Gynecologic and Obstetric

Pharmacology III:
Drug and Teratogenicity

Tanchun Wang Ph.D

Tanchun.wang4@touro.edu

2017 Tanchun Wang. Reproduction for non-profit educational use by TouroCOM students
permitted, all other rights reserved. Distribution and/or duplication for
1 any other purposes
 Learning Objectives

1. Define teratogen and identify the effects and

general principles of drug use during pregnancy.
Describe the FDA regulation of drug safety during
pregnancy

2. Identify antimicrobial drugs and their fetal or

neonatal teratogenic effects.

3. Identify CNS drugs and their fetal or neonatal

teratogenic effects.

4. Identify other teratogenic drugs and their fetal or

neonatal teratogenic effects.
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 Objective 1

Define teratogen and identify the effects and

general principles of drug use during pregnancy.
Describe the FDA regulation of drug safety
during pregnancy.

3
Teratogen and Drug Teratogenicity
Teratogen: an agent that when administered
to the pregnant mother causes structural or
functional abnormalities in the fetus or in the
child after birth, which may not be apparent
until later life.

Therapeutic drugs accounts for 2-3% of all

fetal congenital malformations; Others result
from genetic, environmental, or unknown
causes.
Factors that affect drug use during pregnancy

1. Whether the Drugs able to cross placenta

Direct teratogenic effect vs indirect effect:
Molecular weight, lipid solubility, drug ionization,
extent of protein binding etc.

2. Fetal age at the time of drug exposure

. 20 days after fertilization: all-or-nothing effect
. 20 to 56 days after fertilization: (phase of
organogenesis):Teratogenesis happens
most often.
. 2nd and 3rd trimesters (After organogenesis):
Less teratogenesis but drug may still affect
growth and function of normally formed fetal
organs.
General principles of drug use during
pregnancy
Use the safest drug, smallest dose and shortest
amount of time during pregnancy. Avoid all drugs
in first trimester if possible.

Assess the risks vs benefits of drug treatment

during pregnancy. Each drug should be assessed
on an individual patient basis.

Monotherapy is desirable during pregnancy when

possible because drugs may act synergistically in
terms of teratogenic potential.
FDA regulation of drug safety during pregnancy

Traditionally: the FDA classified OTC and

prescription drugs into 5 categories of safety for use
during pregnancy (A, B, C, D, X).

Category A: No proven harmful effects been

observed in large number controlled human studies.

Category B: No proven harmful effects been

observed in limited number of human studies

Category C: May cause harmful effects to fetus

based on their pharmacological effects. No well-
controlled studies are done in human.
FDA regulation of drug safety during pregnancy
Category D: Positive evidence of increased
incidence of human fetal malformations or
irreversible damage human fetal risk, but benefits
may outweigh risk.

Category X: Drugs that have such a high risk of

causing permanent damage to the fetus that they
are contraindicated in pregnancy and in those
who may become pregnant.
New FDA regulation of drug safety during pregnancy

In December 2014, The FDA ruled against the

current product letter categories A, B, C, D and
X used to classify the risks of using prescription
drugs during pregnancy

Instead, the FDA requires the use of three

subsections in the labeling titled Pregnancy,
Lactation and Females and Males of
Reproductive Potential that provide details about
use of the drug.

The rule has been in effect since June 30, 2015.

 Objective 2

Identify antimicrobial drugs and their fetal

or neonatal teratogenic effects.

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 Antimicrobials

Antibacterials: Antifungals:
Aminoglycosides Griseofulvin
Chloramphenicol
Tetracycline
Antivirual:
Clarithromycin
Ribavirin
Fluoroquinolones
Sulfonamides
Nitrofurantoin

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 Antimicrobials
Aminoglycosides (D): Ototoxicity (eg,
damage to fetal labyrinth), resulting in
deafness.

Chloramphenicol (C): Gray baby syndrome.

