Primary Prevention of Congenital Abnormalities Due to High Fever Related Maternal Diseases by Antifever Therapy and Folic Acid Supplementation

Background: Our previous case-control studies showed an association between high fever related maternal diseases and some congenital abnormalities (CAs). The aim of this review is to summarize the result of these studies completed with available animal and clinical data from the international literature. Materials and Methods: The Hungarian studies were based on the population-based Hungarian Congenital Abnormality Registry and the Hungarian Case-Control Surveillance of Congenital Abnormalities. The latter included 22,843 cases with 25 different CA and 38,151 matched controls without CA Results: High fever related maternal diseases such as influenza, common cold with secondary complications, recurrent orofacial herpes and some other acute infectious diseases showed associations with the higher risk for isolated neural-tube defects, cleft lip ± palate, posterior cleft palate, cardiovascular CAs and multiple CAs. These findings were confirmed in the studies of etiological factors in the origin of isolated neural-tube defects, orofacial clefts and multiple CAs, in addition to congenital cataract. The most important results of animal investigations and other human studies related to the teratogenic effect of high fever are also summarized in order to achieve some general conclusions. Conclusions: Maternal high fever related diseases may associate with some CA and these CAs cover an unusual wide spectrum, which may be connected with the less specific antimitotic effect and heat stress response of hyperthermia. A higher risk for CAs can be expected due to high fever being over 38.5 °C continuing for one or more days. The timing of hyperthermia determines the risk of specific CAs. The high fever induced CAs represent a high proportion (5-7%) of CAs. The basic indication of our studies is that antifever drugs and periconceptional folic acid/multivitamin supplementation can significantly reduce the teratogenic effect of high fever related maternal diseases. Thus, CAs induced by maternal high fever related diseases are preventable.