TERATOGENIC DRUGS

TUJUAN INSTRUKSIONAL
UMUM
Mahasiswa dapat mengetahui dan
memahami kerja obat yang bersifat
teratogenik dan akibat dari kerja
obat-obat tersebut

TUJUAN INSTRUKSIONAL
KHUSUS
Mahasiswa dapat mengetahui kerja
obat teratogenik
Mahasiswa dapat mengetahui
contoh-contoh obat yang bersifat
teratogenik
Mahasiswa dapat mengetahui efek
yang ditimbulkan dari obat-obat
teratogenik

Introduction
Teratogenicity:
The presence of major congenital
malformations
Congenital malformations can be
defined as nonreversible functional or
morphological defects present at birth

 The teratogenic effects of

medications vary temporally
Depends on its period of
development
Different organs have different critical
periods

The span from gestational day 15 to

day 60 is critical

Factors That Determine the Effects

of Teratogens
Dose reaching fetus
Point in development when drug
exposure occurs
Duration of exposure
Environmental factors
Susceptibility of the fetus

 Ex:
The heart is most sensitive during the
third and fourth weeks of gestation
external genitalia are most sensitive
during the eighth and ninth weeks
The brain and skeleton are sensitive
from the beginning of the third week to
the end of pregnancy and into the
neonatal period

 Genetic defects and medications can

cause similar abnormalities
warfarin and Happle syndrome
syndrome is a genetic disease of bone and
cartilage characterized by defective bone
mineralization, telebrachydactyly, and facial
dysmorphism with nasal hypoplasia
WARFARIN

 The FDA assigns a safety category

for medications by using a 5-letter
system:
A, B, C, D, and X.

This safety category must be

displayed on the labels of all drugs

Amlodipine/atorvastatin
Pregnancy category X
Trimesters of risk - First, second, and
third
Associated defects and complications
- Variable; spina bifida
cholesterol biosynthesis are essential
components for fetal development
(including synthesis of steroids and cell
membranes)

Angiotensin II receptor
antagonists (angiotensin II
receptor blockers [ARBs])
Pregnancy category D
Trimesters of risk - First, second, and
third
Associated defects and complications Hypotension, renal dysplasia, anuria or
oliguria, oligohydramnios, IUGR,
pulmonary hypoplasia, patent ductus
arteriosus, incomplete ossification of the
skull, and intrauterine or neonatal death

Antineoplastics (busulfan,
chlorambucil, cyclophosphamide,
mechlorethamine)
Pregnancy categories - D and X
Trimesters of risk - First, second, and third
Associated defects and complications:
Observed problems included IUGR, cleft palate,
renal agenesis, digital malformations, cardiac
anomalies, and cloudy corneas.
First-trimester exposure to antimetabolites
(aminopterin, 5-fluorouracil, methotrexate,
methylaminopterin, and cytarabine) produced a
risk for cleft lip and palate, low-set ears, cranial
anomalies, and anencephaly.

Anticonvulsants, firstgeneration
Pregnancy category - D in general
Trimesters of risk - First, second, and
third
Associated defects and complications Facial dysmorphia, gingival hyperplasia,
neurological hyperexcitability and
multiple malformations including (for
valproic acid) predominantly temporal
atrophy in the left brain hemisphere

Aspirin
Pregnancy category D
Trimesters of risk - First, second, and
third
Associated defects and complications
- Unclear; may be associated with an
increased risk of gastroschisis

Atenolol
Pregnancy category D
Trimesters of risk - First, second, and third
Associated defects and complications
IUGR
Studies:
Animal and human studies have shown growth
retardation in humans and animals, as well as growth
and structural abnormalities in animals. Reduced
fetal size is a function of the length of exposure to
the medication. The earlier the treatment starts, the
greater the incidence of defects.

Benzodiazepines
Pregnancy category - D or X
Trimesters of risk: The first, second,
and third trimesters are times or risk
for flurazepam, temazepam, and
triazolam (category X).
Associated defects and complications
- Unclear; potential for isolated oral
cleft

Colchicine
Pregnancy category D
Trimester of risk Unknown
Associated defects and complications Generally unknown; potential
chromosome aberrations
Studies:
Colchicine has been shown to cause birth
defects in animals.
The drug can lower sperm counts and cause
sperm defects

Corticosteroids
Pregnancy category C
Trimester of risk First
Associated defects and complications
- Reduced birth weight, increased
risk of preeclampsia, and increased
risk of oral and lip clefts

Danazol
Pregnancy category X
Trimesters of risk - First, second, and
third
Associated defects and complications:
Danazol can cause virilization of the
external genital organs, and it has been
linked to pseudohermaphroditism.

