The term thalidomide embryopathy (TE) is used to describe a specific pattern of birth defects caused by a mother's use of the drug thalidomide during her pregnancy. The drug is able to cross the placenta and reaches the developing embryo, causing parts of the embryo's body to form abnormally. The most common birth defects observed in infants with TE include structural abnormalities of the arms, legs, ears, and eyes, although other organs may also be affected. The most harmful time to use thalidomide is during the first three to six weeks of pregnancy.
Thalidomide was originally marketed in Germany in October 1957 as a safe, inexpensive, and effective sedative. Its use was later expanded to include treatment of insomnia, anxiety, upset stomach, and morning sickness during pregnancy. Prior to its release onto the market, thalidomide had been tested in rodents and had been deemed safe; human studies were not performed. It was made available in at least 46 countries. However, the drug was never approved for marketing in the United States due to concerns about the medication's potential side effects, one of which, peripheral neuropathy, was first recognized in 1960. Symptoms of peripheral neuropathy, or nerve damage, include burning, numbness, or tingling in the arms, legs, hands, or feet. The damage may not be reversible even after stopping the medication. Early in the 1960s, an increased number of infants with severe abnormalities of the arms and legs were observed in Germany, Great Britain, and Australia. Once it became clear that the mothers of these infants had taken thalidomide while pregnant, a connection was made between the drug and the birth defects. In 1961, the drug was withdrawn from the worldwide market. It has since become known as a powerful human teratogen , a drug or other agent proven to cause birth defects. The experience with thalidomide also led to greater overall attention to the potential effects of drug and other environmental exposures on a developing fetus, and to improved legislation regarding testing requirements before a new drug is released to the public.
Although the use of thalidomide decreased dramatically after 1961, it remained available in the United States and other countries on a "compassionate use" basis: physicians could obtain special permission to treat ill patients they believed could significantly benefit from the drug. Over time, it became clear that thalidomide is effective in the treatment of a number of medical conditions. This surprising resurgence of thalidomide has, in turn, led to concern over the possibility of another generation of children born with thalidomide-related birth defects. The manufacturer of thalidomide, Celgene Corporation, is working in close partnership with the U.S. Food and Drug Administration (FDA) to tightly control the use of the drug and to maintain close follow-up on all individuals to whom it is prescribed. The drug is marketed under the brand name Thalomid.
Limb abnormalities are the most readily identified, and most well known, type of birth defect caused by prenatal thalidomide exposure. However, other types of physical problems may also occur in an exposed infant. In addition to limb abnormalities, TE may include abnormalities of the ears, eyes, kidneys, heart, intestinal tract, and nervous system. Mental retardation has been reported in approximately 5% of older individuals with TE.
TE is not an inherited medical condition. However, thalidomide is a known teratogen. Therefore, women who use this medication while pregnant are at risk of having infants with physical, and possibly mental, birth defects. A woman who does not use thalidomide during pregnancy cannot have a child with TE. As of 2001, it is still not entirely clear how thalidomide causes birth defects. One hypothesis is that the drug prevents formation of new blood vessels. Research is continuing in this area.
It is estimated that 10,000–12,000 infants were born with birth defects consistent with TE following its initial period of use in the late 1950s to early 1960s. According to the Teratology Society 1998 Public Affairs Symposium,
approximately 40%, or roughly 5,000, of the affected individuals survived.
In July 1998, the FDA approved the use of thalidomide in the United States, under a very tightly controlled protocol, for the treatment of erythema nodosum leprosum (ENL), a painful skin complication of leprosy. The drug has been available in South America, an area where leprosy is more common than in the United States. Reports of thalidomide-affected South American infants were published as recently as 1996.
Medical researchers are studying whether or not thalidomide may be effective in the treatment of other medical conditions, including certain skin and immunologic disorders, certain complications associated with human immunodeficiency virus (HIV) infection, and certain cancers. Although pregnancies among female patients with any of these conditions may be rare, unintended pregnancies will occur and will be at risk for fetal abnormalities if the mothers are taking thalidomide.
Signs and symptoms
TE includes a spectrum of physical abnormalities, all of which may occur at various levels of severity. An affected individual may not have every type of birth defect. All affected infants, however, have been exposed to thalidomide in early pregnancy, a time when the organs and body of an embryo are rapidly developing. Although use of thalidomide at any point in pregnancy is strongly discouraged, women who use the drug during the first six weeks of pregnancy are at the greatest risk of having children with birth defects. Rigorous control of the drug is necessary since many pregnancies are unplanned and may go unrecognized until after the drug exposure has occurred.
