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Drug in Pregnancy...

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DrugsinPregnancy DanaG.Carroll,PharmD  Contributionsby:Drs.DougCarroll,ElizabethAnderson,MelissaCarter,MistyClark,ElizabethFlynn,Lindsey Johnson,ChadHolley,MeghanMorgan,ShelleyO’Bryan,HemalPatel,JasonSmiley  Pregnancyisauniqueperiodinawoman’slife.Manychangesarehappeningtoherbodythatmayaffectthe pharmacologyofmedications.Duringpregnancy,awoman’sgastricpHisincreasedandgastricmotilityis reducedwhichmayinterferewiththerateandextentofmedicationabsorption.Maternalplasmavolumeis increasedleadingtochangesinthevolumeofdistribution.Inaddition,increasesinprogesteroneand estradiollevelsmayaffectthehepaticmetabolismofsomemedications.Glomerularfiltrationrateis increasedduetoincreaserenalbloodflowwhichmayaffectrenallyclearedmedications.Despitethe changes,thepharmacologyofmostmedicationsisnotalteredenoughtorequiredosingchanges.1  Theplacentaisanorganofexchangeallowingthemothertopassnutrientsandmedicationstothefetus; therefore,medicationsadministeredtopregnantwomenhavethepotentialtoaffectthegrowingfetus.The fetusisgenerallyatthegreatestriskofdevelopingteratogeniceffectsfrommedicationsduringthefirst trimester,butitisdrugspecific.Theuseofmedicationsinpregnancyshouldbeevaluatedforthebenefits andriskstoboththemotherandfetus.Uponevaluation,somemedicationsmaybeusedsparinglyduring sometrimestersandcontraindicatedinothers.2Alleffortsshouldbemadetooptimizetheriskbenefitratio.  Drugswithlowmolecularweight,lowmaternalproteinbinding,lowionization,andhighlipophilicityare morelikelytocrosstheplacentaandcausepharmacologicaffects.1Thedevelopingfetus’sbodysystemsare notmature;therefore,thefetusmaylacktheabilitytometabolizemedicationscausingteratogeniceffects.2  TheFDAhascategorizedthepotentialteratogenicriskofmedicationsbyanA,B,C,D,Xsystem.  CategoryA:Controlledstudiesinwomenhavefailedtodemonstratearisktothefetusinthefirsttrimester andthereisnoevidenceofriskinlatertrimesters.Thepossibilityoffetalharmappearsremote.Medications inthisclassareconsideredsafetouseinpregnancy.Examplesofmedicationsinthisclassarevitaminsand levothyroxine.  CategoryB:Eitheranimal‐reproductionstudieshavenotdemonstratedafetalriskbutthereareno controlledstudiesinpregnantwomen,oranimalstudieshavedemonstratedrisktothefetusthatwasnot confirmedincontrolledstudiesinpregnantwomeninthefirsttrimesterandthereisnoevidenceofariskin latertrimesters.Medicationsinthisclassaregenerallyconsideredsafe.Examplesofmedicationsinthisclass areacetaminophenandamoxicillin.  CategoryC:Studiesinanimalshaverevealedadverseeffectsonthefetusandtherearenocontrolledstudies inwomen,orstudiesinwomenandanimalsarenotavailable.Drugsfromthisclasscanbegiventopregnant womenifthebenefittothemotheroutweighstherisktothefetus.Examplesofmedicationsinthisclassare diltiazemandspironolactone.  CategoryD:Evidenceofhumanfetalriskhasbeendocumented,butthebenefitstothemothermaybe acceptabledespitetherisktothefetus.Drugsinthisclassmaybeusedinpregnancyifthebenefitstothe motheroutweightherisktothefetus(i.e.alifethreateningsituationoraseriousdiseaseforwhichsafer medicationcannotbeusedorarenotefficacious).Examplesofmedicationsinthisclassarephenytoinand valproicacid.  CategoryX:Studiesinanimalsorhumanshavedemonstratedteratogeniceffects.Therisktothefetus clearlyoutweighsanypotentialbenefittothemother.Drugsinthiscategoryarecontraindicatedin pregnancy.Examplesofmedicationsinthisclassarethalidomideandwarfarin.2

Antibiotics  Generic(Brand)

Pregnancy Category

Nitrofurantoin(Macrobid)

B

Sulfamethoxazole(SMX)/ trimethoprim(TMP) (BactrimDS/SeptraDS) 

C

Metronidazole(Flagyl)

B

Yes



Crosses placenta

Reportedadverseeffectstomomor babyfromuseinpregnancy

Placeintherapy

Yes

Fetus:Hemolyticanemia



SMX:Unknown TMP:Yes

Fetus:SMX:jaundice,hemolyticanemia, andpossiblykernicterusTMP:neuraltube defects(NTD),oralclefts,cardiacdefects, andurinarytractdefects

