Teratogens

Front 1

Fetal Alcohol Syndrome

Back 1

The classic triad of FAS involves a pattern of growth
deficiency, CNS involvement and facial dysmorphology.
Prenatal and postnatal growth deficiency (97%)
 Microcephaly (93%)
 Developmental delay (average IQ = 63) (90%)
 Fine motor dysfunction (98%)
 Short palpebral fissures (92%)
 Long smooth philtrum, thin vermillion border (94%)
 Cardiac defects (50%)
 Mild to severe joint contractures (49%)

Front 2

Cigarette Smoking

Back 2

Children born to women who smoke cigarettes during pregnancy may have an increased incidence of structural defects, and smoking in pregnancy does appear to affect fetal growth.
Pattern of Malformations:
 Decrease in birth weight of 170 to 250g
 Decreased birth length (average = 49cm)
 Cleft palate,craniosynostosis, club foot
Effects on IQ are unknown
 Long-term behavioral effects?

Front 3

Heroin

Back 3

40-50% increased incidence of pregnancy
complications
 Strabismus
 Low birth weight, SGA, small head size,
respiratory distress, jaundice
 40-94% neonatal withdrawal
 Increase risk for SIDS
 No decrease in IQ

Front 4

Methadone

Back 4

Strabismus
 Adverse effects on fetal growth
 Increased risk for developmental,
neurological and behavioral problems
 ↑ stillbirth, premature birth, neonatal death,
decreased fetal movement, SIDS, jaundice
 Neonatal withdrawal

Front 5

Buprenorphine

Back 5

Buprenex®, Subtex®
 Does not significantly increase risk for birth
defects
 60% neonatal withdrawal

Front 6

Naloxone

Back 6

 Narcan®
 Suboxone® (naloxone and buprenorphine)
 No human data (first trimester), but animal
data reassuring
 Neonatal withdrawal possible

Front 7

Naltrexone

Back 7

Revia®, Trexan®
 Limited human data, does not significantly
increase risk for birth defects
 Theoretical risk for behavioral
abnormalities

Front 8

Cocaine

Back 8

Initial concern was raised in 1985
 Confounding variables:
 Poly-drug exposure
 Postnatal factors associated with living in the
home of a parent addicted to cocaine
Prematurity
 Intrauterine growth retardation
 Developmental- behavior problems
 Intracranial hemorrhage
 Nonduodenal intestinal atresia – infarction
 Limb reduction defects
 Urinary tract anomalies

Front 9

Toluene

Back 9

 Toluene is an aromatic hydrocarbon found in some
spray paints, glues and lacquers. It is inhaled to cause
acute intoxication
 Pattern of Malformations:
 Microcephaly
 Mental retardation
 Growth deficiency
 Craniofacial anomalies similar to those seen in FAS

Front 10

Occupational Exposure to
Solvents (in general)

Back 10

 Spectrum of Effects:
 Spontaneous abortion
 Neural tube defects
 Association is controversial

Front 11

Prescription Drugs with Known
Teratogenic Effects

Back 11

 Aminopterin
 ACE Inhibitors
 Anticonvulsants
 Danazole
 DES
 Fluconazole
 Lithium
 Methimazole
 Misoprostol
 Penicillamine
 Retinoids
 Streptomycin
 Tetracycline
 Thalidomide
 Warfarin

Front 12

Thalidomide

Back 12

Thalidomide is a sedative-- initially used in
Europe to treat hyperemesis and pregnancy-related
nausea
 New uses:
 Type 2 leprosy reactions
 AIDS-associated otopharyngeal and esophageal ulcers
 chronic graft-versus-host disease
 Behcet’s syndrome
 Discoid lupus erythematosis.
Pattern of Malformations:
 Phocomelia (usually of upper limbs)
 Amelia (10%)
 Facial hemangioma
 Esophageal and duodenal atresias
 Defects of the heart
 Renal and genitourinary anomalies
 Anomalies of eyes and external ears
 Oral clefts
Critical Period:
 34-50 days post-LMP
 Prevalence:
 Approximately 20% of women exposed during
the critical period give birth to affected infants.

Front 13

Retinoids
(Vitamin A derivatives)

Back 13

 Examples of retinoids:
 isotretinoin
 etretinate
 tretinoin
 dietary vitamin A
 Vitamin A has both a retinoid and beta-carotene
form.

Front 14

Isotretinoin (Accutane)

Back 14

 Pattern of Malformations:
 CNS anomalies
 Ear anomalies
 Cardiovascular defects
 Thymus anomalies
 Intellectual Deficiency
Critical period:
 15th day following conception through the end of the
first trimester of pregnancy.
 Accutane half-life is approximately 16-20 hours (out of
body < 1 week).
Prevalence:
 Approximately 30-35% for babies born to women who are exposed to drug during the critical period. There is also a significantly increased risk for miscarriage after exposure.

Front 15

Etretinate

Back 15

Etretinate is an orally active synthetic retinoid.
 A pattern of malformations similar to that seen
with isotretinoin has been reported.
 Etretinate is stored in adipose tissue and is
released into the circulation over a prolonged
period. The biological half life is 100 days,
meaning that the drug can be detected in the body
for 2-3 years.

