This document discusses the teratogenic risks of various medications. It describes how alcohol consumption can cause fetal alcohol syndrome and spectrum disorders. Certain anticonvulsants, antifungals, antihypertensives, NSAIDs, chemotherapy agents, antivirals and hormones are also described as carrying risks of birth defects if taken during pregnancy. The effects of lithium, SSRIs and antipsychotics on neonates are summarized as well. Throughout, specific malformations and risks associated with different medication classes are outlined.

1. Hale Teka, M.D,
Resident Physician

2. Tuesday, April 3, 2018 Hale T., M.D., Resident Physician 2

3. Tuesday, April 3, 2018 Hale T., M.D., Resident Physician 3

4. Tuesday, April 3, 2018 Hale T., M.D., Resident Physician 4

5. Alcohol
• Alcohol Consumption
̶ The most frequent nongenetic causes
of mental retardation and
preventable birth defects in the United
States
̶ fetal alcohol syndrome
• Spectrum of alcohol-related fetal
defects
̶ Fetal alcohol spectrum disorder
• Full range of prenatal alcohol
damage that may not meet the
criteria for fetal alcohol syndrome
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6. Fetal Alcohol Syndrome
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Fetal Alcohol Spectrum Disorder

7. • Short palpebral fissures,
• Epicanthal folds,
• Flat midface,
• Hypoplastic philtrum, and
• Thin upper vermilion border
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8. • Dose Effect
̶ Fetal vulnerability to alcohol is modified by
• genetic factors,
• nutritional status,
• environmental factors,
• coexisting maternal disease, and
• maternal age
̶ The minimum amount of alcohol required to produce adverse
fetal consequences is unknown
̶ Binge drinking, however, is believed to pose particularly high risk
for alcohol-related birth defects and has also been linked to an
increased risk for stillbirth
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9. Anticonvulsant Medications
• Generally
̶ Pragmatically, no anticonvulsant drugs are considered truly “safe”
in pregnancy
̶ Pregnant mothers taking antiepileptic drugs at 2-3x higher risk of
congenital anomalies
̶ Older antiepileptic agents at higher risk
̶ Newer agents lesser risk
• Valproic Acid
̶ orofacial clefts, cardiac malformations,
and neural-tube defects
̶ In 9% of babies, and 4% have NTDs
̶ Lower IQ at 3 years of age
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10. Fetal hydantoin
syndrome:
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Features include:
• Upturned nose,
• Mild midfacial hypoplasia,
• Long upper lip with thin vermilion border
• Distal digital hypoplasia.
• Several older anticonvulsants produce a constellation of malformations similar to
the fetal hydantoin syndrome