Notrecommendedinpregnancy

Fetus:Lowbirthweightbabies, spontaneousabortions,andcarcinogenic possibilities

Safeforuseonlyin2 and3  trimester

Notmutagenicorteratogenic

Contraindicatedin1sttrimester

Fetus:Increaseinneonatalinfectionand lowbirthweightseenwithvaginal preparation1,12

ForBVasoralalternative,butnot thetopical

Topical‐(Metrogel) Clindamycin(Cleocin, Clindagel,Cleocin‐T)

B

Yes

nd

rd

GroupBstrep.diseaseinpatients withpenicillinallergy Fetus:Hypospadia(1sttrimesteronly), inguinalhernia,limbhypoplasia,teeth nd rd  discoloration(2 ,3 ) cataracts,cleft palates,spinabifida,polydactyly

Notrecommendedinpregnancy

Tetracyclines

D

Yes

Cephalosporins

B

Yes

Nonereported

Generallyconsideredsafein pregnancyunlesspenicillin allergic

Penicillins+/‐Beta‐ lactamaseinhibitor

B

Yes

Nonereported

Safestclassofabxinpregnancyif notallergic

Maternal:livertoxicity,irreversibleshock

Txofchoiceforsyphilis (desensitizeifpenicillinallergic) Macrolides

Azithro, Erythro:B

Yes

Fetus:Cardiovascularabnormalitiesand cleftpalatewithClarithromycin.



Claritro:C Fluoroquinolones

C

Yes

Erosionofweight‐bearingcartilageinrats anddogs,butnohumanreports

Notrecommendedinpregnancy

Aminoglycosides (Amikacin,Gentamicin,and Tobramycin)

D

Yes

Fetus:ototoxicity/deafness(damageof8th  CN)Neuromuscularweakness,respiratory depressionwithconcomitantgentamicin andMagsulfate

Donotuseinpregnancynot unlessthebenefitoutweighsthe risktothefetus.





AntiepilepticDrugs(AEDs)  Pregnancy category

Crosses placenta

Reportedadverseeffectstomomor babyfromuseinpregnancy

Carbamazepine (Tegretol)

D

Yes:levels50‐80% ofmaternal,highest infetalliverand kidneys

Fetus:dysmorphicfacialfeatures,cranial defects,cardiacdefects,spinabifuda,fingernail hypoplasia,developmentaldelay,mildmental retardation,neuraltubedefects

Ethosuximide (Zarontin)

C

Unknown

Fetus:spontaneoushemorrhage,patentductus arteriosus,cleftlip/palate,mongoloidfacies, shortneck,alteredpalmarcreaseandaccessory nipple,hydrocephalus

Felbamate(Felbatol)

C

Unknown

Fetus:mentalretardation.Maternal:aplastic anemia,acuteliverfailure

LimitedHumanData– AnimalDataSuggest ModerateRisk.Drugcrossesplacentain animals,notyetdescribedinhumans.But shouldoccurbecauseofLMW

Phenytoin(Dilantin)

D

Unknown

Fetus:congenitalabnormlaities,hemorrhageat birth,neurodevelopmentabnormalities

Compatible–MaternalBenefit>> Embryo/FetalRisk



Dose‐related teratogenic effect

Maternal:folicaciddeficiency

SignificantRisks:major/minorcongenital abnormalities,hemorrhageatbirth, neurodevelopment





Fosphenytoin (Cerebyx)

D

Unknown

Gabapentin (Neurontin)

C

Unknown

Maintainlowestlevelrequiredtoprevent seizuresinordertolessenriskoffetal anomalies Fetus:congenitalmalformations,orofacialclefts, Benefitsfromuseinpregnantwomenmaybe acceptabledespitetherisk(e.g.,ifthedrugis cardiacdefects,minoranomalies,mental neededinalife‐threateningsituationorfora deficiency seriousdiseaseforwhichsaferdrugscannotbe Maternal:Anincreaseinseizurefrequencymay usedorareineffected) occurduringpregnancybecauseofaltered phenytoinpharmacokinetics Limited humandatadoesnotallowan LimitedEvidence:Ifrequired,benefitsappear> assessmentastothesafetyofgabapentin fetalrisks

Lamotrigine (Lamictal)

C

Yes

Fetus:frequencyofmajordefectsamong1 trimestermonotherapyexposurewas2.9%(12 of414)

HumanDataSuggestLowRisk;Adjustdoseto maintainclinicalresponse

Levetiracetam (Keppra) Oxcarbamazepine (Trileptal)

