fetal echocardiogram may be considered in pregnancies exposed to lithium
duringembryogenesis,althoughitsusefulnesshasnotbeenestablishedgivena
verylowlikelihoodofCHD.

Anticonvulsants
Anticonvulsants, a class of drugs that includes hydantoin/phenytoin,
carbamazepine, trimethadione, and sodium valproate, are occasionally used in
the treatment of epilepsy or pain management in pregnancy. An incidence of
congenital defects varying from 2.2% to 26.1% has been noted in pregnancies
exposedtophenytoin(42).Someevidencesuggeststhattheteratogeniceffectof
phenytoin is related to elevated amniotic fluid oxidative metabolites secondary
tolowactivityoftheclearingenzymeepoxidehydrolase(43).Afetalhydantoin
syndrome,consistingofvariabledegreesofhypoplasiaandossificationofdistal
phalangesandcraniofacialabnormalities,hasbeendescribed(44).CHDisoften
observed in conjunction with this syndrome (45). Trimethadione, an
anticonvulsantprimarilyusedinthetreatmentofpetitmalseizures,isassociated
with a high incidence of congenital defects. Defects include craniofacial
deformities, growth abnormalities, mental retardation, limb abnormalities, and
genitourinaryabnormalities(45).Cardiacabnormalitiesarecommon,withseptal
defects occurring in about 20% of exposed fetuses (45). Sodium valproate has
alsobeenassociatedwithcongenitaldefects,withthemostseriousabnormality
beingneuraltubedefects(1%–2%)(45).Althoughsomereportshavesuggested
anincreasedriskofCHDinfetusesexposedtovalproate(46),otherscouldnot
establish a causal relationship (47). Carbamazepine has been associated with
1.8%riskofCHDwhencomparedtocontrols(48).Fetalechocardiogrammay
beconsideredinpregnanciesexposedtoanticonvulsantsinearlygestation.

Alcohol
The fetal alcohol syndrome, consisting of facial abnormalities, growth
restriction, mental retardation, and cardiac abnormalities, has been well
described in women consuming heavy amounts of alcohol in pregnancy (49).
Cardioteratogeniceffectsofethanolinthechickembryohavebeenconfirmedin
concentrations comparable to human blood alcohol levels (50). CHD has been

identified in 25% to 30% of infants with fetal alcohol syndrome, with septal


defectsrepresentingthemostcommonlesions(49,51).Fetalechocardiogramis
recommendedforpregnancyexposuretoalcoholinearlygestation.

RetinoicAcid
Retinoic acid is a vitamin A derivative prescribed for the treatment of severe
cysticacne.Sinceitsintroduction,severalreportshaveappearedintheliterature
describing the teratogenic effect of this medication. A characteristic pattern of
malformationsisobserved,whichincludescentralnervoussystem,craniofacial,
branchialarch,andcardiovascularabnormalities(52).Cardiacabnormalitiesare
usually conotruncal defects and aortic arch abnormalities (45, 53). The
mechanism of teratogenicity is probably related to free radical generation by
metabolism with prostaglandin synthase (54). Fetal echocardiogram is
recommendedforexposuretoretinoicacidinpregnancy.

NonsteroidalAnti-inflammatoryDrugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of
pretermlabororinpaincontrolinpregnancy.IndomethacinisanNSAIDthatis
commonlyusedfortocolysisinthesecondandthirdtrimestersofpregnancy.In
thefetus,indomethacintherapymayleadtoprematureconstrictionoftheductus
arteriosus(seeChapter24fordetails).Dopplerevidenceofductalconstrictionis
evidentinupto50%offetusesexposedtoindomethacininthelatesecondand
thirdtrimestersofpregnancy(55,56).Typically,theductalconstrictionismild
andresolveswithdrugdiscontinuation.Ductalconstrictionmayalsooccurwith
theuseofotherNSAIDs(57).Severalneonatalcomplications,whichappearto
be limited to indomethacin exposure beyond 32 weeks of gestation, include
oliguria, necrotizing enterocolitis, and intracranial hemorrhage (58). Fetal
echocardiogram is recommended with NSAID use in the late second or third

trimester.

Angiotensin-ConvertingEnzymeInhibitors
ACEinhibitorsarecommonlyusedantihypertensivemedications.Fetalexposure
toACEinhibitorsinthefirsttrimesterofpregnancyhasbeenassociatedwithan
increasedriskofmajorcongenitalmalformationthatwas2.7timesgreaterthan
the background risk or the risk of fetuses exposed to other antihypertensive


medications (59). The increase in major malformations primarily affects the
cardiovascular (risk ratio, 3.72) and central nervous systems (risk ratio, 4.39)
(59). Atrial and ventricular septal defects represent the most common cardiac
abnormalities (59). Fetal exposure to ACE inhibitors in the second and third
trimesters of pregnancy is associated with “ACE inhibitor fetopathy,” which
includes oligohydramnios, intrauterine growth restriction, hypocalvaria, renal
failure, and death (60). Fetal echocardiogram is recommended for pregnancies
exposedtoACEinhibitors.

SelectiveSerotoninReuptakeInhibitors
SSRIs represent a class of antidepressants that has gained wide acceptance for
the treatment of depression and anxiety during pregnancy (61). Specific SSRI
medicationsincludecitalopram(Celexa),fluoxetine(Prozac),paroxetine(Paxil),
andsertraline(Zoloft).PregnanciesexposedtoSSRIsinthefirsttrimesterhave
shown an increased risk of congenital heart defects in some studies (62–64).
Paroxetine has been singled out as the SSRI with the greatest association with
congenital heart malformations, primarily atrial and ventricular septal defects
(64).Ameta-analysisofsevenstudiesnotedasignificantoverallincreasedrisk
of 74% for cardiac malformations in women exposed to paroxetine in the first
trimester of pregnancy (65). Recent large population studies have provided
conflicting information with regards to the association of SSRI with CHD. A

cohortstudyof72,280pregnancies,reviewedwithhighcaseascertainmentfrom
theDanishadministrativeregisterdatafortheperiod1995to2008,hasshown
thatmaternaluseofSSRIsduringthefirsttrimesterisassociatedwithafourfold
increaseintheriskofsevereCHD(66).Thisstudydidnotsupportanincreased
riskofseptaldefects,however,ashasbeenshownbefore(66).Inapopulationbased cohort study in Quebec, from 1998 to 2010 and involving 18,493
pregnancies,sertralineuseduringthefirsttrimesterofpregnancywasassociated
withanincreasedriskofatrial/ventriculardefects(RR,1.34;95%CI,1.02–1.76)
andcraniosynostosis(RR,2.03;95%CI,1.09–3.75)aboveandbeyondtheeffect
of maternal depression (67). Nonsertraline SSRIs were associated with an
increasedriskofcraniosynostosisandmusculoskeletaldefects(67).Theriskof
majorCHDamonginfantsborntowomenwhotookantidepressantsduringthe
firsttrimesterwascomparedtotheriskamonginfantsborntowomenwhodid
not use antidepressants in a large cohort of 949,504 pregnant women from
Medicaid data for the period of 2000 through 2007 (68). When the data were