Hyperthermia was the first teratogen in animals that was subsequently proven to be teratogenic in humans. Animal studies have demonstrated heat to be a significant cause for reproductive problems in a wide variety of mammals. These problems range from embryonic death and abortion to teratogenically induced anomalies, and are heavily dependent on the dose and timing of the exposure (Edwards, '86; Edwards et al., '95). The threshold of effect in many species begins at about 1.5°C over normal core body temperature. In general, higher temperatures and/or longer durations are most likely to cause abortions, while lower elevations cause embryonic death and resorption, or abnormalities of embryogenesis, if exposure occurs at critical stages of development.
The range of defects induced by hyperthermia in experimental animals includes: anencephaly/exencephaly, encephalocele (Webster and Edwards, '84; '92), micrencephaly (Edwards, '69b; Edwards et al., '84; Upfold et al., '89), microphthalmia, talipes, arthrogryposis, abdominal wall defects, and limb reduction defects (Edwards, '86). Such defects (Figs. 1,2) have been induced by heat in a variety of mammals, including guinea pigs, hamsters, rats, mice, rabbits, sheep, pigs, monkeys, and humans (Edwards, '86), though the confounding effects of the febrile illnesses themselves and their therapies remain problematic in the interpretation of human data. Central nervous system (CNS) defects appear to be the most common consequence of hyperthermia in all species, and cell death or delay in proliferation of neuroblasts is believed to be one major explanation for these effects (Edwards et al., '74; Wanner et al., '75; Upfold et al., '89). Vascular disruption may also be involved in the pathogenesis of some defects of the CNS and other structures (Nilsen, '85; Webster et al., '87).
In the human, heat-induced vascular disruption has been implicated in the pathogenesis of Moebius syndrome (Graham et al., '88; Lipson et al., '89), oroman-dibular-limb hypogenesis syndrome (Superneau and Wertelecki, '85), and the amyoplasia form of arthrogryposis (Ivarsson and Henriksson, '84; Edwards et al., '90). In this review, we confirm an association between febrile maternal illnesses and offspring born with these conditions, as well as other central nervous system problems. The nature of the specific associated anomalies appears to relate to the extent, duration, and timing of the maternal fever. These associated defects are similar to those induced experimentally in guinea pigs, monkeys, and a wide variety of other experimental animals (Hendrickx et al., '79; Edwards, '86; Edwards et. al., '95).