C

Unknown

Risktohumanfetus/embryounknown

Risktohumanembryo/fetusisunknown

C

Yes

Fetus:nomajorcongenitalmalformations reported,mildfacialdefectsobservedinone case

Noepoxidemetabolites:lowerriskof teratogenicitycomparedtootheragents, Supplementwithfolicacid

Phenobarbital (LuminalSodium)

D

Yes

Fetus: congenitaldefects,hemorrhageatbirth, addiction,AEofneurobehavioraldevelopment Maternal:Benefit>Risk

Benefits>Riskduringatlowesteffectivelevel

Pregabalin(Lyrica)

C

Unknown

Animalstudies– fetalabnormalities,skeletal malformations,male‐mediatedteratogenicity Nohumanstudies

Useonlyifmaternalbenefit>fetalrisk

Tiagabine(Gabitril)

C

Unknown

Fetus:oneincidencewithunspecified malformations,otherwiseunknown

Safestcourse:Avoidin1 trimester ;later trimestersunknown,

Primidone (Mysoline)

D

Unknown

Ifbenefits>risks(e.g.,drugneededinlife‐ threateningsituationorseriousdiseasewithno saferdrug)

Topiramate (Topamax)

C

Yes

Newborn: neurologicmanifestations (overactivity/tumor);mechanismfor hemorrhagiceffectsisduetosuppressionof VitK‐dependentclottingfactors,recommend administrationofVitKtoinfantimmediately afterbirth Hypospadiasinmales(relationshipnot established);Datatoolimitedtoassess embryo/fetusrisk

Generic(Brand)



st

Placeintherapy Compatible–MaternalBenefit>> Embryo/FetalRiskIfdrugisrequiredduring pregnancyitshouldnotbewithheldbecause thebenefitsofpreventingseizuresoutweigh potentialfetalharm Limitedhumandata.Probablycompatible. Succinamideanticonvulsants:DOCfortxof petitmalepilepsyin1sttrimester

st

st

Avoidifpossiblein1 trimester

ValproicAcid (Depakene)

D

Yes

Fetus:neuraltubedefects,minorfacialdefects, defectsofthehead,face,digits,urogenitaltract, mentalandphysicalgrowth

Benefits>Risks(e.g.,drugneededinlife‐ threateningsituationorseriousdiseasewithno saferdrug)

Zonisamide (Zonegran) Trimethadione

C

Unknown

Congenitalanomaliespossible

Avoidifpossiblein1 trimester

D

Unknown

Contraindicatedin1 trimester

Clonazepam (Klonopin)

D

Unknown

Fetus:mentalretardation,craniofacialdefects, genitourinarydefects,malformedhands, clubfoot Humandatasuggestlowrisk;fetalandneonatal toxicityhasbeenreported

Lorazepam(Ativan)

D

Yes

Fetus:highIVdosesmaycause“floppyinfant” syndrome,higherincidenceofrespiratory distress

Benefits>Risks(e.g.,drugneededinlife‐ threateningsituationorseriousdiseasewithno saferdrug)

Carbamazepine (Tegretol)

D

Yes

Fetus: minorcraniofacialdefects,fingernail hypoplasia,developmentaldelay,mildmental retardation

Ifrequired,Benefits>risks

 



st

st

1

st

Safestcourseistoavoidduringthe1 trimester;however,ifindicated,itshouldnot bewithheldbecauseofpregnancy

CoughandCold  Generic(Brand)

Class

Pregnancy Category

Crosses placenta

Reportedadverseeffectstomomor babyfromuseinpregnancy

Diphenhydramine (Benadryl)

Antihistamine

B

Yes

1 trimester – cleftpalate,cardiovascular defects,oralclefts,spinabifida, polydacytly,limbreductiondefectsand hypospadias. Maternal:prematurelabor

st

Chlorpheniramine (Chlorphen,Aller‐ Chlor)

Antihistamine

B

Unknown

Fetal: polydactyly,GIdefects,eyeandear defects,inguinalhernia,hydrocephaly, congenitaldislocationofthehipand malformationofthefemalegenitalia.

