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DrugUseduringPregnancy
Dateofrevision:May2015
OrnaDiavCitrinMDGideonKorenMDFRCPCFACMTFAACT
Thefollowingisanoverviewofdruguseduringpregnancy.Thisinformationisnotintendedtobeacomprehensive
reviewthereaderisthereforeencouragedtoseekadditionalandconfirmatoryinformation.

PrinciplesofPrescribinginPregnancy
Manypregnantwomenareexposedtoavarietyofmedicationsthatmayexerttherapeutic,toxicorteratogenic
effectsonthefetus.Sincethethalidomidedisaster,manyphysiciansandpregnantwomentendtowithholdany
medicationduringpregnancy,althoughtheriskofteratogeniceffectfrommostdrugsintherapeuticdosesis
nonexistent.Majorcongenitaldefectsoccurin13%ofthegeneralpopulationatbirth.1Ofthemajordefects,

about25%areofgeneticorigin(geneticallyinheriteddiseases,newmutationsandchromosomalabnormalities)
and65%areofunknownetiology(multifactorial,polygenic,spontaneouserrorsofdevelopmentandsynergistic
interactionsofteratogens).Only23%ofmalformationsarethoughttobeassociatedwithdrugtreatment.The
remainingdefectsarerelatedtootherenvironmentalexposuresincludinginfectiousagents,maternaldisease
states,mechanicalproblemsandirradiation.2,3
Optimalprescribinginpregnancyisachallengeandshouldprovidemaximalsafetytothefetusaswellas
therapeuticbenefittothemother.Todate,veryfewdrugsareproventeratogensinhumans.However,drug
inducedmalformationsareimportantbecausetheyarepotentiallypreventable.
Maternalphysiologicchangesduringpregnancymayalterthepharmacokineticsofdrugs.Clearanceratesofmany
drugsincreaseduringlatepregnancyduetoincreasesinbothrenalandhepaticelimination(e.g.,digoxin,
phenytoin),whileforotherdrugstheclearanceratedecreases(e.g.,theophylline).Generally,littleisknownabout
therelationshipbetweenmaternalserumdrugconcentrationandriskofteratogenicity.
Theimportanceoftimingofdrugexposureisbetterunderstoodtheeffectproducedbyateratogenicagent
dependsuponthedevelopmentalstageinwhichtheconceptusisexposed.Severalimportantphasesinhuman
developmentarerecognized:3
Theallornoneperiod,thetimefromconceptionuntilsomiteformation,correspondstothefirst17days
afterconception.Insultstotheembryointhisphasearelikelytoresultineitherdeathandmiscarriageor
intactsurvival.Theembryoisundifferentiated,andrepairandrecoveryarepossiblethroughmultiplicationof
thestilltotipotentialcells.Considerthatexposuretoteratogensduringthepresomiticstageusuallydoesnot
causecongenitalmalformationsunlesstheagentpersistsinthebodybeyondthisperiod.3,4

Theembryonicperiod,from1860daysafterconceptionwhenthebasicstepsinorganogenesisoccur.This
istheperiodofmaximumsensitivitytoteratogenicitysincetissuesaredifferentiatingrapidlyanddamage
becomesirreparable.Exposuretoteratogenicagentsduringthisperiodhasthegreatestlikelihoodofcausinga
structuralanomaly.Thepatternofanomaliesproduceddependsonwhichsystemsaredifferentiatingatthe
timeofteratogenicexposure.
Thefetalphase,fromtheendoftheembryonicstagetoterm,whengrowthandfunctionalmaturationof
formedorgansandsystemsoccurs.Teratogenexposureinthisperiodwillaffectfetalgrowth(e.g.,intrauterine
growthrestriction)andthesizeorfunctionofanorgan,ratherthancausegrossstructuralanomalies.Theterm
fetaltoxicityiscommonlyusedtodescribesuchaneffect.
Thepotentialeffectofpsychoactiveagents(e.g.,antidepressants,antiepileptics,alcoholandotherdrugsofabuse)
onthedevelopingcentralnervoussystemhasledtothenewfieldofbehaviouralteratology.
Manyorgansystemscontinuestructuralandfunctionalmaturationlongafterbirth.Mostoftheadenocarcinomas
associatedwith1sttrimesterexposuretodiethylstilbestroloccurredmanyyearslater.
Teratogensmustreachthedevelopingconceptusinsufficientamountstocausetheireffects.Largemoleculeswith
amolecularweightgreaterthan1000(e.g.,heparin)donoteasilycrosstheplacentaintotheembryonicfetal
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bloodstream.Otherfactorsinfluencingtherateandextentofplacentaltransferofdrugsincludepolarity,lipid
solubilityandtheexistenceofaspecificcarrierprotein(e.g.,Pglycoprotein).
Inanattempttoprovidethepractitionerwithabetterassessmentoffetalrisk,theUSFoodandDrug
Administration(FDA)developedaclassificationoffetalriskin19795(seeGlossary).Thesecategoriesinitially

