3-2drugs in pregnancy

8/2/2019 3-2Drugs in Pregnancy

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Drugs inPregnancy


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major malformations in general

population 2 - 3 % 10 % of congenital abnormalities

caused by teratogens

Teratogenacts during embryonic / fetal development

permanent alteration of form / function

chemicals, viruses, environmental agents,physical factors, and drugs


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Developmental Period

1. Preimplantation period

2 weeks from fertilization to implantation

"all or none" period

large number of cells damage : embryo death few cells injury : continue normal development

2. Embryonic period 2 - 8 week following conception

organogenesis

critical periods of sensitivity

structural malformations


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Food and Drug AdministrationCategories for Drugs and Medications

Category A

Controlled studies in human: no fetal risk

Category B Animal studies no fetal risks, but nohuman studies; or adverse effects in

animals, but not in well-controlled humanstudies

Category C no adequate studies, either animal orhuman, or adverse fetal effects in animal

studies but no available human data.Category D evidence of fetal risk, but benefits are

thought to outweigh these risks

Category X Proven fetal risks clearly outweigh any

benefits


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mechanismsofteratogenesis

disruption of folic acid metabolism

essential for normal meiosis and mitosis

neural-tube defects, cardiac defects,cleft lip and palate

antiseizure: impair folate absorption oract as antagonists


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mechanisms ofteratogenesis

toxic oxidative intermediates

antiseizure: metabolized by microsomesto arene oxides or epoxides

free oxide radicals have carcinogenic,mutagenicand other toxic effects

detoxified by cytoplasmic epoxide

hydrolase fetal epoxide hydrolase activity is weak


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Counseling for teratogen exposure

All women have ~ 3% chance ofhaving a neonate with birth defect

exposure to confirmed teratogenmay increase risk, by only 1 - 2%or at most double or triple

risk versus benefit


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Drugs or Substances Suspected orProven to Be Human Teratogens

ACE inhibitors

Aminopterin

Androgens

A-II antagonists

Busulfan

Carbamazepine

Chlorbiphenyls

Cocaine

Coumsarin

Cyclophosphamide Danazol

Diethylstilbestrol (DES)

Ethanol

Etretinate

Isotretinoin

Kanamycin

Lithium

Methimazole

Methotrexate

Misoprostol Penicillamine

Phenytoin

Radioactive iodine

Streptomycin

Tamoxifen Tetracycline

Thalidomide

Tretinoin

Trimethadione

Valproic acid


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Ethyl alcohol Fetal Alcohol Syndrome

Behavior disturbances

Brain defects

Cardiac defects

Spinal defects

Craniofacial anomali Absent or hypoplastic philtrum

Broad upper lip

Flattened nasal bridge

Hypoplastic upper lip vermilion

Micrognathia

Microphthalmia

Short nose

Short palpebral fissures


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Ethyl alcohol

Clinical Characteristics

congenital heart and joint defects

failure to thrive

persistent irritability

Delay growth & development

poor coordination

Comorbid: mental retardation, attentiondeficit/hyperactivity disorder, cerebralpalsy and epilepsy


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Ethyl alcohol

highest risk: chronic ingest largequantities

fetal injury can result from 1-2 drink/d

alcohol 0.5 ounce/day: no alcohol-related effects

increase risk of pregnancy complications


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anticonvulsants

Women with epilepsy increase risk offetal malformations

most frequent defects: orofacialclefts and cardiac malformations

Clefts 10 times more frequently thangeneral population

more prevalent: high serumconcentration and polytherapy


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anticonvulsants

fetal hydantoin syndrome

microcephaly

growth deficiency

developmental delaysmental retardation

dysmorphic craniofacial features

fingernail hypoplasia

cardiac defect

facial clefts


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anticonvulsants

Drug Teratogenesis Affected

Phenytoin Fetal hydantoin syndrome 5-11%

Carbamazepine Fetal hydantoin syndrome;