Front 16

Tretinoin (Retin A)

Back 16

Theoretical risk because tretinoin is related
to isotretinoin
 Tretinoin is generally administered topically
 Risk is likely to be low

Front 17

Dietary Vitamin A

Back 17

Preformed vitamin A (vitamin supplement)
is metabolized to retinoids and retinoid
metabolites.
 Teratogenic at high concentrations.
 ß-carotene is a provitamin A compound
provided by vegetables. It is not
teratogenic.
Prenatal exposure to vitamin A has been
associated in a number of case reports with
defects of the CNS, urinary tract, face,
palate, heart and ears at daily doses of
25,000 IU to 150,000 IU.
 Threshold for increased risk of structural
defects-- 10,000 IU per day?

Front 18

Anticonvulsants

Back 18

Phenytoin (Hydantoin), trimethadione, valproic
acid, carbamazepine, barbiturates
 The “anticonvulsant embryopathy”
 Effects of medication or underlying maternal
epilepsy?
 Risks may be different when medications are
used to treat other indications
Anticonvulsant Embryopathy
Features:
 Broad depressed nasal bridge
 Short nose with anteverted nares
 Long philtrum
 Maxillary hypoplasia
 Fingernail hypoplasia

Front 19

Lithium

Back 19

 Pattern of Malformations:
 Cardiac defects, particularly Ebstein’s anomaly
 Manufacturer’s registry: significant association
between prenatal lithium use and Ebstein’s anomaly and other cardiac defects
 Prospective study of 148 women who took Lithium: one fetus with Ebstein’s anomaly; no other cardiac defects
 Three case-control studies: no association between lithium and cardiac defects
Critical period:
 1st trimester:
 The anterior cusp of the tricuspid valve is formed very early, while the posterior and medial cusps develop much later in the 1st trimester

Front 20

ACE Inhibitors

Back 20

 ACE = Angiotensin Converting Enzyme
 Anti-hypertensive medications
 ACE inhibitors are the only antihypertensives
associated with structural defects.
 In contrast to most known teratogens, the critical period for ACE inhibitor exposure is the second and third trimester.
Pattern of Malformations:
 IUGR
 Hypocalvaria manifested by very large anterior
fontanel
 Persistent patent ductus arteriosus
 Renal tubular dysplasia leading to oligohydramnios and Potter’s sequence
Mechanism of Action:
 ACE inhibitors reduce uterine blood flow,
leading to decreased placental perfusion and
severe fetal hypotension
 ACE inhibitors block fetal ACE activity,
thereby affecting systemic and renal
hemodynamics in the fetus

Front 21

Tetracycline + derivatives
(minocycline, doxycycline)

Back 21

 Pattern of Malformations:
 Increased risk for defects of primary teeth
 Critical Period:
 Beyond the 4th month of pregnancy
 Mechanism:
 Tetracycline binds to calcium, which is integral
in bone/teeth formation

Front 22

Influenza Viruses

Back 22

 3 types: A, B and C – only A and B cause human
disease
 Type A and B seasonal flu; only type A have caused pandemics
 Type A : neuraminidase (N) and hemagglutinin (H)
 Subtle changes: annually
 Major changes: mutation or re-assortment of animal and
human viruses
Maternal Risks:
 Shift from cell-mediated toward humoral immunity
(greater susceptibility to viral infections)
 Mechanical forces lead to↑ heart rate, stroke volume,
oxygen consumption and enlarged uterus can ↓lung
capacity
 Fever
 Antiviral medications
 Other existing illnesses
 Viremia and placental transfer rare with known
viruses
 Increased rates of pregnancy loss and preterm
birth
 ? Increase in birth defects, esp. CNS

Front 23

Antiviral Medications

Back 23

 Pregnancy
 Animal data - majority no increased maternal or fetal
risks
 Oseltamivir – Approximately 300 cases, no
adverse pregnancy outcome
 Zanamivir – 4 exposed pregnancies
 Oseltamivir is currently recommended due to
concerns about bioavailability of zanamivir,
especially with significant respiratory infection
 Most effective within 48 hours of symptoms
 Pregnant women may be reluctant to treat
symptoms
Breastfeeding
 amount in breast milk is estimated to be less
than that used for chemoprophylaxis in children

Front 24

Radiation

Back 24

Diagnostic x-ray < 5 rads: not believed to
be teratogenic
 5-10 rads: potential for concern
 Serious risk to the fetus occurs when the
absorbed dose is 10 rads or more.
 Pattern of malformations:
 Microcephaly
 Mental retardation
 Other central nervous system effects, such as seizures
 Growth retardation
 Minor anomalies of the eyes in offspring
 Controversial increase in carcinogenesis
Critical Periods:
Mental retardation-- 8-15 weeks
Microcephaly-- 4-17 weeks
 However, neurologic development occurs
throughout pregnancy.

Front 25

Lead

Back 25

Pattern of Malformations:
 No increased risk for structural malformations has been
associated with high dose lead exposure during
pregnancy
 Inconsistent data regarding intrauterine growth
deficiency or length of gestation
 Greatest concern is for neurobehavioral development