Which is the most common teratogenic effect associated with thalidomide

Hematologic

Thalidomide can cause leukopenia. In controlled trials in patients with HIV infection the incidences of neutropenia were 9%, 17%, and 25% in those who took placebo, thalidomide 100 mg/day, and thalidomide 200 mg/day respectively [21].

Neutropenia occurred in 14 of 80 patients treated with thalidomide for refractory chronic graft-versus-host disease [69]. The median thalidomide dose at which neutropenia developed was 200 mg qds. Erythrocyte and platelet counts were not affected. After withdrawal of thalidomide the neutropenia resolved within a month (except in three patients, who died with refractory graft-versus-host disease). Six patients were rechallenged with thalidomide and again became neutropenic.

Of 44 patients who took thalidomide for refractory multiple myeloma, 10 developed grade 3 or 4 neutropenia, usually in the first or second week of treatment [70]. There was concomitant progression of thrombocytopenia in five cases and bone marrow hypoplasia without a significant increase in myeloma cell numbers in five. Neutropenia was more common in patients with low neutrophil and platelet counts, anemia, or a high percentage of plasma cells in the bone marrow before thalidomide treatment.

Of 50 Taiwanese patients with relapsed and/or refractory multiple myeloma who took thalidomide on a dose-escalation schedule, 100–800 mg/day, 18 of 22 responders had reduced leukocyte counts before there was significant reduction in M proteins, compared with only four of the 28 non-responders [71]. The median time from the start of thalidomide treatment to the minimum leukocyte count was 28 (range 7–150) days, with a mean cell count of 2.19 (range 0.96–3.35) × 109/l. The leukopenia was generally transient, with rapid recovery despite continuation of thalidomide.

Myeloproliferative reactions have been reported in three patients with myelofibrosis taking thalidomide 200 mg/day [72]. Thalidomide-associated leukemic transformation has also been reported in five patients with multiple myeloma [73].

TERATOGENICITY

Thalidomide is a powerful teratogen, producing effects when taken during much of pregnancy, particularly days 34 to 50 after the final period. The main categories of thalidomide embryopathy include limb deformity, craniofacial defects (microtia or anotia, eye defects, choanal atresia), cardiac disturbances (ductus arteriosus, conotrocal defects, septal defects), intestinal disorders (duodenal atresia, anal atresia, pyloric stenosis), genitourinary tract abnormalities (ectopic kidney, vaginal duplication, renal/testicular agenesis), and lung abnormalities. Limb deformities such as phocomelia occurred when women took any amount of thalidomide during the 20th to the 36th day of pregnancy. Most birth defects, including phocomelia, have been attributed to the drug's antiangiogenesis effects. Thalidomide does not produce second-generation birth defects.31

When it approved thalidomide, the FDA and drug manufacturer instituted severe controls over the drug. To minimize the risk for birth defects, the FDA has mandated that physicians prescribing thalidomide be registered in the System for Thalidomide Education and Prescribing Safety (STEPS) program. Patients taking the drug must receive drug education and acknowledge that they received this education. Women must agree in writing to have no intercourse or to use two methods of birth control should they engage in intercourse. Women must also undergo periodic pregnancy tests.

In an experiment with Drosophila melanogaster, the teratogenic effect of heliotrine to the larvae was also demonstrated.

Reproductive Toxicity

Teratogenic effects, including cleft palates, open-eye, skeletal malformations, and decreased thymus size, have been reported in the offspring of mice injected intraperitoneally during the period of organogenesis with the equivalent of 4–13 times the maximum human therapeutic dose of azathioprine. Increased frequencies of cleft palates, ocular anomalies, and limb malformations also occurred among the offspring of rabbits injected intraperitoneally in doses equivalent to 2–6 times those used in humans. This drug induced embryolethality and growth retardation in the offspring of rats and mice injected intraperitoneally during the period of organogenesis in doses equivalent to up to 4 times the human therapeutic dose, but no malformations were noted in the surviving fetuses. Azathioprine also caused temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose.

The US Food and Drug Administration classified azathioprine in category D (positive evidence of human fetal risk). The data currently available in humans are both limited and conflicting. Although there are no well-controlled studies in pregnant women, some studies have reported that azathioprine may cause fetal harm when administered during pregnancy. Effects associated with prenatal exposure to azathioprine, such as spontaneous abortions and low birth weight, appear to be increased in pregnancies of renal transplant recipients treated with the drug, particularly if the woman requires a high dose therapy. Exposure to azathioprine during pregnancy has been associated with a slight increase in the frequency of anomalies in infants, including hydrocephalus, anencephaly, microcephaly, hypospadias, malformed hand and face, polydactyly, cleft palate, pulmonary artery stenosis, and congenital heart disease. The incidence of pregnancy-related complications (spontaneous abortions and congenital abnormalities) has also been shown to increase when fathers used azathioprine or 6-MP within 3 months before conception. In contrast, some studies suggested that treatment with azathioprine/6-MP before or at conception or during pregnancy for other conditions such as inflammatory bowel disease appears to be safe. A recent study in 2012, the largest study so far with over 100 prospectively ascertained pregnancies of spouses of male patients exposed to azathioprine or 6-MP, concluded that no specific adverse effects were observed after paternal treatment with the drug and, although data are still limited, there is no need for termination of pregnancy or invasive diagnostics only because parents were treated with these drugs.

12.11.7 Multigenerational Effects of Altered Perinatal Environment

The teratogenic effects of NRTIs have been the subject of intense study. NRTIs provide necessary protection to the developing fetus from one type of deadly disease while potentially predisposing them to a new set of biological changes. Current work points to mitochondrial dysfunction as the source of the lactic acidosis, pancreatitis, cardiomyopathy, and neuropathy associated with NRTI treatment (Foster and Lyall 2008). Specifically, NRTIs appear to impair mitochondrial DNA replication and induce the accumulation of mutations within the mitochondrial genome by inhibition of DNA polymerase γ (Lewis et al. 2006a). The potential to induce new, deleterious mutations in the mitochondrial DNA of an exposed fetus is significant because it provides the potential to spread the effects of the NRTIs to subsequent generations if the offspring is female. Fixing mutations in the mitochondrial DNA, which is only inherited from the mother, instead of just altering normal development makes the drug-induced toxicity of NRTIs heritable. A family history of neurological disease could be avoided if drug exposure could be controlled to protect the child from the virus yet avoid damaging the mitochondria of the fetus.

Reproductive and Developmental Toxicity