spinabifida

1-2%

Valproate Neural-tube defects 1-2%

Trimethadione,

paramethadione

Craniofacial anomalies,

including cleft palate, V-shape

eyebrows, microcephaly,growth deficiency, mental

retardation, speech

disturbance, cardiac defects

70%


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anticonvulsants

Drug Teratogenesis Affected

Phenobarbital Clefts, cardiac anomalies,

urinary tract malformations

10-20%

Lamotrigine Theoreticallowers fetal folatelevels by inhibiting

dihydrofolate reductase

Topiramate Theoreticalhas produced

defects or abnormal

pregnancy outcomes in allanimals tested, even at low or

therapeutic doses


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Anticoagulants

Warfarin (Coumadin)

low molecular weight

cross placenta

1/6 of exposed pregnancies: abnormalliveborn neonate

1/6: abortion or stillbirth


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Anticoagulants

warfarin embryopathy

expose between 6 - 9 week

nasal and midface hypoplasia

stippled vertebral and femoral epiphyses Inhibit coagulation proteins osteocalcins

dose dependent: >5 mg/d

phenocopy : chondrodysplasia punctata

genetic diseases

defects in osteocalcin


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Anticoagulants


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Anticoagulants

fetopathy second and third trimester

disharmonic growth from hemorrhage anddeformation from scarring

dorsal midline CNS dysplasia; agenesis of thecorpus callosum, Dandy-Walker malformation

midline cerebellar atrophy

ventral midline dysplasia; microphthalmia, opticatrophy, and blindness

developmental delay / mental retardation


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ACE inhibitors

ACE inhibitor fetopathy

renal papillary and tubular atrophy

impair urinary concentrating ability

prolong fetal hypotension and hypoperfusion renal ischemia, renal tubular dysgenesis,

anuria

Oligohydramnios; pulmonary hypoplasia, limb

contractures Reduced perfusion; growth restriction, limb

shortening, and maldevelopment of calvarium


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Retinoid

Vitamin A

Beta-carotene; precursor of provitamin A

Retinol; preform vitamin A

vitamin A supplements may be safeduring pregnancy

recommend 5000 IU/ day


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Retinoid

Isotretinoin

13-cis-retinoic acid

effective for treatment of cystic acne

26-fold increased malformation rate

1/3 spontaneous aborted

1/3 neonate with major malformation

serum half-life = 12 hours


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Retinoid

Isotretinoin

bilat microtia/anotia, often asymmetrical

Agenesis/stenoses of external ear canal

cleft palate

maldevelopment of facial bones and cranium

conotruncal or outflow tract defects

hydrocephalus

Thymus; aplasia, hypoplasia, or malposition


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Retinoid

Isotretinoin


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Retinoid

Etretinate treat psoriasis

anomalies similar to isotretinoin

half-life 120 days

women plan future childbearing shouldnot use etretinate

If etretinate is used, suggest wait atleast 2 years


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Retinoid

Tretinoinall-trans-retinoic acid

Gel; treat acne vulgaris

Oral; antineoplastic therapy for acutepromyelocytic leukemia

topical tretinoin not increase anomalies


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Hormones

external genitalia: bipotential for first 9 wks

9 - 14 wks testis secrete androgen anddevelops male perineal phenotype

female phenotype complete by 20 wks

Exposure to exogenous sex hormones before 7 completed wks no effect on external

structures

7 - 12 wks female genital tissue fullmasculinization

13 - 20 wks partial masculinization or genitalambiguity


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Hormones

Androgens: masculinizing female externalgenitalia

Testosterones & anabolic steroid: varying

degrees of virilization

progesterone: DMPA; no congenital defects

Danazol: clitorimegaly, fused labia, andurogenital sinus malformation

Estrogen: most not affect fetal development


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1940 1971 use DES to "support"

high-risk pregnancies

vaginal clear-cell adenocarcinoma

cancer risk increase to 1 per 1000

not dose related

excess cervical eversion (ectropion)

ectopic vaginal glandular epithelium(adenosis)


