of late spontaneous abortions or the birth of a stillborn child or a child with severe health problems.

A wide array of abnormalities and defects have been observed in reproductively cloned animals, both before and after birth [4; 6; 8-10; 13; 16; 20; 23; 24; 29; 32; 38-45]. However, these abnormalities have not always been studied in detail, possibly because most reproductive animal cloning has been done for commercial purposes and there is less interest in the failures than in the successes. The panel was told that funding for studies to catalog and understand the basis of the abnormalities is sorely needed [39].

The reported defects in cloned animals are summarized in Table 1 and detailed in Table 2. The most notable defects are increased birth size, placental defects, and lung, kidney, and cardiovascular problems [39; 46]. Other problems have included liver, joint, and brain defects, immune dysfunction, and postnatal weight gain. Thus, a wide variety of tissues and organs can fail to develop properly in cloned animals, and some of the reported defects (such as aberrant growth and development of lung tissue and the immune system) cannot be diagnosed or prevented with current technology, such as prenatal screening with ultrasonography.

Many of the defects seen in cloned cattle and sheep (for example, high birth weight, abnormal placentation, fluid accumulation associated with maternal and fetal distress, and cardiovascular abnormalities) are the same as those described for “large offspring syndrome” (LOS). This is frequently seen in uncloned offspring produced after in vitro fertilization and embryo manipulation in these species (but not in others, including humans [47]) and is attributed to, among other things, the exposure of eggs and embryos to suboptimal culture conditions in the laboratory [41; 47-49]. In spite of much work to identify the causative factors (given the economic benefits that could come from efficient embryo manipulation in cattle), the etiology and species specificity of LOS are not understood. All that can be said is that it probably results from abnormal gene expression in the early embryo, including the misexpression of imprinted genes (see later) [41; 47]. As will be discussed again below, this highlights the fact that perturbations in gene expression during the preimplantation period can have serious consequences for later development. For the purposes of this report, it is important to stress two other things: some of the postnatal defects described in cloned cattle have not so far been associated with LOS (for example, [13]); and species that do not show LOS after normal