Acne? Or birth defects?

Isotretinoin is a relative of vitamin A. The Food and Drug Administration (FDA) approved the first form of the drug, Accutane, in 1982. Since then it has been widely used to treat nodular acne. Other brands of isotretinoin began to enter the market in 2002. All brands of isotretinoin pose the same risk of birth defects.

Nodular acne causes many red, swollen lumps in the skin and can leave permanent scars. Nodular acne sometimes does not respond to treatments other than isotretinoin. The drug clears the skin of most affected individuals for prolonged periods.

Before isotretinoin was approved by the FDA, testing had shown that it could cause birth defects in animals. The manufacturer of Accutane, Roche Pharmaceuticals (a division of Hoffmann-La Roche, Inc.), warned against its use by pregnant women, but pregnancies resulting in birth defects still occurred. As a result, the FDA and the manufacturers of Accutane and other brands of isotretinoin implemented voluntary risk-management plans to prevent pregnant women from using isotretinoin. These programs were not successful in preventing drug exposure during pregnancy, and in 2005 the FDA started a stronger, mandatory risk management program called iPLEDGE. This program aims to assure that no pregnant woman starts taking isotretinoin, and no woman taking isotretinoin becomes pregnant.

What are the risks of using isotretinoin during pregnancy? There is an extremely high risk of birth defects if a woman takes isotretinoin during pregnancy, even if she takes a small amount of the drug for a short period. Birth defects caused by isotretinoin include:

* Hydrocephaly (enlargement of the fluid-filled spaces in the brain)
* Microcephaly (small head and brain)
* Mental retardation
* Ear and eye abnormalities
* Cleft lip/palate and other facial abnormalities
* Heart defects

Isotretinoin can cause these birth defects in the early weeks after conception when a woman often does not know she is pregnant. Even babies without obvious malformations may have mental retardation or learning disabilities. The drug also increases the risk of miscarriage, premature delivery and infant death.

Antihistamines and birth defects

Antihistamines - Antihistamines are, by the very nature of their pharmacological activity, immunosuppressant. An allergic reaction occurs when a foreign antigen activates T-cells passing through the site of the allergic response. These activated T-cells stimulate B-cells to produce high levels of IgE antibodies. At the same time, the T-cells release chemotactic factors which attract basophils into the affected tissue. The basophils, bind with the newly produced IgE and when these cells come in contact with the allergen, they release stores of histamine, heparin and other mediators amplifying the allergic response. Antihistamines block the effects of histamine on blood vessels and smooth muscle, thus they help to suppress the body's reaction to a foreign antigen.

Standard adverse reaction warnings on most antihistamines include many symptoms which are also characteristic of chemically-induced immune dysfunction: rash, photosensitivity, fatigue, dizziness, disturbed coordination, insomnia, tinnitus, paresthesia, neuritis, blurred vision, headache, gastrointestinal problems, hemolytic anemia, thrombocytopenia and so on. Like other immune modulators, antihistamines can also produce the paradoxical effects of sedation in some people, restlessness and excitation in others. (PDR 1988)

Doxylamine succinate, an antihistamine in a number of over-the-counter products as well as the controversial morning sickness remedy Bendectin, has been associated with a statistically significant increase in acute nonlymphoblastic leukemia in children whose mothers took Bendectin for eleven weeks or more during pregnancy. (Robinson et al 1988) In 90-day chronic toxicity studies at the National Toxicology Program, doxylamine was associated with toxic lesions of the livers and parotid glands of mice and rats. (NTP 1986)

Bendectin has been associated with limb reduction defects, heart defects, oral clefts and other serious birth defects in animal and human studies. (ABDC 1988) Other antihistamines, diphenhydramine (Benadryl), meclizine and cyclizine have also been associated with birth defects in animal and human studies.

However, The Centers for Disease Control and Department of Social and Health Services studied the use of antihistamines by pregnant women and the potentiality of birth defects. Their presentation (with notes) revealed "Limited evidence of association between antihistamine use and selected birth defects."

Teratogen

Teratogen means, in Greek, "monster forming." Teratogens are chemicals that cause abnormalities in embryos. The most well-known is thalidomide, a drug originally designed to combat morning sickness in pregnant women. It caused the long bones in the arms or legs of fetuses to not develop properly, resulting in babies with severely stunted arms or legs.

Teratogen is a type of mutagen that causes mutations in somatic cells (cells that are not part of the reproductive system). Mutagens induce mutations of deoxyribonucleic acid (DNA), the hereditary material in cells. The damage of DNA may either kill the cells or, when misrepaired, produce abnormal sequences that will be passed on to daughter cells. This may result in birth defects by injuring developing organs or by disorganizing growth and differentiation.

Apart from thalidomide, the steroid hormones have also been identified as teratogens. The use of male sex hormones as a treatment for breast cancer has resulted in the masculinization of a number of female fetuses when such treatment was commenced prior to the twelfth week of gestation. In addition, the accepted practice of using progesterone from natural sources for the treatment of miscarriage led to the widespread use of synthetic hormones between 1950 and 1960. The result was the birth of more than 600 female babies with equivocal or frankly masculinized external genitalia. It was found later that these synthetic compounds had appreciable androgenic (related to the male sex hormone) activity.

There are other chemicals suspected of being teratogenic because they are occasionally associated with malformations in the offspring of women treated during pregnancy. These include anticonvulsants and some oral hypoglycemics when taken at high doses during pregnancy. It is, however, very difficult to determine the teratogenesis of a drug. Long and costly surveys must be done on a very large population to associate a particular drug with birth defects.