TERATOLOGY, TERATOGENS AND FETOTOXIC AGENTS

2-3% of all newborns have major congenital anomaly detectable at birth

All women have an approximate 3% chance of having an infant with birth defect

3% diagnosed by age 5

8-10% by age 18 have one or more apparent functional or developmental abnormalities

<1% of all birth defects are caused by medications

70% of birth defects do not have obvious etiology, identified cause, far more likely to be genetic than teratogenic

Teratology Study of birth defects and their etiology

Teratogen A drug or other chemical substance, a physical or environmental factor such as heat or radiation,

a maternal metabolite such as phenylketonuria or diabetes, a genetic abnormality or an infection

Teratogen – causes structural abnormalities Hadegen – agent that interferes with normal maturation and function of an organ Trophogen – agent that alters growth How do they affect? Disturb specific physiological processes which in turn lead to abnormal cellular differentiation,

altered tissue growth or cell death Different teratogens may disturb similar processes that may produce similar phenotypic

abnormalities Even the most potent teratogen induces birth defects in only a fraction of exposed embryos The reason why some infants are affected and others are not remains largely unknown

FDA CATEGORIES FOR DRUGS AND MEDICATIONS

Drug Category Description Example

A (-) pregnant women Levothyroxine, K+ supplement, prenatal vitamins

B (-) animals or (+) animals but (-) well controlled pregnant

women

Penicillins, cephalosporins, macrolides

C Teratogenic in animals, or no studies available Albuterol, Zidovudine, Ca++ channel blockers

D Causes fetal harm Corticosteroids, azathioprine, carbamazepine, lithium

X Contraindicated in pregnant women Rubella Vaccine

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Gee, 2014 FDA New System for Labeling Drugs

1. A fetal risk summary 2. A section on clinical considerations 3. Section on prescribing decisions for pregnant and lactating women 4. Detailed discussion of human and animal data

TERATOGENS 1. Alcohol Fetal Alcohol Syndrome Dysmorphic features: small palpebral fissures, thin vermilion

border, and smooth philtrum Prenatal and/or postnatal growth impairment CNS abnormalities: head size <10

th percentile, significant brain

abnormality on imaging, neurological and functional 2. Anticonvulsants Orofacial clefts, cardiac malformation and neural tube defects 3% risk major malformation in pregnancies treated with single anticonvulsant 4% risk for major malformation in pregnancies untreated

3. Angiotensin-Converting Enzyme Inhibitors (ACEI’s) and Angiotensin-Receptor Blocking Agents

(ARB’s)

Fetal hypotension and renal hypoperfusion with subsequent ischemia and anuria Cardiac and CNS abnormalities

4. Antifungal Medications Oral clefts, abnormal fascies, cardiac, skull, long bone and joint abnormalities 400-800 mg/day

5. Anti-inflammatories NSAIDs (ASA, Ibuprofen, and Indomethacin) Constriction of the fetal ductus arteriosus Reduced amniotic fluid volume

6. Leflunomide Hydrocephalus, eye anomalies, skeletal abnormalities and embryo death

7. Antimicrobials

a. Nitrofurantoin Hypoplastic left heart syndrome, microphthalmia/anophthalmia, clefts, ASDs

b. Sulfonamides Anencephaly, left ventricular outflow tract obstruction, choanal atresia, diaphragmatic hernia

8. Antineoplastics a. Cyclophosphamide

Pregnancy loss, skeletal abnormalities, limb defects, cleft palate, eye abnormalities b. Methotrexate

Craniosynostosis with cover leaf skull, wide nasal bridge, low set ears, micrognathia, limb abnormalities

c. Tamoxifen DES-like syndrome

d. Trastuzumab Oligohydramnios, anhydramnios, fetal renal failure, pulmonary hypoplasia, skeletal

abnormalities, and neonatal death

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9. Antiviral Agents a. Ribavirin

Skull, palate, eye, skeleton and GI abnormalities

b. Efavirenz CNS abnormality

10. Sex Hormones a. Testosterone and anabolic steroids

Labioscrotal fusion, and phallic enlargement

b. Danazol Clitoromegaly, fused labia and urogenital sinus malformation

DERMATOLOGICAL DISORDERS

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