Fexofenadine(Allegra)

Antihistamine

C

Unknown

Loratadine(Alavert, Claritin)

Antihistamine

C

Unknown

Nowell‐controlledstudiespublished; avoidinfirsttrimester Fetal: Cleftpalate,microtia, microphthalmia,deafness,triscuspid dysplia,diaphragmatichernia.

nd

DOCifparenteralantihistaminesare indicated

Meclizineandcyclizine:viable alternatives Meclizineandcyclizinedonot requirearestrictiononusein pregnantwomenandwouldbe viablealternatives Considerdiphenhydramineor chlorpheneramine Considerdiphenhydramineor chlorpheneramine st

Bin2 /3rd Cetirizine(Zyrtec)

Placeintherapy

Notrecommendedin 1 trimester Unknown

st

Antihistamine

C

Dextromethorphan (Robitussin,Pediacare)

Anti‐tussive

Bin2 and 3rd C

Unknown

generallysafebasedonobservation

Benzonatate(Tessalon Perles)

Anti‐tussive

C

Unknown

Therehasnotbeensufficientclinical experiencetoestablishthesafetyof benzonatateingeneralduringpregnancy

Codeine/ Hydrocodonerxcough syrups

Anti‐tussive

C;Dathigher dosesfor longertime

Unknown

1 trimester – physicaldependence, withdrawal,growthretardation, respiratorydepression,cleftlip/palate, dislocatedhip,musculoskeletaldefects. nd 2 trimester– alimentarytractdefects

Guaifenesin(Mucinex, Humibid)

Expectorant

C

Unknown

1 trimester –increasefrequencyof inguinalherniasandcardiovascular defects

UseonlyifBenefits>Risks

SalineNasalSpray



A

Unknown

Noknownadverseeffects

Safetouseduringalltrimestersin pregnancy.

Phenylephrine (Tannate)

Sympathomimetic

C

Unknown

1 trimester – ear/eyemalformation, syndactyly,preauricularskintag,club foot,inguinalhernia.

nd



1 trimester– spontaneousabortion, ectopickidney,undescendedtestes

Considerdiphenhydramineor chlorpheneramine

Exposuretoolowassesspotentialrisks

Notrecommendedinthe1 trimester DOCforcoughduringpregnancy; combinationproductscontaining alcoholshouldbeavoidedduring pregnancy;avoidliquidalcohol containingpreparations

st

st

st

st

Ifpossible,useofbenzonatate duringpregnancyshouldbeavoided Useonlyifclearlyneeded

Untilmoreinformationisavailable, useofphenylephrineshouldbe avoidedduringpregnancy

Congenitalhipdislocation, musculoskeletaldefects,umbilicalhernia Maternal:uterinevesselvasoconstriction andreducedbloodflowresultsinfetal hypoxia st



st

Thebenefitsoftreatmentmustbe carefullyweighedagainstthe potentialrisksoftherapy.Ofthe nasalcorticosteroids,budesonideis thebestchoice.Itistheonlyinhaled corticosteroidthatiscategoryB

Pseudoephedrine (Sudafed,Dimetapp)

Sympathomimetic

C

Unknown

1 trimester– inguinalhernia,clubfoot. Mayresultinfetalhypoxia.Teratogenicis someanimalspecies

NasalSteroids Budesonide (Rhinocort) Fluticasone(Flonase) Mometasone (Nasonex) Triamcinolone (Nasacort)

Cortico‐steroid

CBudes:B Triamcin:Din 1sttrimester)

Unknown

1 trimester ‐ orofacialclefts,conotruncal defects,neuraltubaldefectsandlimb abnormalities.Congenitalmalformations, prematurebirth,lowbirthweight,C‐ section,stillbirthmultiplebirths.



Budenoside:noincreasedriskoftheseAE.



Triamcinolone:inanimalscleftpalate, umbilicalhernia,undescendedtestes, reducedossification,growthretardation.





DiabetesMellitus  Generic(Brand)

Class

Pregnancy Crosses Reportedadverseeffectstomom Category placenta orbabyfromuseinpregnancy

Glyburide(Diabeta, Micronase,Glynase)

Sulfonylurea

C

Yes

Possibleeardefectsin1sttrimester, fetalhypoglycemia

Insulinisrecommendedfirstline bytheADA;ACOGrecommends useofthisagentinD2orGDM

Glipizide(Glucotrol)

Sulfonylurea

C

Yes

Possibleeardefectsin1sttrimester,no teratogenicityinanimalstudies

Notrecommended;limited humandata

Glimepiride(Amaryl)

Sulfonylurea

C

Unknown

Skeletalmalformationinhighdoses

Notrecommended;Nohuman data

Metformin (Glucophage, Fortamet,Glumetza)

Biguanide

B

Unknown

Neuraltubedefectsinanimalsathigh doses.Fewabnormalitiesinhumansat normaldosesandlikelyduetopoorBG control

Insulinisrecommendedfirstline bytheADA;ACOGrecommends useofthisagentinD2orGDM

Sitagliptin(Januvia)

Dipeptidyl peptidaseIV inhibitor

B

Unknown

Nogoodstudiesinhumans;animal studiesshownodefects/complicationat highdoses

Possible;Nohumandata