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ABSTRACT & COMMENTARY
Synopsis: Using in vitro fertilization and preimplantation genetic diagnosis, a couple, both of whom had sickle cell trait, delivered normal twins. This technique may offer parents at risk for having infants with severe genetic diseases a chance to have unaffected offspring.
Source: Xu KP, et al. First unaffected pregnancy using preimplantation genetic diagnosis. JAMA 1999;281: 1701-1706.
Xu and colleagues at the cornell medical College in New York report on their work with a couple, both of whom were carriers for a sickle cell gene (Hb AS). Each pregnancy of this couple had a one in four chance of resulting in a child with sickle cell anemia (Hb SS). The mother had had two previous pregnancies interrupted after sickle cell anemia was diagnosed by DNA analysis. The couple was offered the option of undergoing in vitro fertilization (IVF) and prenatal genetic diagnosis (PEG) in order to ensure an unaffected baby. A first IVF was not successful. In a second attempt, IVF resulted in seven embryos that were subjected to PEG by taking a single cell from the embryos and analyzing the DNA using polymerase chain reaction and analysis for the presence of sickle cell and normal hemoglobin genes. Of the embryos tested, four were normal (Hb AA) and two had sickle cell trait (Hb AS). Three of the normal embryos were transferred to the uterus on day four after oocyte retrieval and later ultrasonography revealed a twin pregnancy. Pregnancy was uneventful. Amniocentesis showed that both fetuses had normal hemoglobin genes, and healthy twins with normal hemoglobin genotype were delivered at 39 weeks.
Xu et al conclude that their work indicates that IVF and PEG offer an alternative for couples at risk for having a child with a severe genetic defect who wish to avoid the presently available method of prenatal diagnosis by chorionic biopsy at 8-12 weeks of pregnancy followed by termination of pregnancies in which the fetus is affected.
Comment by Howard A. Pearson, MD, FAAP
The availability of prenatal diagnosis for a number of serious genetic diseases has made it possible to diagnose an affected infant as early as 8-12 weeks of gestation by analyzing fetal DNA obtained by chorionic villus biopsy. Availability of this technique has resulted in marked reductions in births of infants with genetic diseases such as thalassemia major and Tay-Sachs disease in the United States and elsewhere. Implicit in this procedure is the assumption that the parents will usually opt to terminate an affected pregnancy shortly after diagnosis, in the first trimester.
The report by Xu et al describes an alternative. IVF has become a fairly standard, albeit technically difficult and expensive, technique over the past decade. Xu et al combined IVF with PEG in order to ensure the birth of a normal infant to a couple at risk for sickle cell anemia. It is of some interest that this couple had previously had two standard prenatal diagnoses with termination of affected pregnancies. I have a little trouble with the rationale and justification of this kind of scientific tour de force. I completely understand parents who do not accept abortion on religious and moral grounds. Such individuals also usually believe that life begins at conception and that a multicell embryo is a "person." In this procedure, the embryos that have sickle cell anemia (and in the present report those with sickle cell trait) would presumably be destroyed and this should pose the same kind of ethical dilemma for individuals who object to any abortion for any reason.
IVF is a difficult, often unsuccessful, and expensive procedure but is widely performed throughout the world. PEG is still in the research stage and is available in relatively few centers. Whether IVF and PEG can be completely justified for carrier couples who "desire to have a healthy child but wish to avoid the difficult decision of whether to abort an affected child" is a debatable issue. Because of the expense and difficulty, I doubt that there will be many of these procedures performed except on an investigational basis in the foreseeable future.
a. A diagnosis can be made at 8-10 weeks of gestational age by analysis of fetal DNA obtained by chorionic villus biopsy.
b. A diagnosis can be made within days of conception by pre-implantation genetic diagnosis.
c. The combination of IVF and preimplantation genetic diagnosis is widely available for general use for couples at genetic risk.
d. IVF and PEG are experimental at the present time.