11. Antifungal Medications
• Fluconazole
̶ Only antifungal drug studied to be teratogenic
̶ Category D
̶ But single 150 mg dose to treat vulvovaginal candidiasis does not
apear to be teratogenic
̶ Associated with a pattern of congenital malformations resembling the
autosomal recessive Antley-Bixler syndrome
̶ Abnormalities include
• oral clefts,
• abnormal facies, and
• Cardiac (3 fold increased risk of TOF), skull, long-bone, and
• joint abnormalities
̶ Such findings have been reported only with chronic, high-dose
treatment in the first trimester—at doses of 400 to 800 mg daily
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12. Angiotensin-Converting Enzyme Inhibitors
and Angiotensin-Receptor Blocking Drugs
• ACE-I
̶ Normal renal development depends on the fetal renal-angiotensin
system
̶ Fetotoxic
̶ ACE-inhibitor medication causes fetal hypotension and renal
hypoperfusion, with subsequent ischemia and anuria
̶ Reduced perfusion may cause fetal-growth restriction and calvarium
maldevelopment, whereas oligohydramnios may result in pulmonary
hypoplasia and limb contractures
̶ First-trimester ACE-inhibitor exposure was associated with a two- to
threefold increased risk for cardiac and central nervous system
abnormalities
• ARB
̶ Same mechanisim of action to ACE-I
̶ Considered to be Fetotoxic
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13. Antiinflammatory Agents
• Nonsteroidal Antiinflammatory Drugs
̶ This drug class includes both aspirin and traditional “NSAIDs” such as
ibuprofen and indomethacin
̶ They exert their effects by inhibiting prostaglandin synthesis
1. Aspirin
• Avoid use late in pregnancy
2. Indomethacin
• Constriction of the fetal ductus arteriosus, resulting in pulmonary
hypertension when taken after 30 weeks
• Decrease fetal urine production and thereby reduce amnionic fluid
volume
• This is presumed due to an increase in vasopressin levels and
vasopressin responsivenes
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14. 3. Lefluomide
• This is a pyrimidine-synthesis inhibitor used to treat rheumatoid
arthritis
• Contraindicated in pregnancy
• Related with:
1. Hydrocephalus,
2. Eye anomalies,
3. Skeletal abnormalities, and
4. Embryo death
• Women of childbearing potential who discontinue this
medication should consider cholestyramine treatment/washout,
followed by verification that serum levels are undetectable on
two tests performed 14 days apart
• This is also true for males who considering fatherhood
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15. Antimicrobial Drugs
• Medications used to treat infections are among those most
commonly administered during pregnancy
• With a few exceptions cited below, most of the commonly used
antimicrobial agents are considered safe for the embryo/fetus.
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16. • Aminoglycosides
̶ Preterm infants treated with gentamicin or streptomycin have
developed nephrotoxicity and ototoxicity
̶ Despite theoretical concern for potential fetal toxicity, no
adverse effects have been demonstrated, and no congenital
defects resulting from prenatal exposure have been identified.
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17. • Chloramphenicol
̶ This antimicrobial is not considered teratogenic and is no
longer routinely used in the United States
̶ More than 50 years ago, a constellation of findings termed
the gray baby syndrome was described in neonates who
received the medication
̶ Preterm infants were unable to conjugate and excrete the
drug and manifested abdominal distention, respiratory
abnormalities, an ashen-gray color, and vascular collapse
̶ Chloramphenicol was subsequently avoided in late
pregnancy due to theoretical concerns.
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18. • Nitrofurantoin
̶ Fourfold increased risk for hypoplastic left heart
syndrome and microphthalmia/anophthalmia
and a twofold increased risk for clefts and atrial
septal defects
̶ For postexposure counseling purposes, the
absolute risk of these defects remains quite low
̶ For example, a fourfold increased incidence of
hypoplastic left heart would result in a
prevalence of less than 1 per 1000 exposed
infants
̶ Nitrofurantoin is a proven first-line treatment of
urinary infections
̶ The American College of Obstetricians and
Gynecologists (2013b) has concluded that first-
trimester nitrofurantoin use is appropriate if no
suitable alternatives are available
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19. • Sulfonamides
̶ These drugs are often combined with trimethoprim and used to treat
various infections during pregnancy
̶ One example is treatment of methicillin-resistant Staphylococcus
aureus (MRSA)
̶ Associated with
• 3x increased risk for anencephaly and left ventricular outflow tract
obstruction,
• 8x increased risk for choanal atresia, and
• 2x increased risk for diaphragmatic hernia
̶ There are also theoretical concerns that because sulfonamides
displace bilirubin from protein binding sites, they may worsen
hyperbilirubinemia if given near the time of preterm delivery
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20. • Tetracyclines
̶ These drugs are no longer commonly used in pregnant women
̶ They are associated with yellowish-brown discoloration of
deciduous teeth when used after 25 weeks, although the risk for
subsequent dental caries does not appear increased
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21. Antineoplastic Agents
• Cancer management in pregnancy includes many
chemotherapeutic agents generally considered to be at least
potentially toxic to the embryo, fetus, or both
