Andersons pediatric cardiology 288

Epilepsy65
Prepregnancyoverweight/obesity66
MATERNALTHERAPEUTICDRUGEXPOSURE
Anticonvulsants67,68
Ibuprofen69
Sulfasalazine70
Thalidomide71
Trimethoprim-sulfonamide70,72,c
VitaminAcongeners/retinoids73,74,c

b

1.13–1.40
4.2
1.86
3.4
b

2.1–4.8
b

aExposuresassociatedwithdefiniteorpossibleriskofoffspringwithanycongenital

cardiovasculardefect.
bOddsrationotavailable.
c

Riskreducedifmothertookfolicacidsimultaneously.

ModifiedfromJenkinsKJ,CorreaA,FeinsteinJA,etal.Noninheritedriskfactorsandcongenital
cardiovasculardefects:currentknowledge:ascientificstatementfromtheAmericanHeart

AssociationCouncilonCardiovascularDiseaseintheYoung:endorsedbytheAmerican
AcademyofPediatrics.Circulation.2007;115:2995–3014.

Maternalexposuretoorganicsolventshasfrequentlyandconsistentlybeen
reportedtobeassociatedwithrelativelyhighoddsratiosforthedevelopmentof
specificcongenitalcardiacmalformations.Incontrasttomaternalillnessesand
useofmedications,itisfeasibletoavoidexposuretoorganicsolvents,and
preventionstrategiesmightbedirectedatreducingmaternalexposurestothese
materials.
Othermaternalexposures,includingpesticides,airpollutants,andlead,have
beenreportedtohaveanassociationwithcongenitalheartdefects.9,10The
Baltimore-WashingtonInfantStudywasalargepopulation-basedsurveillance
withcarefulverificationofmaternalexposures.1Theattributablefraction,which
istheproportionofcasesofspecificheartdefectthatmightbeattributableto
specificexposure,issummarizedinTable13.4.Notethatsomeofthesignificant
exposureswerepaternalratherthanmaternal.
Table13.4
AttributableFractionofCongenitalCardiacLesionstoPotential
RiskFactors
MalformationandPotentialRiskFactors
Transpositionwithintactventricularseptum(n=106)
Influenza

P<.01
AF(%)
12.1
7.0

95%CI
8.5–15.8

3.6–10.3

RelativeRisk
2.2


Miscellaneoussolvents
TetralogyofFallot(n=204)
Paternalanesthesia
Clomiphene
AtrioventricularseptaldefectwithDownsyndrome(n=190)
Ibuprofen
Hypoplasticleftheartsyndrome(n=138)
Solvent/degreasingagent
Familyhistoryofcongenitalheartdisease
Coarctationoftheaorta(n=120)
Familyhistoryofcongenitalheartdisease
Macrodantin
Clomiphene
Isolated/simpleperimembranousVSD(n=459)
Paternaluseofmarijuana
Maternaluseofcocaine
Multiple/multiplexperimembranousVSD(n=181)
Paternaluseofcocaine
Diabetesmellitus
Metronidazole
Atrialseptaldefect(n=187)
Gestationaldiabetesmellitus
Paternaluseofcocaine
Familyhistoryofcongenitalheartdisease

Corticosteroids

4.8
6.5
3.9
2.4
4.6
4.6
8.6
4.6
4.0
9.4
4.6
2.3
2.0
7.9
6.0
1.7
8.3
4.8
2.1
1.4
14.1
4.4
3.7
3.4
2.6

3.0–6.6
4.8–8.3

2.4–5.5
1.5–3.4
2.7–6.5
2.7–6.5
6.9–10.3
3.2–6.0
3.1–4.9
8.1–10.8
3.5–5.7
1.8–2.8
1.4–2.7
4.2–11.6
2.2–9.7
0.9–2.5
6.0–10.5
2.6–6.9
1.4–2.8
1.1–1.7
11.3–17.0
2.5–6.2
1.9–5.4
2.4–4.3
1.9–3.2

3.2
2.5
3.0
2.4
3.4
4.8

4.6
6.7
4.5
1.4
2.4
2.3
3.9
7.6
2.4
2.3
3.9
4.8

AF,Attributablefraction;CI,confidenceinterval;VSD,ventricularseptaldefect.
FromWilsonPD,LoffredoCA,Correa-VillasenorA,FerenczC.Attributablefractionforcardiac
malformations.AmJEpidemiol.1998;148:414–423

GeneticFactors
Theprevalenceofcongenitalcardiacdiseaseisincreasedinchildrenwith
specificchromosomalabnormalitiesandsyndromes,andtheknowledgeofthese
associationsisexpanding.Thesegeneticfactorsarefurtherexploredinother
chapters.Ahighprevalenceofcongenitalcardiacdiseasehasbeenobserved
amongchildrenwithtrisomy21(Downsyndrome),11trisomy18(Edwards
syndrome),12,13trisomy13(Patausyndrome),12,14andmonosomyXO(Turner
syndrome).
Withtheaveragematernalageincreasing,theprevalenceofinfantswith
chromosomalabnormalitiesislikelytorise,inparticularthenumberofinfants
withtrisomy21.Thisisassociatedwithcongenitalcardiacdiseasein40%to
50%ofpregnancies.15,16Aftertheageof30years,amother'sriskofhavinga
childwithtrisomy21increasesexponentially,suchthatbythetimesheis35

years,theriskis1in365pregnancies.17


Thedeletionofthe22q11genehasbeenimplicatedasanimportant
contributortothedevelopmentofcongenitalcardiacdisease.18Studieshave
estimatedtheprevalenceofthedeletiontobeapproximately1.5casesineach
10,000livebirths.18,19Ithasbeensuggestedthatmorethan1%ofall
congenitallymalformedheartsareassociatedwiththisdeletion,accountingfor
halfofthecaseswithinterruptedaorticarch,20%ofthosewithcommonarterial
trunk,andapproximately16%ofthosewithtetralogyofFallot.18
Theriskofrecurrenceisalsohigherinfamiliesandmotherswith
nonsyndromiccongenitalheartdisease,assummarizedinTable13.5.20,21The
prevalenceofacongenitalheartdefectinatleastonetwinofamonochorionic
pairisestimatedatalmost10%,22withtheprevalenceinthesecondtwin
increasingtomorethan25%ifthefirsttwinisaffected.23,24Furthermore,
assistedreproductiontechniquesmayresultinamodestincreaseintheriskof
congenitalheartdisease,witharecentmeta-analysisshowinganoddsratioof
1.3comparedwithfetusesconceivedspontaneously.25
Table13.5
NonsyndromicCongenitalHeartDefectsandImplicatedModesof
Inheritance,RisksofRecurrence,andGenes
CongenitalHeartDefect
Atrioventricularcanaldefect

TetralogyofFallot

Transpositionofthegreatarteries

Congenitallycorrectedtranspositionofthe
greatarteries

Left-sidedobstructions

Atrialseptaldefect

RecurrenceRisk
Genes
(%)
Multifactorial
3–4
–
Autosomaldominant 50
p93
CRELDI
GATA4
PTPN11
Multifactorial
2.5–3
—
Autosomaldominant 50
NKX2.5
Autosomalrecessive 25
Jagged1
Three-genemodel
2.5–3
FOG2
—
—
Multifactorial
1–1.8
–

Autosomal
50
CFC1
dominant
Multifactorial
5.8
–

ModeofInheritance

Multifactorial
3
Autosomaldominant 50
Autosomalrecessive 25
Multifactorial

3

–
NOTCH1
NKX2.5
—
–

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