••• Chapter 63^ Reproductive Toxicology^631
❍ Is lithium use for manic depression indicted in pregnancy?
Lithium is a category D drug and its use in the first trimester can result in Ebstein anomaly (tricuspid value is
abnormal and has only two leaflets). Although there is a strong association between the drug and the cardiac lesion,
it is very rare and does not warrant routine pregnancy termination.
❍ How does thalidomide affect the developing fetus?
Thalidomide is a sedative, hypnotic, and anti-inflammatory medication, which was prescribed during the late 1950s
and early 1960s to pregnant women as an antiemetic to combat morning sickness as well as a sleep aid. It was sold
in almost 50 countries under at least 40 names, including Distaval, Talimol, Nibrol, Sedimide, Quietoplex,
Contergan, Neurosedyn, and Softenon. From 1956 to 1962, approximately 10,000 children were born with
severe malformations, about 5000 survived beyond childhood. Malformations were amelia (absence of limbs),
phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities, facial palsy, eye
abnormalities, and congenital heart defects, because their mothers had taken thalidomide during pregnancy. The
medication never received approval for sale in the United States, but 2.5 million tablets had been given to > 1200
American doctors during Richardson-Merrell “investigation,” and nearly 20,000 patients received thalidomide
tablets, including several hundred pregnant women. In the end, 17 American children were born with thalidomide-
related deformities.
❍ What is the mechanism behind thalidomide-induced teratogenesis?
The mechanism of action of thalidomide is not fully understood. Thalidomide possesses immunomodulatory, anti-
inflammatory, and anti-angiogenic properties. Available data from in vitro studies and clinical trials suggest that
the immunologic effects of this compound can vary substantially under different conditions, but may be related
to suppression of excessive tumor necrosis factor-alpha (TNF-α) production and down-modulation of selected
cell surface adhesion molecules involved in leukocyte migration. Thalidomide is racemic—it contains both left-
and right-handed isomers in equal amounts. One enantiomer is effective against morning sickness. The other is
teratogenic and causes birth defects.
❍ Is thalidomide still on the market in some countries?
Yes. Thalidomide is currently used in three countries: Mexico, Brazil, and in the United States. The current
indication of thalidomide use is erythema nodosum leprosum (ENL), a severe and debilitating complication
of leprosy (Hansen’s disease) and multiple myeloma. Effective contraception must be used for at least 4 weeks
before beginning thalidomide therapy, during thalidomide therapy, and for 4 weeks following discontinuation of
thalidomide therapy.
❍ What are the risks of amphetamine use during pregnancy?
Infants born to mothers dependent on amphetamines have an increased risk of premature delivery and low birth
weight. Also, these infants may experience symptoms of withdrawal as demonstrated by dysphoria, agitation, and
significant lassitude. However, there is no known association with structural abnormalities.
❍ Are all social and illicit drugs associated with increased rates of placental abruption?
No. Only cocaine and smoking are known to cause increased rates of placental abruption. Alcohol, coffee, heroin,
marijuana, and amphetamines have no such association.