Birth Defects Class Action Lawsuit
THYROID-ACTING AGENTS 465 not inducing developmental defects in guinea pigs and rabbits, the chemical did affect the thyroid in these species, causing atrophic thyroids and pituitaries in the former (Peterson, 1953) and goiter in the latter (Isono, 1960). Triatricol induced cardiac muscle malformations in rats that were elucidated by electron microscopy (Hawkey et al., 1981). Of the antithyroid compounds, only the substituted thiouracil agents, but not thiouracil itself, were teratogenic in animals (see Table 14-1). Methyl thiouracil induced eye defects in rats (Langman and vanFaassen, 1955), clubfoot in mice (Miyamoto, 1967), and brain and cardiovascular anomalies In chinchillas (Klosovskii, 1963). Only thyroid effects were obsen’ed in rabbits (Toriumi, 1959) and guinea pigs (Hagemann, 1955). Propylthiouracil caused loss of hearing in mice (Deol, 1973); three other species exhibited thyroid lesions only. Metbimazole had no teratogenic activity in the rabbit, but postnatal behavioral alterations have been described in both mice (Rice et al., 1987) and rats (Comer and Norton, 1982) from low-dose prenatal administration.
The former species is, in fact, a suitable model for behavioral test validation with this drug (Rice et al., 1987). 2′-Thiourea, given as a 0.2% aqueous solution ad lib to rats on gastation days 1-14 induced a wide variety of severe malformations (Kern et al, 1980). Notably, no congenital defects were obsen’ed with either thiouracil itself or iothiouracil. Virtually all of the antithyroid agents have shown the capacity to induce fetal goiter in animals, as would be expected. Sheep grazing on certain range plants manifested congenital goiter in an
older report (Sinclair and Andrews, 1958), presumably by ingestion of goitrogenic substances of unknown composition.
Several reports have been published that associate human use of thyroid drugs during pregnancy with congenital malformation. With thyroxinc, eye defects were observed in an infant after treatment
of the mother during gestation (Mayer and Hemmcr, 1956). Medication with this drug was also considered to be a risk factor for limb defects among ]08 cases analyzed (Polednak and Janerich,
1985). Heinonen and colleagues (1977) reported a suggestive association with cardiovascular malformations among some 537 women medicated during pregnancy with thyroxine. No further associations
with malformation have occurred with this drug in recent years, and reports of some 75 pregnancies found no increased incidence of birth defects (Harris and Podolsky, 1969; Pekonen et al.,
1984). With thyroid (extract), multiple defects were obsen’ed in a child whose mother received only one treatment with the drug, but drug therapy also included several other drugs (Degenhardt, 1968).
According to another publication, a child with unspecified defects was bom to one of five mothers who were taking thyroid extract during pregnancy (Castellanos, 1967). Two more cases of malformation
were reported from treatment with desiccated thyroid: one infant had central nervous system birth defects and the other had Down syndrome (Man et al., 1958). Some 22 normal births were reported with exposure to thyroid in one publication (Harris and Podolsky, 1969). In addition to the biological effect on the thyroid (see later discussion), a number of case reports have associated antithyroid drugs with the production of serious structural congenital malformations. MaiernaJ hyperthyroid status may be one of the factors involved in ihe etiology of malformations; thyroxin-binding globulin values were significantly lower at the I5th-16th weeks of pregnancy among women giving birth to infants with birth defects 172 cases (Sparre, 1989).
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