The clinical features of TE include:
The most well known type of abnormality is referred to as phocomelia. Phocomelia occurs when most of the bones in the arms or legs are missing, and the hand or foot is attached directly to the body, similar to a flipper. Radial aplasia, or absence of the thumb and connecting bone in the forearm (radius), is another common abnormality. Abnormalities of the digits include a triphalangeal thumb (three small bones in the thumb, rather than two, such that the thumb looks like a finger), or an absent (hypoplastic) thumb only. Similar defects of the legs may also occur. Frequently, affected infants have abnormalities on both sides of their bodies, involving all four extremities.
Malformations of the ears are common. These range from complete absence of the ear (severe microtia, also sometimes referred to in the medical literature as anotia) to mild changes in the appearance of the external ear. Abnormalities of the inner ear frequently cause deafness. Inner ear malformations may occur even if the external ear appears normal.
A range of eye abnormalities have been reported, including a very small eye (microphthalmos), glaucoma , strabismus, cataract, and abnormal production of tears.
- Structural heart defects.
- Kidney malformations, most often an absent or misplaced kidney.
- Abnormalities of the intestinal system.
- Structural defects of the spine and chest.
- Central nervous system abnormalities, such as mental handicap, described in a small percentage of older individuals with TE.
- Paralysis of the nerves of the face on either one side, both sides equally, or both sides but asymmetrically.
- An increased risk for early infant death, particularly among those infants with severe abnormalities of their internal organs.
Exposure to thalidomide during the first six weeks of pregnancy poses a significantly increased risk of having a child with TE. It is important to note that the exact dosage of the drug during this period is irrelevant. Thalidomide is rapidly broken down in the mother's body and is therefore able to reach her developing embryo quickly. There is no direct genetic test to accurately diagnose all thalidomide-related birth defects before delivery. However, prenatal ultrasound examinations may be used to identify major structural abnormalities, such as those involving the limbs, heart, kidneys, and intestinal tract. A careful physical examination by a knowledgeable and experienced physician(s) is warranted after birth to document the nature and severity of any thalidomide-induced birth defects. Additional studies, such as hearing evaluations, are also indicated.
Treatment and management
Management of the individual with TE is primarily symptomatic. Specialized medical care, such as heart surgery, may be necessary in certain situations, and should be determined on a case-by-case basis. Deaf individuals may require hearing aids and/or will need to learn sign language. Severe limb abnormalities may lead to the use of a wheelchair or other device to assist in mobility.
In order to try to minimize the number of future children born with TE, the drug manufacturer and the FDA implemented the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) program in 1998. The goals of the program are three-fold: (1) to limit the risk of fetal exposure to thalidomide; (2) to enforce universal compliance of patients, physicians, and pharmacists with the designated components of the program; and, (3) to support appropriate, controlled use of the drug. To achieve this, the S.T.E.P.S. program requires informed consent from all patients to whom the drug will be given. Face-to-face counseling, a patient information booklet, and videotape are all used to review the potential benefits and side effects of the medication. Plans for birth control (contraception) and/or abstinence from sexual inter-course are also discussed. All women of childbearing age must agree to a pregnancy test prior to receiving their medication and at frequent intervals during treatment. Two methods of birth control are additionally required. Physicians who will be prescribing thalidomide must be registered in the S.T.E.P.S. program and must agree to follow each step of the program. Prescriptions may only be filled at registered pharmacies. No more than a one-month supply of the medication may be provided at one time; there are no automatic refills. It is recommended that women receive only a one-week supply, particularly during the first four weeks of treatment. Weekly refills are granted only with proof from a physician of a negative pregnancy test. In the event that a woman becomes pregnant, or suspects that she may be pregnant, an immediate referral is made for medical evaluation. Follow-up care is provided, and a database of all patients taking thalidomide is maintained.
Despite this unprecedented level of strict control, the S.T.E.P.S. program is unlikely to completely prevent the birth of every child in the United States with TE. Other countries in which the drug has been approved for use have been encouraged to develop similar methods to follow outcomes of pregnancies exposed to thalidomide. In the meantime, research is continuing to find drugs that will be as effective as thalidomide without the same dangers to embryonic development.
There is no data addressing long-term survival rates among individuals with TE. Nonetheless, the presence and severity of thalidomide-related birth defects, particularly those involving the heart, would be expected to have the greatest impact on longevity. Severe heart malformations that cannot be corrected by surgery are likely to lead to early death. In the absence of such abnormalities, a normal life span is anticipated.
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Friedman, J.M., and C.A. Kimmel. "Teratology Society 1998 Public Affairs Committee Symposium." Teratology 59 (1999): 120-123.
Miller, Marilyn T., and Kerstin Stromland. "Teratogen Update: Thalidomide: A Review, With a Focus on Ocular Findings and New Potential Uses." Teratology 60, no. 5 (November 1999): 306-321.
Public Affairs Committee. "Teratology Society Public Affairs Committee Position Paper: Thalidomide." Teratology 62, no. 3 (September 2000): 172-173.
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Terri A. Knutel, MS, CGC