appearedlogicalbutarenothelpfulincounsellingindividualpatients.Drugmanufacturersmayhavelegalrather
thanscientificreasonsforassigningparticulardesignations.Theclassificationfrequentlyresultsinambiguityand
evenfalsealarm.Forexample,oralcontraceptivesaredenotedasX(contraindicatedinpregnancy),despitefailure
of2metaanalysestoshowincreasedteratogenicrisk.In1994theTeratologySocietystatedthattheFDAratings
areinappropriateandshouldbereplacedbynarrativestatementsthatsummarizeandinterpretavailabledata
regardinghazardsofdevelopmentaltoxicityandprovideestimatesofteratogenicrisk.6Duringthelastfewyears
theFDAhasbegunaprocesstochangethepresentsystem.

TeratologyCounselling
Ascertaintheclinicalfactsregardingthenatureoftheexposure:thelength,dosageandtimingduring
pregnancy,aswellasotherexposuresofconcern(e.g.,alcohol,cigarettesmoking,herbalremedies).
Collectallavailablecurrentdataregardingtheagentandtheriskofexposure.
Counsellingshouldincludebackgroundhumanbaselineriskformajormalformations,whetherthefetusisat
increasedrisk,whichanomalyhasbeenassociatedwiththeagentinquestion,ariskassessment,methodsof
prenataldetectionwhenavailable,limitationsinourknowledgeandlimitationsofprenataldiagnostic
capabilities.
Additionalconsiderationsincludethepotentialriskofthemedicalconditionforwhichadrugisprescribed,
knowninteractionsbetweenthediseasestateandthepregnancy,andpreventivemeasureswhenapplicable
(e.g.,folicacidsupplementationincarbamazepineexposure).
Becausemorethan50%ofpregnanciesareunplanned,teratogenicriskassessmentshouldbestartedpriorto
pregnancy.
Table1listsdrugswithsufficientevidencetoprovetheirteratogeniceffectinhumans.Useanalternativein
pregnancywhenpossible.Table2listspossibleteratogenicdrugswithinsufficientevidenceasyetforteratogenicity
inhumans.

Table1:ProvenTeratogenicDrugsinHumans7
Drug

AdverseEffects

Angiotensin
converting
enzyme
inhibitors
(ACEIs)and
AngiotensinII
antagonists

AdverseeffectsrelatetohemodynamiceffectsofACEIsandangiotensinIIantagonistsonthe
fetus.Inlatepregnancy,ACEIfetopathy:intrauterinerenalinsufficiency,neonatalhypotension,
oliguriawithrenalfailure,hyperkalemia,complicationsofoligohydramnios(fetallimb
contractures,lunghypoplasiaandcraniofacialanomalies),prematurity,intrauterinegrowth
restrictionandfetaldeath.1sttrimesterexposure:questionableteratogenicriskof

Antineoplastic
agents

Asignificantincreaseintheincidenceofvariousfetalmalformationsandearlymiscarriages
following1sttrimesterexposure.15

cardiovascularandCNSmalformations.8Severalcohortstudiesandmetaanalysessuggestthe
observedriskisassociatedwiththeunderlyingmaternalconditions.9,10,11,12,13,14

Carbamazepine 1sttrimesterexposure:1%riskofneuraltubedefects(10baselinerisk)andanincreased
riskofcardiovascularmalformations.Apatternofmalformationssimilartothefetalhydantoin
syndromehasalsobeenassociated.16
Cocaine

Abruptioplacenta,prematurity,fetalloss,decreasedbirthweight,microcephaly,limbdefects,
urinarytractmalformationsandpoorerneurodevelopmentalperformance.Methodological
problemsmakethefindingsdifficulttointerpret.Cocaineabuseisoftenassociatedwithpoly
drugabuse,alcoholconsumption,smoking,malnutritionandpoorprenatalcare.Human
epidemiologyindicatestheriskofmajormalformationfromcocaineisprobablylow,butthe
anomaliesmaybesevere.17

Corticosteroids
(systemic)

