J. Comp. Path. 2007, Vol. 136, 256^265 Foot-and-Mouth Disease Virus Crosses the Placenta and Causes Death in Fetal Lambs E. Ryan *,y , Z. Zhang * , H. W. Brooks y , J. Horsington * and J. Brownlie y * Institute forAnimal Health, Pirbright Laboratory, Ash Road, Pirbright,Woking GU24 0NF and y RoyalVeterinary College, Hawkshead Lane, North Mymms, Hat¢eld AL9 7TA, UK Summary Eighteen pregnant sheep, six at 45 days gestation and twelve at 75 days gestation, were infected with foot-and- mouth disease virus (FMDV) type O UKG 34/2001. Two sheep from each gestational group were killed at 2, 4, and 7 days post-inoculation (dpi).Three sheep, pregnant for 75 days at infection, were killed at 17 and 18 dpi. Real- time reverse-transcriptase polymerase chain reaction (RT-PCR) and virus isolation (VI) were used to detect viral RNA and infectious virus, respectively, in fetal tissues taken post mortem. Eleven fetuses were obtained from the six sheep inoculated at day 45 of gestation. Of these, two of three fetuses at 2 dpi had viral RNA detected by RT-PCR and virus was detected in one byVI.Viral RNA was detected in two of four fetuses at 4 dpi, while viral RNA and virus were detected in all four fetuses at 7 dpi. No gross abnormalities were evident in these fetuses. In the group inoculated at day 75 of gestation, viral RNAwas detected in three of four fetuses at 4 dpi.Virus and viral RNAwere detected in three of four fetuses at 7 dpi. Of the seven fetuses examined at 17 and 18 dpi, viral RNA was detected in ¢ve, and four of these had died in utero . Gross abnormalities including haemorrhage and oedema in a number of tissues were evident in many of the fetuses in this group, but no vesicular lesions were found.Viral RNA and virus were detected in the amniotic £uid associated with infected fetuses. This study is the ¢rst to demonstrate that FMDV may cause transplacental infection and fetal death. r 2007 Elsevier Ltd. All rights reserved. Keywords: foot-and-mouth disease virus; infection; fetus; sheep Introduction Foot-and-mouth disease virus (FMDV) is the aetiolo- gical agent of foot-and-mouth disease (FMD), a highly contagious acute vesicular disease of cloven-hoofed an- imals. FMDV is classi¢ed within the Aphthovirus genus as a member of the Picornaviridae family (Belsham, 1993 ). FMD is a major hindrance to international trade in animals and animal products, and the cost of eradi- cation can be enormous. The 2001 outbreak in the Uni- ted Kingdom is estimated to have cost the agricultural sector »3.1 billion, with similar losses to the tourism sector (Thompson et al ., 2002 ). In sheep, the disease is milder than in cattle or pigs, with viraemia present for up to 3 days before the ap- pearance of vesicular lesions (Alexandersen et al ., 2003b). During this time the sheep may be pyrexic and distressed, with lameness spreading through the £ock. Agalactia may occur in ewes.Vesicular lesions oc- cur in the interdigital cleft, along the coronary bands and on the bulb of the heels. Oral lesions are less com- mon but can occur on the dental pad, tongue and gums. There are ¢eld reports of FMD causing severe out- breaks of abortion in sheep (Geering, 1967 ; Nazlioglu, 1972 ) yet there are no published studies of experimental infection of pregnant farm animals. Oppermann (1921) (cited by Littlejohn,1970 ) reported that in the 1920 epi- zootic in Germany the average abortion rate was 3^10% but was sometimes up to 37%, and as high as 100% in some cases. Abortion occurred in ewes at var- ious stages of gestation and usually began 10 days to 6 weeks after the startof the outbreak. Parakin (1961) (cited by Littlejohn, 1970 ) described an outbreak in www.elsevier.com/locate/jcpa ARTICLE IN PRESS 0021-9975/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi: 10.1016/j.jcpa.2007.03.001 Correspondence to: Z. Zhang, Institute for Animal Health, Pirbright La- boratory, Ash Road, Pirbright, Woking GU24 0NF, UK (e-mail: zhidong. zhang@bbsrc.ac.uk).