Ergotamine
Pregnancy category X
Trimesters of risk - First, second, and
third
Associated defects and complications
- Low birth weight and preterm birth
Ergotamine treatment may be
connected with ergotamine-induced
vasoconstriction in the placenta of
pregnant women

Fluconazole
Pregnancy category C
Trimester of risk Unknown
Associated defects and complications
- Craniofacial, skeletal, and cardiac
effects

Folic acid antagonists

Pregnancy category - D in general
Trimester of risk - First, during normal
closure of the fetal neural tube
Associated defects and complications
- Variable; neural tube defects

Folic acid antagonists (2)

Studies:
Dietary factors, such as cholesterol and
folic acid, appear to be critical for
normal closure of the fetal neural tube.
Pregnant woman should take
supplemental folic acid, 0.4 mg per day.

Folic acid antagonists (3)

The following drugs interfere with folic acid
metabolism:
Phenobarbital, phenytoin, carbamazepine and
primidone
Antibiotic combination of trimethoprim and a
sulfonamide
Triamterene
Sulfasalazine
Valproic acid
Cimetidine
Beta-blockers and calcium channel blockers
Cholestyramine

Methimazole
Pregnancy category D
Trimesters of risk - First, possibly
second, and third
Associated defects and complications Prematurity, small-for-gestational-age
infants, and scalp defects; possible
choanal and esophageal atresia

Phenobarbital or
methylphenobarbital
Pregnancy category D
Trimester of risk - Late in pregnancy
Associated defects and complications Phenobarbital or methylphenobarbital
slightly increases the risk of cleft palate
or lip and congenital heart disease.

Phenytoin
Pregnancy category D
Trimester of risk Unknown
Associated defects and complications
- Varied

Phenytoin
Associated defects and complications
Varied Hand and foot defects
Dermatoglyphic abnormalities consist of
abnormal palmar creases and nail hypoplasia
or aplasia.
Internal abnormalities include variable
coarctation of the aorta, endocardial cushion
defect, double-outlet right ventricle,
ventricular septal defect, atrial septal defect,
bicuspid pulmonic valve, and intestinal
malrotation. Etc

Retinoids
Pregnancy category X
Trimesters of risk: The first, second,
and third trimesters are times of risk.
The critical window of exposure is at
3-5 weeks of pregnancy.
Associated defects and complications
- Deformities of the cranium, ears,
face, limbs, and liver; hydrocephalus;
microcephalus; heart defects; etc

Statins (HMG-CoA reductase

inhibitors)
Pregnancy category X
Trimesters of risk - First, second, and
third
Associated defects and complications
- Possible spina bifida

Tetracyclines
Pregnancy category D
Trimesters of risk - Second and third
(20th gestational week or later)
Associated defects and complications Dental staining
Studies:
As little as 1 g/d of tetracycline for 3 days
during the third trimester can produce
yellow staining of deciduous teeth.

Valproic acid
Pregnancy category D
Trimesters of risk - First, second, and
third
Associated defects and complications
Lumbosacral spina bifida with
meningomyelocele or meningocele,
congenital heart disease, and decreased
postnatal growth

Warfarin
Pregnancy category X
Trimesters of risk - First, second, and third
Associated defects and complications
Deformities of the axial and appendicular
skeleton; also, a hypoplastic nose, eye
abnormalities, mental retardation,
brachydactyly, and scoliosis
The teratogenic mechanism of warfarin is
unknown, : alteration in posttranslational
carboxylation of proteins may result in the
chondrogenic disorders.

FDA 2007
Fetal risk not revealed in controlled studies in
humans
Fetal risk not confirmed in studies in humans
but has been shown in some studies in animals
Fetal risk revealed in studies in animals but not
established or not studied in humans; may use
if benefits outweigh risk to fetus
Fetal risk shown in humans; use only if benefits
outweigh risk to fetus
Contraindicated; benefit does not outweigh risk

Treatment
Medication taking does not stop during
pregnancy
Chronic maternal must continue to be
treated throughout pregnancy to protect
the mothers health as well as the integrity
of the childs development
Temporary changes in treatment regimens
may be necessary

Treatment (2)
Pregnancy can also cause various physical
conditions or symptoms that may be
relieved through drug treatment
managed with nonprescription drug
products

Social or recreational drugs

perinatal complications, such as stillbirth,
preterm birth, spontaneous abortion or
low birth weight infants

THANKS FOR YOUR ATTENTION