1sttrimesterexposure:<1%increasedriskoforalclefts.18

Coumarin
anticoagulants

1sttrimesterexposure(69wkgestation):fetalwarfarinsyndrome(nasalhypoplasiaand
calcificstipplingoftheepiphyses).Intrauterinegrowthrestrictionanddevelopmentaldelay

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(e.g.,
acenocoumarol,
warfarin)

(CNSdamage),eyedefectsandhearingloss.Warfarinembryopathyisfoundinuptoofthe
caseswhereacoumarinderivativewasgiventhroughoutpregnancy.Associatedwithhighrate
ofmiscarriage.RiskofCNSdamageduetohemorrhageafterthe1sttrimester.19,20

Diethylstilbestrol Vaginalclearcelladenocarcinomainoffspringexposedinuterobefore18thwk(>90%ofthe

cancersoccurredafter14yofage).Highincidenceofbenignvaginaladenosis.Increased
miscarriagerateandpretermdelivery.Inmalesexposedinutero:nosignsofmalignancybut
genitallesionsin27%andpathologicchangesinspermatozoain29%.Thedrugisnotcurrently
availableinCanada.21
Ethanol

Fetalalcoholspectrumdisordersinclude4diagnosticcategories:fetalalcoholsyndrome(FAS)
partialFASalcoholrelatedneurodevelopmentaldisordersalcoholrelatedbirthdefects.FAS
presentsasgrowthimpairment,developmentaldelayanddysmorphicfacies.Cleftpalateand
cardiacanomaliesmayoccur.Fullexpressionofthesyndromeoccurswithchronicdaily
ingestionof2galcoholperkg(8drinks/day)inaboutonethirdofoffspringandpartialeffects
inthreequartersofoffspring.22,23,24,25,26Alcoholrelatedneurodevelopmental
disordersaremuchmorecommonthanFAS.27

Folicacid
antagonists:
aminopterinand
methotrexate

Fetalaminopterinmethotrexatesyndrome:CNSdefects,craniofacialanomalies,abnormal
cranialossification,abnormalitiesinfirstbranchialarchderivatives,intrauterinegrowth
restrictionandmentalretardationafter1sttrimesterexposure.Maternaldoseofmethotrexate

Hydantoins
(phenytoin)

Fetalhydantoinsyndrome:craniofacialdysmorphology,anomaliesandhypoplasiaofdistal
phalangesandnails,growthrestriction,mentaldeficiencyandcardiacdefects.29

Lithium

Smallincreaseinriskforcardiacteratogenesisinearlygestation(1%).TheriskofEbstein's
anomaly(acongenitalheartdefect,characterizedbyanteriordisplacementofthetricuspid
valve,enlargedrightchambers,oftenwithatrialseptaldefectandarrhythmias)exceeds
spontaneousrateofoccurrence.Fetalechocardiographyifexposedin1sttrimester.30,31,32

neededtoinducedefectsisprobablyabove10mg/wk.28

Misoprostol

1sttrimesterexposure:limbdefects.Moebiussequence(acongenitalfacialpalsywith
impairmentofocularabduction,asaresultofdysfunctionofcranialnervesVIandVII)and
CNSinjuries.Absoluteteratogenicrisk:12%.Uterinecontractioninducingactivitycausing
vasculardisruptiondefects.33,34,35

Mycophenolate
mofetil

1sttrimesterexposure:ear,eyeandcraniofacialmalformations,oralclefts,cardiac,finger,
urogenital,gastrointestinal,CNSandskeletalmalformations.36,37,38

Retinoids
(acitretin,
isotretinoin)
andmegadoses
ofVitaminA

Systemicexposure:potenthumangeneralandbehaviouralteratogens.Riskofretinoicacid
embryopathy:craniofacialanomalies,cardiacdefects,abnormalitiesinthymicdevelopment
andalterationsinCNSdevelopment(congenitalanomaliesin28%ofprospectivelyascertained
pregnanciesthatresultedinbirths).Riskforassociatedmiscarriage:40%.39,40

Tetracyclines

Discolourationoftheteethafter17wkgestationwhendeciduousteethbegintocalcify.Closeto
term:crownsofpermanentteethmaybestained.Oxytetracyclineanddoxycyclineassociated
withalowerincidenceofenamelstaining.41,42

Thalidomide

Malformationslimitedtotissuesofmesodermalorigin,primarilylimbs(reductiondefects),ears,
cardiovascularsystemandgutmusculature.Criticalperiod:3450thdayafterthebeginningof
thelastmenstrualperiod.Asingledoseof<1mg/kghasproducedthesyndrome.
Embryopathyfoundinabout20%ofpregnanciesexposedinthecriticalperiod.43

