Most embryonic organs and the central nervous system are extremely sensitive to the teratogenic affects of pharmaceuticals in the first two months of development. Often times these drugs cause embryonic malformations before the woman knows she is pregnant. Below we discuss a selection of prescription drugs, used to treat maternal illness, which could possibly be avoided during pregnancy, thereby reducing the quantity of human birth defects.

Page Contents: (Click on the Teratogen name or scroll down)

• Thalidomide
• Diethylstilbestrol
• Retinoic Acid
• Valproic Acid
• Warfarin

Thalidomide was released in 1956 as a mild sedative used to combat nausea in pregnant women. It was later (1961) withdrawn from the market once it was discovered thalidomide was a human teratogen. As little as one dose could cause a significant birth defect. Approximately 5,000-7,000 malformed infants were born to women who ingested thalidomide during pregnancy.
Fetuses exposed to thalidomide in the womb may have malformed intestines, hearing defects, absent ears, and/or ocular and renal anomalies. However, the most striking phenotype is phocomelia: severe limb malformations in which the long bones of the limb are either greatly reduced in length or absent all together.
The cases of phocomelia seen in the University clinic in Hamburg, Germany were recorded through out the late 1950�s into the 1960�s (see the table below). Thalidomide was introduced in Germany in the late 1950�s. Interestingly enough, this is exactly when the first few cases of phocomelia were seen in the clinic. This number increased steadily until 1962 when the last few exposed infants were born. By 1963, there were no cases of phocomelia.

Further thalidomide testing revealed limitations in previous animal studies. Not all animal species tested produced reactions to thalidomide exposure similar to those seen in humans. For instance, there was no effet in treated rodents while primates were phocomelic. Rabbits had malformed limbs yet they were still different from the human anomaly.

Many mechanisms of action have been proposed for thalidomide yet the true mechanism remains unknown. One theory suggests that neural crest cells are effected, another mentions an alteration in the metanephros-limb interaction thereby stunting the limb�s outgrowth. Other possibilities include a reduced ganglia size (therefore limb development is inhibited because limb growth is dependant upon neuronal growth) or inhibited cell-cell interactions and reduced quantities of cell adhesion molecules making limb growth impossible.

Retinoic acid is teratogenic in humans at very low doses. The critical exposure time is between 3-5 weeks of pregnancy, often before the woman knows she is pregnant. Exposure to retinoic acid during pregnancy may result in malformations of the fetus: craniofacial alterations, cleft palate, neural tube defects, cardiovascular malformations, thymic aplasia, psychological impairments, absent or defective ears, small jaw, kidney alterations. Fifty percent of affected children have an IQ below 85 (average intelligence being an IQ of 110-100).

Retinoic acid is the active ingredient in Accutane�, a drug used to treat severe acne. Since its introduction in September of 1982, an estimated 160,000 women of child bearing age have ingested the drug. Between 1982 and 1987, approximately 900-1300 malformed children, 700-1000 spontaneous abortions and 5000-7000 elective abortions are due to Accutane� exposure. Exposed children may have hydrocephaly, ear malformations, cardiovascular defects and decreased IQ. Accutane carries a pregnancy category X warning, meaning it is a known human teratogen.

Retinoic acid is biologically active in two forms: all trans retinoic acid and 9-cis retinoic acid. Vitamin A and 13-cis retinoic acid are converted to these biologically active forms. A proposed mechanism is that biologically active retinoic acid binds retinoic acid receptors which in turn bind DNA enhancer elements such as the retinoic acid response elements. Several Hox genes (responsible for early patterning of the embryo) contain this enhancer element in their promotors. Therefore, Hox signaling may be altered due to increased retinoic acid concentrations resulting in multiple birth defects.

Valproic acid was released in 1967 in Europe and in 1978 in the United States to treat epilepsy. Approximately 11,500 epileptic women become pregnant each year, many of which use valproic acid. By 1980, publications began linking malformed children to in utero exposure to valproic acid (greater than 500 mg/day). These children were born with lumbosacral spina bifida with menigomyelocele or menigocele, often accompanied by midfacial hypoplasia, deficient orbital ridge, prominent forehead, congenital heard disease and decreased postnatal growth. The proposed mechanism of action is that valproic acid influences folate metabolism, thereby altering the closure of the spinal column resulting in spina bifida.

Warfarin is an anticoagulant used by patients with artificial heart valves. The primary teratogenic effect of warfarin is in the axial and appendicular skeleton. Effected children also have a hypoplastic nose, eye abnormalities, mental retardation, brachydactyly and scoliosis. The effect of warfarin is directly dependant upon the time of dosage. The embryopathy described above results from maternal use during early pregnancy while central nervous system disorders are due to dosage at a later stage in pregnancy. The teratogenic mechanism of warfarin is unknown but it has been proposed that an alteration in post-translational carboxylation of proteins may result in the chondrogenic disorders.

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• Schardein, J. (1993). Chemically Induced Birth Defects. New York, Marcel Dekker, Inc.
  
• Smith, D.W. (1982). Smith's Recognizable Patterns of Human Malformations. Philadelphia, W. B. Saunders Company.
  
• Teratology Society Paper