25. teratogenic drugs

8/13/2019 25. Teratogenic Drugs

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TERATOGENIC DRUGS

Darmawan,dr.,M.Kes


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Teratogenicity:

The presence of major congenital malformations

Congenital malformations can be defined as

nonreversible functional or morphological defects

present at birth


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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


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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


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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 ofpregnancy and into the neonatal period


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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


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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


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Amlodipine/atorvastatin

Pregnancy categoryX

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)


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Angiotensin II receptor antagonists

(angiotensin II receptor blockers [ARBs])

Pregnancy categoryD


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


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Antineoplastics (busulfan, chlorambucil,

cyclophosphamide, mechlorethamine)

Pregnancy categories - D and X


Associated defects and complications: Observed

problems included IUGR, cleft palate, renal agenesis,digital malformations, cardiac anomalies, and cloudycorneas.

First-trimester exposure to antimetabolites(aminopterin, 5-fluorouracil, methotrexate,methylaminopterin, and cytarabine) produced a riskfor cleft lip and palate, low-set ears, cranial anomalies,and anencephaly.


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Anticonvulsants, first-generation

Pregnancy category - D in general


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


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Aspirin

Pregnancy categoryD


Associated defects and complications -Unclear; may be associated with an increased

risk of gastroschisis


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Atenolol

Pregnancy categoryD


Associated defects and complicationsIUGR

Studies:

Animal and human studies have shown growthretardation in humans and animals, as well as growthand structural abnormalities in animals. Reduced fetal

size is a function of the length of exposure to themedication. The earlier the treatment starts, thegreater the incidence of defects.


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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).


Unclear; potential for isolated oral cleft


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Colchicine

Pregnancy categoryD

Trimester of riskUnknown

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


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Corticosteroids

Pregnancy categoryC

Trimester of riskFirst

Associated defects and complications -Reduced birth weight, increased risk of

preeclampsia, and increased risk of oral and

lip clefts


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Danazol

Pregnancy categoryX


Associated defects and complications: Danazol can

cause virilization of the external genital organs,

and it has been linked to pseudohermaphroditism.


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Ergotamine

Pregnancy categoryX


Associated defects and complications - Lowbirth weight and preterm birth

Ergotamine treatment may be connected with

ergotamine-induced vasoconstriction in the

placenta of pregnant women


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Fluconazole

Pregnancy categoryC


Associated defects and complications -Craniofacial, skeletal, and cardiac effects


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Folic acid antagonists

Pregnancy category - D in general

Trimester of risk - First, during normal closure

of the fetal neural tube


Variable; neural tube defects


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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.


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Folic acid antagonists (3)

The following drugs interfere with folic acidmetabolism:

Phenobarbital, phenytoin, carbamazepine and primidone

Antibiotic combination of trimethoprim and a sulfonamide

Triamterene

Sulfasalazine

Valproic acid

Cimetidine

Beta-blockers and calcium channel blockers

Cholestyramine


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Methimazole

Pregnancy categoryD

Trimesters of risk - First, possibly second, and

third


Prematurity, small-for-gestational-age infants, and

scalp defects; possible choanal and esophageal

atresia


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Phenobarbital or

methylphenobarbital

Pregnancy categoryD

Trimester of risk - Late in pregnancy


Phenobarbital or methylphenobarbital slightly

increases the risk of cleft palate or lip and

congenital heart disease.


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Phenytoin

Pregnancy categoryD


Associated defects and complications - Varied


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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


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Retinoids

Pregnancy categoryX

Trimesters of risk: The first, second, and thirdtrimesters are times of risk. The critical

window of exposure is at 3-5 weeks ofpregnancy.


Deformities of the cranium, ears, face, limbs,and liver; hydrocephalus; microcephalus;heart defects; etc


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Statins (HMG-CoA reductase

inhibitors)

Pregnancy categoryX


Associated defects and complications -Possible spina bifida


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Tetracyclines

Pregnancy categoryD

Trimesters of risk - Second and third (20thgestational week or later)

Associated defects and complications - Dentalstaining

Studies:

As little as 1 g/d of tetracycline for 3 days duringthe third trimester can produce yellow staining ofdeciduous teeth.


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Valproic acid

Pregnancy categoryD


Associated defects and complications Lumbosacral spina bifida with meningomyelocele

or meningocele, congenital heart disease, and

decreased postnatal growth


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Warfarin

Pregnancy categoryX


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.


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FDA 2007

Fetal risk not revealed in controlled studies inhumans

Fetal risk not confirmed in studies in humans buthas been shown in some studies in animals

Fetal risk revealed in studies in animals but notestablished or not studied in humans; may use ifbenefits outweigh risk to fetus

Fetal risk shown in humans; use only if benefitsoutweigh risk to fetus

Contraindicated; benefit does not outweigh risk


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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


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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

25. teratogenic drugs

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