TERATOGENIC

DRUGS

Darmawan,dr.,M.Kes,Sp.PD
• 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
• 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, first-generation
• 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
 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 mother’s health
as well as the integrity of the child’s 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