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1/4 exposed females: cervix or vaginaabnormalities

uterine cavity: hypoplastic, T-shaped

cervical collars, hoods, septa, and coxcombs withered fallopian tubes

Exposed men normal sexual function and fertility

increased risk for epididymal cysts,microphallus, cryptorchidism, and testicularhypoplasia


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Antineoplastic agent

Cyclophosphamide

cell death and DNA alterations

Missing/hypoplastic digits on hands and

feet

cleft palate

single coronary artery

imperforate anus fetal growth restriction with microcephaly


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Antineoplastic agent

Methotrexate and Aminopterinalter folic acid metabolism

growth restriction

failure of calvarial ossification craniosynostosis

hypoplastic supraorbital ridges

small posteriorly rotated earsMicrognathia

severe limb abnormalities


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Thalidomide

1956 - 1960 anxiolytic and sedative drug

Treat; erythema nodosum leprosumcutaneous lupus erythematosus, chronic

graft-versus-host disease, prurigo nodularis,and malignancies

recommend reproductive-aged womentaking thalidomide use 2 highly effective

forms of birth control

20% exposedfetusproduce malformations


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Thalidomide

Defects to structures from mesodermallayer limbs, ears, cardiovascular system, and bowel

relationship between timing of expose andtype of defect

27 - 30 daysupper limb phocomelia

30 - 33 days lower limb phocomelia

42 - 43 daysgallbladder aplasia

40 - 47 daysduodenal atresia


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Tobacco

nicotine, cotinine, cyanide,thiocyanate, carbon monoxide,cadmium, lead, and hydrocarbons

doubles risk of low birthweight

increase incidence of subfertility,spontaneous abortion, placenta

previa and abruption, and pretermdelivery


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Tobacco

twice risk of combine cleft lip & palate

4 - 7 times risk for cleft palate alone

hydrocephaly, microcephaly

omphalocele, gastroschisis hand abnormalities

use with vasoconstrictive drugs:fourfold risk of gastroschisis and smallintestinal atresia


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Cocaine

vasoconstrictive and hypertensive effects

Maternal complications

myocardial infarction

arrhythmias

aortic rupture

stroke

seizure

bowel ischemia sudden death

fourfold risk of placental abruption


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Cocaine

cocaine-related congenital anomalies

skull defects, microcephaly

cutis aplasia

porencephaly

subependymal and periventricular cysts

ileal atresia

cardiac anomalies

visceral infarcts

fourfold risk of urinary tract defects

behavioral abnormalities, cognitive defects anddevelopmental delay

Drugs commonly used in


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Drugs commonly used inpregnancy

Analgesic

aspirin: not increase risk of anomalies

Acetaminophen: not increase risk of anomalies

NSAIDs indomethacin

constriction fetal ductus arteriosus andsubsequent pulmonary hypertension

decrease fetal urine output and reduceamnionic fluid

reversible if discontinue after 34 weeks

Drugs commonly used in


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Drugs commonly used inpregnancy

Analgesic Narcotic

meperidine, morphine, codeine,propoxyphene, oxycodone, and hydrocodone

not associate with congenital anomalies chronic maternal ingestion: neonatal

withdrawal syndrome 20 % expose fetus: sinusoidal FHR pattern

Migraine

Ergotamine, Sumatriptan vasoconstriction

not increase anomalies Third-trimester ergotamineuse: fetal

bradycardia


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Anesthetic agents

General anesthesiaAll cross placenta to some degree

None is teratogen

Local anesthesia

not associate with fetal malformations

fetal bradycardia from diastolic affect

hyperthermia from maternal malignanthyperthermia


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Anticoagulant

Warfarin/coumarin derivatives causeembryo-fetal defects

heparin is anticoagulant of choice

low-molecular-weight heparins; enoxaparin

not cross placenta

not associated with fetal malformations

cause maternal osteopenia

thrombolytic agents Urokinase, streptokinase, tissue plasminogen

activator (t-PA)

