TERATOGENIC DRUGS

Darmawan,dr.,M.Kes

 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, 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

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, doubleoutlet 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