Category Archives: Ethics


Can a personalized approach improve IVF success rates?

Test Tube Baby

This post was written by Robert D. Nerenz, PhD, an assistant professor of pathology and laboratory medicine at the University of Kentucky, in Lexington.

In the United States, an estimated one in seven couples experience infertility and for many of these couples, in vitro fertilization (IVF) represents their best chance of achieving pregnancy. However, IVF cycles constitute a significant expense (approximately $12,500 per cycle), disrupt patients’ daily lives and only result in a healthy, live birth 30% of the time! Furthermore, the majority of IVF cycles performed in the United States involve the transfer of multiple embryos. This is of particular concern because multiple embryo transfer carries a finite risk of a multiple gestation pregnancy. Bringing multiple infants to term is associated with an increased risk of poor fetal and maternal outcomes including decreased birth weight, increased rate of fetal death, preeclampsia, gestational diabetes and preterm labor. Clearly, there is a significant need to improve IVF success rates while also minimizing the likelihood of multiple gestation pregnancies.

One strategy that may accomplish both of these goals is to perform “single embryo transfer” by implanting one embryo that has a high likelihood of producing pregnancy and, ultimately, a live birth. This is the focus of an upcoming symposium at the AACC meeting to be held July 29th at 10:30 am in Atlanta, Georgia. Fertility clinics around the world currently attempt to do this by observing embryos under a microscope and choosing the best embryo on the basis of its physical appearance. Unfortunately, this approach does not provide any information about the embryo’s genetic status. This is an important limitation because aneuploidy (the gain or loss of a chromosome) is the most common cause of pregnancy loss. It is also estimated to occur in ≥10% of clinical pregnancies and becomes more frequent with increasing maternal age.

To ensure that aneuploid embryos are not selected for transfer, several research groups have developed methods collectively known as comprehensive chromosome screening (CCS). CCS involves culturing embryos for 5-6 days, removing a few cells from the trophectoderm (the outer cell layer that develops into the placenta), isolating the DNA from those cells and assessing the copy number of each chromosome using techniques such as quantitative PCR, comparative genomic hybridization, or single nucleotide polymorphism arrays. Following determination of the embryos’ genetic status, only embryos with the normal number of chromosomes are chosen for transfer. In multiple prospective, randomized controlled trials described here and here, CCS has been shown to increase the pregnancy rate and decrease the frequency of multiple gestation pregnancies. As a result, CCS is beginning to make the transition from the research setting to use with patients.

The ability to transfer only euploid embryos represents the most promising application of novel technologies to IVF but ongoing research is focused on other ways to improve the IVF success rate. Many different groups are analyzing the culture medium that embryos are grown in prior to implantation. It is hoped that this will provide information about the embryos’ metabolic health and might help identify which embryos are most likely to result in pregnancy and live birth. Other groups are evaluating endometrial gene expression profiles to assess endometrial receptivity and ultimately determine the best time to perform embryo transfer. While both of these approaches have technical limitations and are not quite ready for primetime, they have the potential to greatly improve our current standard of care and may be ready for clinical use in the near future.

Preimplantation Genetic Diagnosis and Screening

BlastocystPreimplantation genetic testing is a way of examining the genetic features of a developing embryo during the process of in vitro fertilization, before pregnancy. After the egg is fertilized with sperm, the embryos develop to the cleavage-stage. On day 3 after fertilization, a single blastomere is removed from the embryo for genetic evaluation using techniques such as PCR, FISH, or comparative genomic hybridization.

Preimplantation genetic diagnosis (PGD) is used to select embryos without certain genetic disorders. This testing including three major groups of disease: sex-linked disorders, single gene defects, and chromosomal disorders.

Preimplantation genetic screening (PGS), is not used to detect disease, but as a screen to select embryos for such things as: matching HLA type in order to be a tissue donor for an affected sibling, selecting gender, selecting embryos with the least predisposition for developing certain cancers, and selecting embryos with a higher chance of implantation and therefore increase the likelihood of achieving pregnancy. Medscape has an excellent overview of PGD and PGS.

For women of advanced maternal age or couples with known genetic mutations, the ability to screen for embryos free of certain genetic mutations is reassuring. However, as with many medical interventions associated with human reproduction, PGS has raised ethical questions. For instance, as stated earlier, PGS can be used to select for a preferred gender. In some cases this is to avoid a sex-specific disease. Other times this is done for so-called "family planning" or "gender balance." In other words, selecting a gender because of personal preference. Some feel this is discriminatory and should not be allowed. In other cases, embryos have been tested so that the resulting child would be compatible to serve as a stem cell donor for a sick sibling (much like the popular fiction book "My Sister's Keeper").   There have also been cases where parents have requested the selection of affected embryos so that the child has the same minor disability, such as deafness or dwarfism, as the parents. Some preimplantation genetics laboratories agree to do this type of testing and some do not.

The New York Times recently ran an article discussing this issue. The article states that:

"In the United States, there are no regulations that limit the method’s use. The Society for Assisted Reproductive Technology, whose members provide preimplantation diagnosis, says it is 'ethically justified' to prevent serious adult diseases for which 'no safe, effective interventions are available.' The method is 'ethically allowed' for conditions 'of lesser severity' or for which the gene increases risk but does not guarantee a disease."

The January issue of Clinical Chemistry published a Question and Answer piece entitled "The Ethical Implications of Preimplantation Genetic Diagnosis." A podcast interview with two of the authors is also available.

The paper summarized the opinions of an ethicist, an attorney, and the director of a preimplantation genetics laboratory. The ethicist indicated that in the past, PGD has focused mainly on reducing the risk of transmitting serious diseases. In the future, he sees a shift away from lifesaving interventions to more ‘eugenically’ inspired interventions. That is, looking for traits that parents do not want in their children and selecting for traits that they do want in an attempt to pass them on. The morality of eugenics is a key moral as this technology moves forward.

Indeed it will be interesting to see where the future of this technology lies. Although it is practiced routinely, the indications, utility, and outcomes of PGD and PGS are still being defined.