Hemolysis in women with G6PD deficiency.

Tetracycline/ Doxycycline (D): Inhibition of

bone growth, enamel hypoplasia, permanent
yellowing of the teeth.

Clarithromycin (C): Miscarriage and

embryotoxicity in early pregnancy.
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 Antimicrobials
Fluoroquinolones (C): Cartilage damage.
Sulfonamides (C): Neonatal jaundice/kernicterus
(near term). Hemolysis in women with G6PD
deficiency.
Nitrofurantoin (B): Contraindicated at term
due to risk of neonate hemolysis. Hemolysis in
women with G6PD deficiency.

Griseofulvin(C): Congenital malformations.

Ribavirin (X): Congenital malformations such as

torticollis, hypospadias, polydactylism.

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 Antimicrobials (continue)

A
A: Ototoxicity
B: Gray baby syndrome C
C: Inhibition of bone growth B
D: Embryotoxicity
E: Cartilage damage
F: Kernicterus

D: Clarithromycin

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 Practice Question 1 A 5-year-old boy is brought to the
Department of Pediatric Dentistry by his mom with a
complaint of discoloration of his teeth since childhood.
On examination, you notice a generalized grayish to
yellow brown discoloration in the teeth. Stains are not
scrapable by dental explorer. The stains fluoresce when
observed under ultraviolet (UV) light. His mother had
used an antibiotic drug during her first trimester of
pregnancy. which of the following statements describes
the mechanism of this drug?
A. Inhibits the formation of initial translation complex
B. Blocks the attachment of aminoacyl tRNA to
acceptor site
C. Inhibits the enzyme peptidyl transferase and block
the formation of peptide bonds
D. Inhibits DNA gyrase and interfere DNA synthesis
E. Block dihydropteroate synthetase and inhibit folate
synthesis 15
 Practice Question 1 A 5-year-old boy is brought to the
Department of Pediatric Dentistry by his mom with a
complaint of discoloration of his teeth since childhood.
On examination, you notice a generalized grayish to
yellow brown discoloration in the teeth. Stains are not
scrapable by dental explorer. The stains fluoresce when
observed under ultraviolet (UV) light. His mother had
used an antibiotic drug during her first trimester of
pregnancy. which of the following statements describes
the mechanism of this drug?
A. Inhibits the formation of initial translation complex
B. Blocks the attachment of aminoacyl tRNA to
acceptor site
C. Inhibits the enzyme peptidyl transferase and block
the formation of peptide bonds
D. Inhibits DNA gyrase and interfere DNA synthesis
E. Block dihydropteroate synthetase and inhibit folate
synthesis 16
 Objective 3

Identify CNS drugs and their fetal or

neonatal teratogenic effects.

17
 CNS Drugs

Anticonvulsants:
Carbamazepine,
Phenytoin
Valproic acid

Drug for depression and bipolar disorder:

Lithium

Alcohol

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 CNS Drugs: Anticonvulsants

Carbamazepine, Phenytoin(D):
Fetal hydantoin/dilantin syndrome: Craniofacial
defects: microcephaly, cleft lip/palate. Facial features
such as short, flat nose, eyes that are farther apart,
dropped eyelids etc. Risk of neural tube defects,
Congenital heart defects

Valproic acid (D):

Fetal Valproate Syndrome. Risk of neural tube
defects (due to inhibition of folate absorption),
cardiac, craniofacial, cleft lip and limb and renal
defects.

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 Ebsteins anomaly
CNS Drugs (continue)
Lithium (D): Ebsteins anomaly. Risk of
major cardiac congenital malformations.
Nephrogenic diabetes insipidus in the
neonate When given in 3rd trimester.

Alcohol (D): Fetal Alcohol Syndrome

(FAS): Intellectual disability(leading
cause), cardiovascular defects,
microcephaly facial abnormalities such shot
nose, thin upper lip, small eye openings.
Wolff-Parkinson-White syndrome

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 Objective 4

Identify other teratogenic drugs and their

fetal or neonatal teratogenic effects.