Valproicacid

1sttrimesterexposure:neuraltubedefectswith12%riskofmeningomyelocele,primarily
lumbarorlumbosacral,cardiovascularmalformationsandhypospadias.Fetalvalproate
syndrome:craniofacialdysmorphology,cardiovasculardefects,longfingersandtoes,
hyperconvexfingernailsandcleftlip,hasbeendelineatedbysomeinvestigations.
Neurobehaviouralteratogen.44,45,46,47,48,49

Table2:PossibleTeratogenicDrugsinHumansa ,50
Drug

AdverseEffects

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Diazepam

Aquestionablesmallincreaseintheincidenceofcleftlipandpalate(small
studies).Largerstudiesdidnotconfirmtheassociation.51

Fluconazole

Highdosetreatment:multiplesynostosis,congenitalheartdefects,skeletal
anomaliesandrecognizabledysmorphicfacialfeatures(casereports).52

HMGCoAreductaseinhibitors
(statins)

AquestionableincreaseintheriskofCNSandlimbanomalies(retrospective
data),notconfirmedbyseveralprospectivecohortstudies.53,54,55,56

Methimazole

Scalpdefectssuchasaplasiacutiscongenitasuggestedthroughcasereports,
anepidemiologicalstudyinwhichmethimazolehadbeenaddedtoanimalfeeds
asaweightenhancer,andlargeepidemiologicstudiesmethimazole
embryopathy(choanalandesophagealatresia,scalpdefects,minorfacial
anomaliesandpsychomotordelay).57,58,59,60

Penicillamine

Highdosetreatment:connectivetissuedisorders(cutislaxa).61

Sulfamethoxazole/trimethoprim Possibleincreasedriskofneuraltubeandcardiovasculardefectsandoralclefts
with1sttrimesterexposure.Folicacidsupplementationmayreducethese
risks.62,63,64

a. Thislistisnotexhaustive.

DrugsofChoiceduringPregnancy
Table3presentsdrugsofchoiceduringgestationforcommonmaternalconditions.

Note:Antenataldrug/chemicalriskcounsellingorinformationonsafetyofdruguseduringbreastfeedingis
availablefromtheMotheriskProgram,HospitalforSickChildren,Toronto,Ontario.Tel.:4168136780email:
momrisk@sickkids.caWebsite:www.motherisk.org.

Table3:DrugsofChoiceforSelectConditionsduringPregnancy 7
Condition

DrugsofChoice

Alternative

Comments

Allergy 65,66

Antihistamines:
chlorpheniramine,
desloratadine,
diphenhydramine,
dimenhydrinate,loratadine

Intranasal
preparationsof
sodium
cromoglycate,
beclomethasone,
budesonide,
fluticasone
cetirizine,
fexofenadine

Anticoagulation

Heparinandlowmolecular
weightheparins67,68

Anxiety

Shorttermtreatment:
benzodiazepines51

Watchforpossibletransientneonatal
effectswhenbenzodiazepinesorSSRIs
usedclosetoterm.
Shortorintermediateacting
benzodiazepines(e.g.,lorazepam,
oxazepam)maybepreferredifneeded
forregularusenearterm.
Fordiazepam,thereisaquestionable
smallincreaseintheincidenceofcleft
lipandpalate(smallstudies).Larger
studiesdidnotconfirmtheassociation.

Systemic
corticosteroidsand

Longtermtreatment:
citalopram,fluoxetine,
sertraline 69,70,71,72

Asthma 73

Inhaledbronchodilators
(ipratropiumbromide,

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salbutamolorterbutaline)
andinhaledcorticosteroids
(beclomethasone,
budesonide,fluticasone)

theophylline

Bacterial

Cephalosporins,clindamycin,
erythromycin,penicillins

Aminoglycosides
(amikacin,
gentamicin,
tobramycin),
azithromycin,
clarithromycin,
quinolones74

Bipolardisorder

Lamotrigine,75quetiapine 76

Carbamazepine,
lithium31,77

Withlithium,monitorusingfetal
echocardiography.Avoidvalproicacid
whenpossible,especiallyinthe1st

infections5

trimester(ifnotpossibletoavoid,limit
doseto<6001000mg/day).With
carbamazepineandvalproicacid,
prescribepericonceptionalfolate
supplementation:5mgpodaily,ideally
starting3monthsbeforetryingto
conceiveandcontinuingatleastuntil
theendofthe1sttrimester.Monitor
usinglevelIIultrasoundforprevention
ofneuraltubedefects.
Constipation78

Bulkformingagents(e.g.,
methylcellulose,psyllium
hydrophilicmucilloid,soluble
andnonsolublefibre)

Cough79

Antihistamines(inthecaseof Dextromethorphan
coughduetorhinitisor
allergy),codeine(when
indicated)

Avoidhighdosesofcodeinecloseto
term(riskofneonatalopioid
withdrawal).

