Drugs in Pregnancy

major malformations in general population 2 - 3 % 10 % of congenital abnormalities caused by teratogens

Teratogen
acts during embryonic / fetal development permanent alteration of form / function chemicals, viruses, environmental agents, physical factors, and drugs

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 - 8 week following conception organogenesis critical periods of sensitivity structural malformations

2. Embryonic period

Developmental Period
3. Fetal period
9 weeks - term Maturation and functional development

Food and Drug Administration Categories for Drugs and Medications

Category A
Category B

Controlled studies in human: no fetal risk

Animal studies no fetal risks, but no human studies; or adverse effects in animals, but not in well-controlled human studies no adequate studies, either animal or human, or adverse fetal effects in animal studies but no available human data.

Category C

Category D evidence of fetal risk, but benefits are thought to outweigh these risks Category X Proven fetal risks clearly outweigh any benefits

mechanisms of teratogenesis
disruption of folic acid metabolism
essential for normal meiosis and mitosis
neural-tube defects, cardiac defects, cleft lip and palate antiseizure : impair folate absorption or act as antagonists

mechanisms of teratogenesis
toxic oxidative intermediates
antiseizure : metabolized by microsomes to arene oxides or epoxides
free oxide radicals have carcinogenic, mutagenic and other toxic effects detoxified by cytoplasmic epoxide hydrolase fetal epoxide hydrolase activity is weak

Counseling for teratogen exposure

All women have ~ 3% chance of having a neonate with birth defect exposure to confirmed teratogen may increase risk, by only 1 - 2% or at most double or triple risk versus benefit

Drugs or Substances Suspected or Proven 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

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

Ethyl alcohol
Clinical Characteristics
congenital heart and joint defects failure to thrive persistent irritability Delay growth & development poor coordination
Comorbid: mental retardation, attention deficit/hyperactivity disorder, cerebral palsy and epilepsy

Ethyl alcohol
highest risk: chronic ingest large quantities fetal injury can result from 1-2 drink/d alcohol 0.5 ounce/day: no alcoholrelated effects increase risk of pregnancy complications

anticonvulsants
Women with epilepsy increase risk of fetal malformations most frequent defects: orofacial clefts and cardiac malformations Clefts 10 times more frequently than general population

more prevalent: high serum concentration and polytherapy

anticonvulsants
fetal hydantoin syndrome
microcephaly growth deficiency developmental delays mental retardation dysmorphic craniofacial features fingernail hypoplasia cardiac defect facial clefts

anticonvulsants
Drug
Phenytoin Carbamazepine Valproate Trimethadione, paramethadione

Teratogenesis
Fetal hydantoin syndrome Fetal hydantoin syndrome; spina bifida Neural-tube defects Craniofacial anomalies, including cleft palate, V-shape eyebrows, microcephaly, growth deficiency, mental retardation, speech disturbance, cardiac defects

Affected
5-11% 1-2% 1-2% 70%

anticonvulsants
Drug Phenobarbital Lamotrigine Teratogenesis Clefts, cardiac anomalies, urinary tract malformations Theoreticallowers fetal folate levels by inhibiting dihydrofolate reductase Theoreticalhas produced defects or abnormal pregnancy outcomes in all animals tested, even at low or therapeutic doses Affected 10-20%

Topiramate

Anticoagulants
Warfarin (Coumadin)
low molecular weight cross placenta
1/6 of exposed pregnancies: abnormal liveborn neonate 1/6: abortion or stillbirth

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

Anticoagulants

Anticoagulants
fetopathy
second and third trimester disharmonic growth from hemorrhage and deformation from scarring dorsal midline CNS dysplasia; agenesis of the corpus callosum, Dandy-Walker malformation midline cerebellar atrophy ventral midline dysplasia; microphthalmia, optic atrophy, and blindness developmental delay / mental retardation

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

Retinoid
Vitamin A
Beta-carotene; precursor of provitamin A Retinol; preform vitamin A
vitamin A supplements may be safe during pregnancy recommend 5000 IU/ day

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

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

Retinoid
Isotretinoin

Retinoid
Etretinate
treat psoriasis anomalies similar to isotretinoin half-life 120 days
women plan future childbearing should not use etretinate If etretinate is used, suggest wait at least 2 years

