methods, whether or not they are carrying a transgene, tend to have higher birth weights and longer gestations than calves or lambs produced by AI (Walker et al., 1996; Young et al., 1998)—a phenomenon referred to as large-offspring syndrome (LOS). Kruip and den Dass (1997) surveyed researchers worldwide who use in vitro reproductive technologies with different breeds of cattle, and also obtained data from a controlled study of Holstein–Friesian calves. The data showed that only 7.4 to 10 percent of calves produced by AI or ET weighed more than 50 kilograms (kg) and only 0.3 to 4.1 percent weighed more than 60 kg, while 31.7 percent of calves produced by in vitro procedures (IVP) weighed more than 50 kg and 14.4 percent weighed more than 60 kg. LOS animals have more congenital malformations and higher perinatal mortality rates, although the incidence and severity of the effects reported vary widely among studies (Van Reenen et al., 2001). The range of abnormalities reported includes skeletal malformations (Walker et al., 1996), incomplete development of the vascular system and urogenital tract (Campbell et al., 1996), immune system dysfunction (Renard et al., 1999), and brain lesions (Schmidt et al., 1996). Even when IVP calves are not excessively large, however, they seem to be less viable and more often experience problems like double-muscling, leg and joint problems, hydroallantois, heart failure, enlarged organs, and cerebellar dysplasia (Mayne and McEvoy, 1993; Schmidt et al., 1996; Kruip and den Dass, 1997). In a large-scale study, van Wagtendonk-de Leeuw et al. (1998) found that 3.2 percent of calves born after IVP showed congenital abnormalities as compared to only 0.7 percent of calves produced by AI. Hydroallantois and abnormal limbs and spinal cords were especially prevalent.

The mechanism(s) responsible for these effects are unknown, but chromosomal abnormalities and disturbances in the regulation of early gene expression and in communication between the fetus and the recipient mother have been implicated (Barnes, 1999; Van Reenen et al., 2001). Cows carrying fetuses produced by IVP show abnormal placental development (Bertolini, 2002). Culture conditions are associated with LOS and other developmental abnormalities, and changing culture conditions (e.g., by not using fetal calf serum and not co-culturing with somatic cells) can help to decrease the rates of LOS and perinatal mortality (Sinclair et al., 1999; Van Wagtendonk-de Leeuw et al., 1998). Oocyte quality also might play a role in LOS and other developmental abnormalities (Kruip et al., 2000).

Because of LOS, difficult calvings (dystocia) can be a problem. The mean rate of dystocia across the five breeds represented in the Kruip and den Dass (1997) dataset was 25.2 percent for IVP-produced animals. In the population of Holsteins studied by Kruip and den Dass, dystocia scores were higher (3.05) in IVP than in AI (2.44) or embryo transfer (ET; 2.74) calves, indicating a more difficult delivery in cows carrying IVP fetuses; 14.4 percent of IVP-produced calves died perinatally as compared to 6.6 percent of ET or 6.1 percent of AI calves, and 13 percent of IVP calves were delivered by emergency Cesarean

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