Depression

Citalopram,fluoxetine,
sertraline,69,71,72,80,

Otherselective
serotoninreuptake
inhibitors,
bupropion,
venlafaxine

Neonatalwithdrawalmayoccurwhen
usedin3rdtrimester.

Humaninsulin82

Metformin83,84in
gestationaldiabetes
in3rdtrimester,

Importanttoachievestrictglycemic
controlbeforeconceptionandduring
the1sttrimester.

Bulkformingagents(e.g.,
methylcellulose,
psylliumhydrophilic
mucilloid)86

Loperamide

Dyspepsia

Alginicacidcompound,
antacids(various
combinationsofaluminum,
calcium,magnesiumsalts),
omeprazole,87ranitidine

Famotidine

Epilepsy 88,89,
90

Carbamazepine,lamotrigine

Benzodiazepines
(e.g.,clonazepam)
(seeAnxiety),
phenobarbital,
phenytoin,valproic
acid(see
Comments)

Thedrugofchoiceforepilepsyin
pregnancyshouldbethedrugthatbest
controlstheseizuresmonotherapy
shouldbefavoured.Usethelowest
effectivedose.
Avoidvalproicacidwhenpossible,
especiallyinthe1sttrimester(ifnot

81tricyclicantidepressants
Diabetesmellitus

Docusatesodium,
glycerin
suppository,
lactulose,mineral
oil,polyethylene
glycol(PEG)

Longtermuseofmineraloilcan
decreaseabsorptionoflipidsoluble
vitaminsA,D,EandK.

glyburide 85
Diarrhea

possibletoavoid,limitdoseto<600
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1000mg/day).
Withcarbamazepineandvalproicacid,
prescribepericonceptionalfolate
supplementation:5mgpodaily,ideally
starting3monthsbeforetryingto
conceiveandcontinuingatleastuntil
theendofthe1sttrimester.Monitor
usinglevelIIultrasoundforprevention
ofneuraltubedefects.

Feverandpain

Acetaminophen91

ASA,NSAIDs92

Avoidfullantiinflammatorydosesof
NSAIDsin3rdtrimesterduetotherisk
ofoligohydramniosandpremature
closureofductusarteriosus.

Hemorrhoids(3rd
trimester)

Topical

Herpetic
infections

Acyclovir,valacyclovir94,95

Hypertension96

Hydralazine,methyldopa

Withbetablockers,reducedbirth
weightandpersistentbetablockade
possibleinnewborn.Monitorgrowth
usingserialultrasoundsinthe3rd

hydrocortisone/pramoxine,93
topicallidocaine,topicalzinc
oxide

Betablockers,
calciumchannel
blockers

trimester.Monitornewbornfor
hypoglycemia,bradycardia,
hypotensionandrespiratoryproblems
duringthefirst2448h.
Hyperthyroidism97 Propylthiouracil

Migraine
(abortivetherapy)

Acetaminophen

ASA,NSAIDs,
Avoidfullantiinflammatorydoseof
sumatriptan98,99, NSAIDsin3rdtrimesterduetotherisk
100
ofoligohydramniosandpremature
closureofductusarteriosus.

Nausea/vomiting

Doxylamine/pyridoxine
(Diclectin)101,102

Dimenhydrinate,

metoclopramide,103
,104

Performfetalultrasoundneartermfor
goitredetection.

ondansetron105
Schizophrenia 106
,107,108

Phenothiazines

Haloperidol,
olanzapine,
quetiapine,
risperidone

Watchneonateforpossibleadverse
effectsiftakenclosetoterm.
Continuepresentantipsychoticifthe
womanisstableandunplanned
pregnancyoccurs.Monitorthewoman
formetaboliccomplications(weight
gain,hyperglycemia,hyperlipidemia),
especiallywithsecondgeneration
antipsychotics.

Vaginal
candidiasis

Vaginal:clotrimazole,
miconazole,nystatin
Topicalazolesare
preferred109,110

Fluconazole:single
systemicdoseof
150mg111

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