no teratogenic risk


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Antihypertensive

Methyldopa

most widely used

Safe

Hydralazine

no adverse fetal effects

sodium nitroprusside

cross placentaTheoretical: accumulation of cyanide in

fetal liver

A tih t i


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Antihypertensive

Beta-Adrenergic antagonistspropranolol, labetalol, atenolol,

metoprolol, nadolol, and timolol

FGR and neonatal hypoglycemia

not link to fetal anomalies

Calcium-Channel BlockersVerapamil:

hypertrophic cardiomyopathyuse with digoxin:fetal cardiac depressionand arrest

Nifedipine: no adverse fetal effects


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Antihypertensive

DiureticsThiazide

not associate with congenital anomalies

associate with neonatal thrombocytopenia,

bleeding, and electrolyte disturbance

Acetazolamide: not ass with anomalies

Spironolactone: not ass with anomalies

furosemide

cross placenta and increase fetal urineproduction

increase patent ductus arteriosus in preterm


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Antibacterial agents

Penicillin: probably safest

Cephalosporin: no adverse embryo-fetal effects

Macrolide:

Erythromycin penicillin-allergic patients

not cause fetal anomalies

not use to treat maternal syphilis

Azithromycin: no fetal anomalies


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Tetracycline doxycycline and minocycline

yellow-brown discoloration of deciduous teeth

deposit in fetal long bones

maternal syphilis in penicillin-allergic woman

Aminoglycosides gentamicin, streptomycin

nephrotoxicity and ototoxicity in pretermnewbornsand adults

prenatal exposure congenital defects notconfirm


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Sulfonamide displace bilirubin from protein binding sites

hyperbilirubinemia in preterm neonate

vancomycin

maternal nephrotoxicity and ototoxicity

not associate with congenital defects

Aztreonam: not teratogenic Imipenem: not teratogenic


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Chloramphenicol notincreasecongenital anomalies

large doses in preterm neonate graybaby syndrome

cyanosis, vascular collapse, and death

Quinolones ciprofloxacin, norfloxacin, ofloxacin, and

enoxacin

irreversible arthropathy and cartilage erosionin dogs, mice, and rats

except for treatment multiresistant infections


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Antimicrobials

tuberculostatic drugs rifampicin, isoniazid and ethambutol

not increase congenital anomalies

Antifungal Agents

Griseofulvin: possible associate withconjoined twins

Fluconazole and Itraconazole: reports ofskull abnormalities, cleft palate, humeral-radial fusion and arm abnormalities


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Antimicrobials

Antifungal Agents

clotrimazole, miconazole and nystatin:no congenital malformations

Amphotericin B: no congenitalmalformations


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Antiviral agents

thymidine analogue reversetranscriptase inhibitorZidovudine or AZT

not increase anomalies

nucleoside analog reversetranscriptase inhibitors (NRTIs)

Zalcitabine (ddC), didanosine (ddI),

stavudine (d4T), lamivudine (3TC),abacavir and zidovudine



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Antiviral agents

protease inhibitors amprenavir, indinavir, lopinavir, ritonavir,

nelfinavir and saquinavir


purine nucleoside analogues Acyclovir, ganciclovir and valacyclovir


Idoxuridine treat adenovirus, cytomegalovirus, varicella,

and vaccinia viral infections

eye, palate, head and limbs malformations inrodents


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Antiparasitic agents

Metronidazole: no teratogenic

Lindane treatment of pediculosis pubis and scabies

10 % absorb systemically

no fetal effects

Antimalarial

Chloroquine not increase congenital anomalies

Mefloquine safe

Quinine/quinidine no defect at therapeutic doses

Mebendazole: no teratogenic


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Asthmamedications

Epinephrine/terbutaline:no adversefetal effects

Metaproterenol/albuterol: no adverse

fetal effects

Theophylline, Aminophylline:safe

Cromolyn: not increase anomalies

Glucocorticoids no adverse humanfetal effects


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Cardiacmedications

Digoxin: no adverse fetal effects

Quinidine: no fetal abnormalities

b-blockers: not teratogenic

Antiarrhythmic drugdisopyramide, amiodarone,

adenosine, bretylium, diltiazem,

local anesthetics (procainamide,lidocaine and tocainide)

calcium antagonists (nifedipineand verapamil)

