IN UTERO HEMATOPOIETIC stem cell transplantation (IUHSCTx) is a theoretical alternative to postnatal stem cell transplantation (SCT) for the treatment of congenital hematologic disorders that can be cured by SCT, and can be diagnosed early in gestation. Advances in prenatal diagnosis and molecular analysis now allow diagnosis of the majority of congenital hematologic disorders by10 to 12 weeks’ gestation. The evolution of high-resolution ultrasound and precise interventional techniques have solved the technical obstacles to performing early gestational cellular transplants. Considering these advances, it stands to reason that there is increasing clinical interest in performing IUHSCTx and that there will inevitably be an increasing number of attempts to treat fetuses with hematologic disorders in utero. The rationale for consideration of IUHSCTx is based on normal developmental ontogeny. The early gestational fetus is immunologically immature and uniquely tolerant to foreign antigen, allowing acceptance of allogeneic or xenogeneic cells without the need for immunosuppression. Under specific circumstances, the fetal environment appears permissive to engraftment of HSC without the requirement for myeloablation. The maternal womb is the ideal sterile isolette, allowing the potential for immunologic reconstitution before birth. Finally, successful prenatal transplantation could preempt clinical manifestations of the disease, avoiding the need for postnatal treatment and the high cost in human suffering, and expense to society, currently associated with SCT. 1, 2 This is the clinical promise of IUHSCTx. To date, this promise remains unfulfilled. With increasing experimental and clinical experience, the naive concept that a simple transplant in utero might cure a large number of diseases has given way to a realistic appreciation of the obstacles to successful engraftment. Reality has forced reconsideration of the original assumptions about fetal transplant biology, and resulted in formulation of new questions. It has also resulted in the consideration of new strategic approaches for the therapeutic application of IUHSCTx, in a variety of clinical circumstances.

‘‘NATURAL’’HEMATOPOIETIC CHIMERISM The best supporting evidence that IUHSCTx might work remains an ‘‘experiment of nature’’first described by Owen in 1945. 3 He observed that dizygotic cattle twins that share cross-placental circulation were born chimeric for their siblings’ blood elements. This state of ‘‘mixed chimerism’’persists for life and is associated with specific transplantation tolerance. 4, 5 Natural chimerism has been observed in other species as well, most notably, humans6, 7 and the cotton-top tamarin (primate). 8, 9 Interestingly, it has been observed that donor hematopoiesis in some chimeric animals can actually predominate, with the persistence of very high levels of donor-derived cells. This experiment of nature represents ‘‘proof in principle’’that, under specific circumstances, allogeneic donor cells can competitively populate a hematopoietically normal recipient, with substantial and stable levels of donor cell expression.