Hyperthermia as a teratogen: A review of experimental studies and their clinical significance

Abstract

Although hyperthermia is teratogenic in birds, all the common laboratory animals, farm animals, and primates and satisfies defined criteria as a teratogen, its study as a human teratogen has been neglected. Homeothermic animals, including humans, can experience body temperature elevations induced by febrile infections, heavy exercise and hot environments which exceed the thresholds (1.5-2.5 degrees C elevation) which are known to cause a syndrome of embryonic resorptions, abortions, and malformations in experimental animals. Hyperthermia is particularly damaging to the central nervous system, and if a threshold exposure occurs at the appropriate stages of embryonic development, exencephaly, anencephaly, encephalocoele, micrencephaly, microphthalmia, neurogenic talipes, and arthrogryposis can be produced in a high proportion of exposed embryos, the incidence and type of defect depending on the species and strain within species, the stage of development, and the severity of hyperthermic exposure. Other defects which can be induced experimentally include exomphalos, hypoplasia of toes and teeth, renal agenesis, vertebral anomalies, maxillary hypoplasia, facial clefting, cataract, coloboma, and heart and vascular defects. Proliferating cells are particularly sensitive to temperature elevations, resulting in arrest of mitotic activity and immediate death of cells in mitosis with threshold elevations (1.5-2.5 degrees C) and delayed death of cells probably in S phase with higher elevations (3.5 degrees C). In general, lower temperature elevations (2.5 degrees C) require longer durations of elevation to cause defects than a simple spike at a higher elevation (4.5 degrees C). The death of cells is largely confined to the brain and in the day 21 guinea pig embryo to the alar regions of the brain. Cell death probably accounts for most of the defects in the central nervous system, but microvascular disturbances leading to leakage, oedema and haemorrhage, placental necrosis, and infarction are other known effects of hyperthermia; and these are probably involved in the pathogenesis of many defects of the heart, limbs, kidneys, and body wall. Recent experiments have demonstrated protection of rat embryos in culture against a known teratogenic exposure by a brief nonteratogenic exposure given at least 15 min earlier. This protection is associated with the synthesis of heat-shock proteins, and temporary arrest of the cell proliferative cycle. Hyperthermia appears to be capable of causing congenital defects in all species and may act alone or synergistically with other agents.(ABSTRACT TRUNCATED AT 400 WORDS)

The safety of obstetrical ultrasound: a review

“…Edwards has demonstrated multiple teratogenic effects within mammalian offspring exposed to hyperthermic temperatures in utero, including musculoskeletal, cardiac, renal, and central nervous system anomalies (Edwards, 1986;Graham, 2005). These findings are less established although proposed in human studies (Chambers et al, 1998;Church and Miller, 2007;Layde et al, 1980;Medveczky et al, 2004).…”

“…No association Tikkanen and Heinonen Case-control 1992(1982-1983 Congenital heart disease No association Campbell et al Case-control 1993(1989 Delayed speech Increased risk in exposed group (OR 2.8, 95% CI 1.5-5.3) Bunin et al Case-control 1994(1986-1989 Astrocytic glioma, primitive neuroectodermal tumor…”

Heat shock proteins and their role in early mammalian development

“…It is now accepted that maternal hyperthermia causes disturbances of prenatal development in animals, including humans (Edwards, 1986;Edwards et al, 1995). Significant experimental demonstration of its teratogenic effects has been published for mice (Webster and Edwards, 1984;Finnell et al, 1986;Shiota, 1988), rats in vivo (Skreb and Frank,1963;Edwards, 1967;Lary, 1982;Germain et al , 1985;Webster et al, 1985) and in vitro (Cockroft and New, 1975;Mirkes, 1985;Walsh et al, 1985;Kimmel e t a l., 1993) guinea pigs (Edwards, 1969;Hutchinson and Bowler, 1984;Upfold et al, 1989) hamsters (Kilham and Ferm, 1976) sheep (Hartley et al, 1974), pigs (Done e t a l., 1982) and monkeys (Poswillo et al, 1974;Hendrickx et al , 1 9 7 9 ) .…”

Encephalocele presented in late third trimester: a case report

“…1 The exact etiology is not known, but malnutrition, genetic predisposition, infection, radiation are postulated in occurrence of it. Some specific factors like Folic acid deficiency 4 & maternal hyperthermia 5 in early gestational age have been proved by some studies. It is usually diagnosed by ultrasound after 10 weeks because skull ossification begins at 10 weeks.…”