Retinoid
Tretinoin
all-trans-retinoic acid Gel; treat acne vulgaris
Oral; antineoplastic therapy for acute promyelocytic leukemia topical tretinoin not increase anomalies

Hormones
external genitalia: bipotential for first 9 wks 9 - 14 wks testis secrete androgen and develops 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 full masculinization 13 - 20 wks partial masculinization or genital ambiguity

Hormones
Androgens: masculinizing female external genitalia Testosterones & anabolic steroid: varying degrees of virilization progesterone: DMPA; no congenital defects Danazol: clitorimegaly, fused labia, and urogenital sinus malformation Estrogen: most not affect fetal development

Diethylstilbestrol (DES)
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)

Diethylstilbestrol (DES)
1/4 exposed females: cervix or vagina abnormalities
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 testicular hypoplasia

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

Antineoplastic agent
Methotrexate and Aminopterin
alter folic acid metabolism growth restriction failure of calvarial ossification craniosynostosis hypoplastic supraorbital ridges small posteriorly rotated ears Micrognathia severe limb abnormalities

Thalidomide
1956 - 1960 anxiolytic and sedative drug Treat; erythema nodosum leprosum cutaneous lupus erythematosus, chronic graft-versus-host disease, prurigo nodularis, and malignancies recommend reproductive-aged women taking thalidomide use 2 highly effective forms of birth control 20% exposed fetus produce malformations

Thalidomide
Defects to structures from mesodermal layer
limbs, ears, cardiovascular system, and bowel

relationship between timing of expose and type of defect

27 30 42 40 30 33 43 47 days upper limb phocomelia days lower limb phocomelia days gallbladder aplasia days duodenal atresia

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 preterm delivery

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 small intestinal atresia

Cocaine
vasoconstrictive and hypertensive effects
Maternal complications
myocardial infarction arrhythmias aortic rupture stroke seizure bowel ischemia sudden death

fourfold risk of placental abruption

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 and developmental delay

Drugs commonly used in pregnancy

Analgesic
aspirin: not increase risk of anomalies Acetaminophen: not increase risk of anomalies NSAIDs indomethacin constriction fetal ductus arteriosus and subsequent pulmonary hypertension decrease fetal urine output and reduce amnionic fluid reversible if discontinue after 34 weeks

Drugs commonly used in pregnancy

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 ergotamine use: fetal bradycardia

Anesthetic agents
General anesthesia
All cross placenta to some degree None is teratogen

Local anesthesia
not associate with fetal malformations fetal bradycardia from diastolic affect hyperthermia from maternal malignant hyperthermia

Anticoagulant
Warfarin/coumarin derivatives cause embryo-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

Antihypertensive
Methyldopa
most widely used Safe

Hydralazine
no adverse fetal effects

sodium nitroprusside
cross placenta Theoretical: accumulation of cyanide in fetal liver

Antihypertensive
Beta-Adrenergic antagonists
propranolol, labetalol, atenolol, metoprolol, nadolol, and timolol FGR and neonatal hypoglycemia not link to fetal anomalies

Calcium-Channel Blockers
Verapamil:
hypertrophic cardiomyopathy use with digoxin: fetal cardiac depression and arrest

Nifedipine: no adverse fetal effects

Antihypertensive
Diuretics
Thiazide
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 urine production increase patent ductus arteriosus in preterm

Antibacterial agents
Penicillin: probably safest Cephalosporin: no adverse embryofetal effects Macrolide:
Erythromycin
penicillin-allergic patients not cause fetal anomalies not use to treat maternal syphilis

Azithromycin: no fetal anomalies

Antibacterial agents
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 preterm newborns and adults prenatal exposure congenital defects not confirm

Antibacterial agents
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

Antibacterial agents
Chloramphenicol
not increase congenital anomalies large doses in preterm neonate gray baby syndrome cyanosis, vascular collapse, and death

Quinolones
ciprofloxacin, norfloxacin, ofloxacin, and enoxacin irreversible arthropathy and cartilage erosion in dogs, mice, and rats except for treatment multiresistant infections

Antimicrobials
tuberculostatic drugs
rifampicin, isoniazid and ethambutol
not increase congenital anomalies

Antifungal Agents
Griseofulvin: possible associate with conjoined twins Fluconazole and Itraconazole: reports of skull abnormalities, cleft palate, humeralradial fusion and arm abnormalities