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 Immuno & Dermatologic drugs
Aspirin (D, full dose): Prolong labor and increase
maternal/neonatal hemorrhage. Increased perinatal
mortality, intrauterine growth retardation, and
premature closing of fetal ductus arteriosus.
Other NSAIDs (D, 3rd trimester): Similar to
aspirin.
Prostaglandin analogues (abortifacient):
Misoprostol, Dinoprostone Carboprostand

Finasteride (X): Birth defects in male babies

(Hypospadias).
Retinoids (X)(e.g. Isotretinoin, Acitretin):
Multiple congenital malformations including cardiac
defects, eye and external defects, spontaneous
abortion 1st trimester 22
 Cardiovascular and Anticoagulants
ACEI and ARBs and Aliskiren (D): Cardiovascular
and renal malformations

HMG-CoA inhibitors:Statins (X): multiple

congenital malformations

Warfarin (X): Fetal warfarin syndrome (if use

during the 1st trimester):Optic atrophy, intellectual
disability, microcephaly, and fetal and maternal
hemorrhage if used later in pregnancy.

Unfractionated/ Low molecular weight

Heparin is preferred.
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 Endocrine drugs and Sex hormones
Radioactive iodine (131I) (X) : Destruction of the
fetal thyroid gland, congenital Hypothyroidism

Danazol (X): Synthetic androgen. Masculinization of

a female fetuss genitals especially during the first
trimester.
Diethylstilbestrol (DES)(X):Synthetic nonsteroidal
estrogen. Adenocarcinoma of vagina and cervix in
young women whose mother had taken DES in
pregnancy.
Mifepristone (abortifacient): Progesterone
receptor blocker.

Levothyroxine/Propylthiouracil (PTU)
preferred during pregnancy 24
 Other Drugs/Substances

Thalidomide (X): Immunomodulator (reduces the

levels of TNF). Treat and prevent a skin disease
caused by leprosy. Also used with dexamethasone to
treat multiple myeloma.
Teratogenicity: Phocomelia (short or absent long
bones of the limbs).
Dr. Frances Kelsey

Tobacco: Risk of Miscarriage and preterm delivery.

Congenital malformations such as cleft lip and high
risk of sudden infant death syndrome (SIDS).

Folic Acid supplements is necessary during

pregnancy to prevent neural tube
25
defects.
 Practice Question 2: A 31-year-old female with a
past medical history of hypertension,
hyperthyroidism, bipolar disorder, and
hypercoagulability disorders undergoes a normal
vaginal delivery. Soon after birth, the infant is
found with AV reentrant tachycardia, severe
tricuspid regurgitation, dyspnea, heart failure, and
cyanosis. Which of the following medications the
patient is likely exposed during pregnancy?

A. Warfarin
B. Lithium
C. Valproic acid
D. Lisinopril
E. 131I
F. Alcohol 26
 Practice Question 2: A 31-year-old female with a
past medical history of hypertension,
hyperthyroidism, bipolar disorder, and
hypercoagulability disorders undergoes a normal
vaginal delivery. Soon after birth, the infant is
found with AV reentrant tachycardia, severe
tricuspid regurgitation, dyspnea, heart failure, and
cyanosis. Which of the following medications the
patient is likely exposed during pregnancy?

A. Warfarin
B. Lithium
C. Valproic acid
D. Lisinopril
E. 131I
F. Alcohol 27
 Review of Objectives

1. Define teratogen and identify the effects and

general principles of drug use during pregnancy.
Describe the FDA regulation of drug safety during
pregnancy

2. Identify antimicrobial drugs and their fetal or

neonatal teratogenic effects.

3. Identify CNS drugs and their fetal or neonatal

teratogenic effects.

4. Identify other teratogenic drugs and their fetal or

neonatal teratogenic effects.
28