The Relationship Between Cleft Lip, Maxillary Hypoplasia, Hypoxia and Phenytoin

Abstract

Cleft lip (CL) is a common malformation that has both genetic and exogenous causes. The main pharmaceutical cause is exposure to phenytoin during early facial development in the 5th to 6th weeks of gestation. Phenytoin also causes CL if administered to pregnant rats during the period of early facial development. Evidence is presented that in the pregnant rat, a teratogenic dose of phenytoin slows the early embryonic heart and causes a prolonged period of embryonic hypoxia. It is proposed that this hypoxia, through an undefined downstream mechanism, leads to the development of CL. The involvement of hypoxia in the pathogenesis of CL is in agreement with studies in mouse strains with a spontaneous rate of CL in which exposure to hypoxia has been shown to increase the rate and hyperoxia to decrease the rate. Other exogenous risk factors during pregnancy for human CL include maternal cigarette smoking, residence at high altitude and exposure to corticosteroids. It is suggested that these exposures all involve an increased risk of embryonic hypoxia. It has been proposed that phenytoin affects the embryonic heart by inhibition of the human-ether-a-go-go (HERG) potassium channel. Phenytoin also inhibits sodium and calcium channels and these properties may also be involved in the observed effect on the embryonic heart. Phenytoin-induced bradycardia leading to embryonic hypoxia may be an important mechanism by which phenytoin causes birth defects.

The effect of drugs with ion channel‐blocking activity on the early embryonic rat heart

“…It has been suggested that similar effects could occur in the human and drugs with I Kr /hERG inhibition as an unwanted side effect could be potential teratogens (Karlsson et al, 2007;Nilsson et al, 2010). In this respect, phenytoin is interesting as it is a known human teratogen (Briggs et al, 2002) that induces malformations that are consistent with periods of embryonic hypoxia (Danielsson et al, 2005;Webster et al, 2006;Webster and Abela, 2007). Phenytoin inhibits potassium, sodium, and calcium channels and if the human embryonic heart is more sensitive to this combination of inhibition than the adult heart it may explain the mechanism of teratogenesis.…”

Hypoxia and the Edema Syndrome: elucidation of a mechanism of teratogenesis

“…Danielsson et al (2003) demonstrated that teratogenic doses of these drugs induce bradycardia and hypoxia in the embryo but not in the mother. During the hypoxic period, embryos show areas of hemorrhage and/or edema in areas that subsequently develop abnormally (Webster et al, 1996(Webster et al, , 2006. Embryonal cardiac arrythmia and transient hypoxia have also been suggested as mechanisms for the teratogenicity of anticonvulsants Danielsson, 1998, 2002).…”

The effect of hypoxia in development

“…This is generally regarded as being hypoxic, with most normal tissues having an oxygen tension of 20-40 mm Hg (Webster, 2007). In normal mouse, rat, and quail embryos, during the organogenic period, there are many areas that stain with pimonidazole, and the location of these areas changes with the age of the embryo (Lee et al, 2001;Danielsson et al, 2003a;Webster et al, 2006;Naňka et al, 2006). The interpretation that the stained cells in the embryos are hypoxic is supported by the demonstration that pimonidazole mostly colocalizes with hypoxia inducible factor (HIF-1a) and vascular endothelial growth factor (VEGF) in mouse and quail embryos (Lee et al, 2001;Naňka et al, 2006).…”