Antimicrobials
Antifungal Agents
clotrimazole, miconazole and nystatin: no congenital malformations Amphotericin B: no congenital malformations

Antiviral agents
thymidine analogue reverse transcriptase inhibitor
Zidovudine or AZT not increase anomalies

nucleoside analog reverse transcriptase inhibitors (NRTIs)

Zalcitabine (ddC), didanosine (ddI), stavudine (d4T), lamivudine (3TC), abacavir and zidovudine not increase anomalies

Antiviral agents
protease inhibitors
amprenavir, indinavir, lopinavir, ritonavir, nelfinavir and saquinavir not increase anomalies

purine nucleoside analogues

Acyclovir, ganciclovir and valacyclovir not increase anomalies

Idoxuridine
treat adenovirus, cytomegalovirus, varicella, and vaccinia viral infections eye, palate, head and limbs malformations in rodents

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

Asthma medications
Epinephrine/terbutaline: no adverse fetal effects Metaproterenol/albuterol: no adverse fetal effects Theophylline, Aminophylline: safe Cromolyn: not increase anomalies Glucocorticoids no adverse human fetal effects

Cardiac medications
Digoxin: no adverse fetal effects Quinidine: no fetal abnormalities b-blockers: not teratogenic Antiarrhythmic drug
disopyramide, amiodarone, adenosine, bretylium, diltiazem, local anesthetics (procainamide, lidocaine and tocainide) calcium antagonists (nifedipine and verapamil) No adverse effect

Cardiac medications
Antiarrhythmic drug
Amiodarone structural similar to thyroxine 10 - 30 % of maternal serum levels cross placenta fetal and neonatal hypothyroidism

 Hormones
Oral contraceptives: not associate with congenital anomalies Gonadotropin-releasing hormone (GnRH) agonists: limit data

Immunosuppressive agents
Azathioprine
not teratogenic increase growth restriction, immune suppression and pancytopenia

Cyclosporine
maternal nephrotoxicity safe for fetus

Psychotropic drugs
Benzodiazepines
Diazepam
cleft palate, limb malformations in rodents not associate fetal anomalies

lorazepam and midazolam

no birth defects long-term maternal use neonatal depression, somnolence and withdrawal symptoms

Alprazolam
not increase anomalies

Psychotropic drugs
apical displacement of Lithium salts septal and posterior treat manic-depression tricuspid valve leaflets
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

Psychotropic drugs
selective serotonin reuptake inhibitors (SSRIs)
Fluoxetine, Paroxetine, Sertraline not cause birth defects

Tricyclic antidepressants
Amitriptyline, Amoxapine, Clomipramine, Desipramine, Doxepin, Imipramine, Nortriptyline not increase anomalies

 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

 Disease treatment in the pregnant patient should be similar to that given to other patients. Rather than using the FDA Drug Classification System, references and information in databases should be sought for particular medications in specific clinical situations.

 Most drugs are safe to use during pregnancy, including most antibiotics and medications to treat common conditions Most antibiotics are safe in pregnancy. Tetracyclines cause tooth discoloration in the second and third trimesters. A few medications are known teratogens

 Most drugs are safe during lactation because the amounts in breast milk are subtherapeutic, ~1% - 2% of the maternal dose. Exception is lithium

Drugs Contraindicate during Breast-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 Require Temporary Cessation of BreastFeeding no radioactivity is detectable in milk

67 Ga, 2 weeks
131 I, 5 days radioactive sodium, 4 days 99 Tc, 24 hours

 Temporary cessation of breastfeeding 12 - 24 hours after a single dose of metronidazole Side effect possible
monitor baby drowsiness: psychiatric drug & anticonvulsant Monitor baby jaundice:sulfonamides, dapsone, bactrim, fansidar

Drug may inhibit lactation

Estrogen, estrogen containing contraception, thiazide diuratic

Minimizing risk from maternal medication

General consideration
Avoid 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 in breast-feeding Use reliable reference for information on medication

Minimizing risk from maternal medication

Medication selection
Choose shortest hafelife & highest protein-binding ability Choose that are well-study in infant Choose poorest oral absorption Choose lowest lipid solubility

Minimizing risk from maternal medication

Medication doseing
Single daily-dose just before fetal longest sleep interval Breast-feeding immediately before medication dose when multiple daily dose are needed