This is a lecture note on medications in pregnancy.

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
acceptedTuesday, April 3, 2018 Hale T., M.D., Resident Physician 23

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 42Tuesday, April 3, 2018

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