No

adverseeffect


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Cardiacmedications

Antiarrhythmic drugAmiodarone

structural similar to thyroxine

10 - 30 % of maternal serum levels

cross placenta

fetal and neonatal hypothyroidism


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HormonesOral contraceptives: not associate with

congenital anomaliesGonadotropin-releasing hormone (GnRH)

agonists: limit data

Immunosuppressive agentsAzathioprine

not teratogenic

increase growth restriction, immunesuppression and pancytopenia

Cyclosporinematernal nephrotoxicity

safe for fetus


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P h i d


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apical displacement ofseptal and posteriortricuspid valve leaflets

Psychotropic drugs

Lithium salts

treat manic-depression

cardiac defect: Ebstein anomaly

toxic fetal effects:

diabetes insipidus,hypothyroidism and hypoglycemia

avoid lithium exposure at least 6 - 8 wks'gestation

MAO inhibitors Isocarboxazid, Phenelzine,Tranylcypromine

Class C


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Iodide

cross placenta may produce large fetal goiter

Antiemetics

Vitamin B6 (pyridoxine): no teratogenicity

Dimenhydrinate:no teratogenicity

Ondansetron: not evaluated for teratogenicity

Acid-Suppressing Drugs

cimetidine, ranitidine, omeprazole no teratogenicity


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Disease treatment in the pregnant

patient should be similar to thatgiven to other patients.

Rather than using the FDA Drug

Classification System, references andinformation in databases should besought for particular medications in

specific clinical situations.


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Most drugs are safe to use during

pregnancy, including most antibioticsand medications to treat commonconditions

Most antibiotics are safe inpregnancy. Tetracyclines cause toothdiscoloration in the second and third

trimesters. A few medications are known

teratogens


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Most drugs are safe during lactation

because the amounts in breast milkare subtherapeutic, ~1% - 2% of thematernal dose. Exception is lithium

Drugs Contraindicate during


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Drugs Contraindicate duringBreast-Feeding

Cytotoxic Agents

Cyclosporine, doxorubicin, cyclophosphamide

immune suppression

Bromocriptine inhibit lactation

Ergotamine

vomiting, diarrhea and convulsions in infant

Lithium

1/3 1/2 therapeutic blood concentration in infant

hypotonia and lethargy

Radioactive Compounds RequireT C ti f B t


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Temporary Cessation of Breast-Feeding

no radioactivity is detectable in milk

67 Ga, 2 weeks

131 I, 5 days

radioactive sodium, 4 days

99 Tc, 24 hours

T ti f b t


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Temporary cessation of breast-feeding 12 - 24 hours after a single

dose of metronidazole Side effect possible

monitor baby drowsiness: psychiatric

drug & anticonvulsantMonitor baby jaundice:sulfonamides,

dapsone, bactrim, fansidar

Drug may inhibit lactationEstrogen, estrogen containing

contraception, thiazide diuratic

Minimizing risk from


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Minimizing risk frommaternal medication

General considerationAvoid drug therapy when possible

Use tropical therapy when possible

Drug that safe for use directly in infant,generally safe fore breast fedding mother

Drug safe in pregnancy not always safe inbreast-feeding

Use reliable reference for information onmedication



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Medication selection

Choose shortest hafelife & highestprotein-binding ability

Choose that are well-study in infant

Choose poorest oral absorption

Choose lowest lipid solubility



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Medication doseing

Single daily-dose just before fetallongest sleep interval

Breast-feeding immediately beforemedication dose when multiple dailydose are needed


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3-2drugs in pregnancy

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