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22. • Cyclophosphamide
̶ Alkylating agent inflicts a chemical insult on developing fetal tissues
and leads to cell death and heritable DNA alterations in surviving cells
̶ Pregnancy loss is increased, and reported malformations include
• Skeletal abnormalities,
• Limb defects,
• Cleft palate, and
• Eye abnormalities
̶ Surviving infants may have
• Growth abnormalities and
• Developmental delays
̶ Environmental exposure among health-care workers is associated with
an increased risk for spontaneous abortion
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23. • Methotrexate
̶ This folic-acid antagonist is a potent teratogen
̶ It is used for
• Cancer chemotherapy,
• Immunosuppression in conditions such as autoimmune diseases and psoriasis,
• Nonsurgical treatment of ectopic pregnancy, and finally, as an abortifacient
̶ It is similar in action to aminopterin, which is no longer in clinical use, and can
cause defects known collectively as the fetal methotrexateaminopterin
syndrome
̶ This includes
• Craniosynostosis with “clover-leaf” skull,
• Wide nasal bridge,
• Low-set ears,
• Micrognathia, and
• Limb abnormalities
̶ The critical developmental period of these abnormalities is believed to be 8 to
10 weeks, at a dosage of at least 10 mg/week, although this is not universally
accepted
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24. • Tamoxifen (Category D)
̶ This nonsteroidal selective estrogen-receptor modulator (SERM)
̶ Used as an adjuvant to treat breast cancer
̶ Has not been associated with fetal malformations in humans
̶ It is fetotoxic and carcinogenic in rodents, inducing
malformations similar to those caused by diethylstilbestrol (DES)
exposure.
̶ It is recommended that women who become pregnant while
either on therapy or within 2 months of its discontinuation be
apprised of potential long-term risks of a DES-like syndrome
̶ Exposed offspring should be monitored for carcinogenic effects
for up to 20 years
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25. • Trastuzumab
̶ Recombinant monoclonal antibody directed to the human
epidermal growth factor receptor 2 (HER2) protein
̶ It is used to treat breast cancers that over express HER2 protein
̶ Has not been associated with fetal malformations, but cases of
• Oligohydramnios,
• Anhydramnios, and
• Fetal renal failure have been described
̶ Use may result in
• Fetal pulmonary hypoplasia,
• Skeletal abnormalities, and
• Neonatal death
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26. Antiviral Agents
• Ribavirin
̶ Nucleoside analogue
̶ Component of therapy for hepatitis C infection
̶ Reported malformations include skull, palate, eye, skeleton, and
gastrointestinal abnormalities
̶ It is recommended that women use two forms of contraception
while on therapy and delay childbearing for 6 months following
drug discontinuation
• Efavirenz
̶ Nonnucleoside reverse transcriptase inhibitor used to treat HIV
infection
̶ Related with CNS and Occular abnormalities
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27. Sex Hormones
• It is intuitive that exposure of female fetuses to excessive male sex
hormones—and vice versa—might be detrimental.
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28. • Testosterone and Anabolic Steroids
̶ Exposure of a female fetus may cause varying degrees of
virilization
̶ May result in ambiguous genitalia similar to that encountered in
cases of congenital adrenal hyperplasia
̶ Findings may include
• Labioscrotal fusion with first-trimester exposure and
• Phallic enlargement from later fetal exposure
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29. • Danazole
̶ This ethinyl testosterone derivative
has weak androgenic activity
̶ It is used to treat
• Endometriosis,
• Immune thrombocytopenic purpura,
• Migraine headaches,
• Premenstrual syndrome, and
• Fibrocystic breast disease
̶ 40 percent of exposed female fetuses
virilized
̶ A dose-related pattern of clitoromegaly,
fused labia, and urogenital sinus
malformation
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30. • Diethylstilbestrol
̶ Women offsprings may develop
• Vaginal clear-cell adenocarcinoma
• Vaginal and cervical intraepithelial neoplasia
• hypoplastic, T-shaped uterine cavity; cervical collars,
hoods, septa, and coxcombs; and “withered” fallopian
tubes
• Higher rates of earlier menopause and breast cancer
• Men offsprings may develop:
• Epididymal cysts,
• Microphallus,
• Hypospadias,
• Cryptorchidism, and
• Testicular hypoplasia
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31. Immunosuppressant Medications
• Corticosteroids
̶ Increased risk of clefts
• Mycophenolate Mofetil + Mycophenolic Acid
̶ 50% risk of abortion
̶ 1/5th of surviving ➔ Malformed (50% of this have ear
malformations)
• Radioiodine
̶ Irreversible fetal hypothyroidism and
̶ May increase the risk for childhood thyroid cancer
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32. • Lead
̶ Fetal-growth abnormalities
̶ Childhood developmental delay
̶ Behavioral abnormalities
• Mercury
̶ Developmental delay
̶ Microcephaly and
̶ Severe brain damage
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33. Psychiatric Medications
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• Lithium
̶ Ebstein anomaly, a cardiac abnormality characterized by apical
displacement of the tricuspid valve
̶ Neonatal lithium toxicity from exposure near delivery has been well
documented
• Findings typically persist for 1 to 2 weeks and may include
✓Hypothyroidism,
✓Diabetes insipidus,
✓Cardiomegaly,
✓Bradycardia,
✓Electrocardiogram abnormalities,
✓Cyanosis, and
✓Hypotonia

34. • Selective Serotonin- and Norepinephrine-
Reuptake Inhibitors
̶ Paroxetine
• has been associated with increased
risk for cardiac anomalies, particularly
atrial and ventricular septal defects
̶ Others
• Neonatal behavioral syndrome
✓Self limitted
• Persistent pulmonary hypertension of
the newborn
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35. Antipsychotic Medications
• Exposed neonates have manifested abnormal extrapyramidal
muscle movements and withdrawal symptoms, including:
̶ Agitation,
̶ Abnormally increased or decreased muscle tone,
̶ Tremor,
̶ Sleepiness,
̶ Feeding difficulty, and
̶ Respiratory abnormalities
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36. Retinoids
̶ Inhibit neural-crest cell migration during embryogenesis,
̶ Result in a pattern of cranial neural-crest defects—
termed retinoic acid embryopathy—that involve the
central nervous system, face, heart, and thymus
̶ Specific anomalies may include
• Ventriculomegaly,
• Maldevelopment of the facial bones or cranium,
• Microtia or anotia,
• Micrognathia,
• Cleft palate,
• Conotruncal heart defects, and
• Thymic aplasia or hypoplasia
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37. Thalidomide and Lenalidomide
̶ The characteristic malformation is phocomelia—an absence of
one or more long bones, which results in the hands or feet being
attached to the trunk by a small rudimentary bone
̶ Cardiac malformations, gastrointestinal abnormalities, and other
limb reduction defects are also common following thalidomide
exposure.
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38. Warfarin
̶ Exposure between the 6th and 9th weeks may result in warfarin
embryopathy
̶ This is characterized by stippling of the vertebrae and femoral
epiphyses and by nasal hypoplasia with depression of the nasal bridge
̶ Choanal atresia, resulting in respiratory distress
̶ The syndrome is a phenocopy of chondrodysplasia punctata, a group
of genetic diseases thought to be caused by defects in osteocalcin
̶ agenesis of the corpus callosum; cerebellar vermian agenesis, which is
the Dandy-Walker malformation; microphthalmia; and optic atrophy
̶ Affected infants are also at risk for blindness, deafness, and
developmental delays
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39. Recreational Drugs
• Amphetamines
̶ Fetal-growth restriction and with behavioral
abnormalities
• Cocaine
̶ cleft palate, cardiovascular abnormalities,
and urinary tract abnormalities
̶ fetal-growth restriction and preterm delivery
̶ Children exposed as fetuses are at
increased risk for behavioral abnormalities
and cognitive impairment
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40. • Opioids–Narcotics
̶ Spina bifida, gastroschisis, and cardiac
abnormalities
̶ Heroin-addicted pregnant women are
at increased risk for preterm birth,
placental abruption, fetal-growth
restriction, and fetal death—in part
due to the effects of repeated
narcotic withdrawal on the fetus and
placenta
̶ Neonatal narcotic withdrawal, which is
called the neonatal abstinence
syndrome, may manifest in up to 90
percent of exposed infants
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41. Tobacco
• Anomalies associated with Tobacco use:
̶ Poland sequence
̶ Cardiac anomalies
̶ Hydrocephaly,
̶ Microcephaly,
̶ Omphalocele,
̶ Gastroschisis,
̶ Cleft lip and palate, and
̶ Hand abnormalities
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42. Reference
1. Robert K. Creas, et al., CREASY & RESNIK'S MATERNAL-FETAL
MEDICINE Principles and Practice 7ed2014: Saunders, an imprint of
Elsevier Inc.
2. Gabbe, et al., Obstetrics: Normal and Problem Pregnancies
7ed2017: Elsevier, Inc.
3. CUNNINGHAM, et al., Williams Obstetrics 24 ed2014: McGraw-Hill
Education.
Hale T., M.D., Resident Physician 42
Tuesday, April 3, 2018

43. Thank you for listening!
43
Hale T., M.D., Resident Physician
Tuesday, April 3, 2018