New uses for assisted reproductive technology
The process of IVF has allowed clinical scientists to have direct access to the human embryo for the first time. Micromanipulation is now widely used to engineer embryo biopsy to remove one or two cells at day 3 of development or to take a trophectoderm biopsy at the day 5 blastocyst stage.
This technology has been applied to develop PGD and PGS. PGD targets a specific mutation that is known to be present within the family undertaking the IVF. Examples include cystic fibrosis, Tay-Sachs disease, thalassaemia, neurofibromatosis, and hundreds of other specific mutations that have a significant effect on the health and life expectancy of the child. PGD can also be applied at chromosomal level for sex selection, for example, to select for female fetuses in the presence of X-linked conditions such as Duchenne muscular dystrophy. Couples undertaking PGD are not necessarily infertile, but rather use the IVF technique to access embryonic DNA to allow exclusion of an affected embryo. Many couples find this approach more ethically acceptable than screening in pregnancy with termination of an affected fetus (21).Embryonic sex selection is also widely practised for ‘family balancing’ in some countries, including the United States, although ethical objections are significant and many other countries, including the United Kingdom and Australia, do not permit non-medical sex selection.
PGS involves use of the embryonic tissue to screen for aneuploidy (22). The frequency of aneuploidy increases with advancing female age. An increasing number of women are starting their IVF journey in their late 30s or older, and in theory they should benefit from transfer of an embryo that is known to be euploid. PGS should improve implantation rates, reduce early miscarriage rates, and may circumvent a need for amniocentesis later in pregnancy. However, early work using fluorescent in situ hybridization, with screening for abnormalities in only a limited number of chromosomes, was shown in randomized controlled trials to result in lower pregnancy rates than seen in controls (24).
Application of methods that assess every chromosome using array comparative genomic hybridization and now ‘next-generation’ sequencing are giving more promising results but adequately powered, well-designed randomized controlled trials are still needed before this technology is introduced into routine practice.ART also allows collection of eggs and embryos for elective cryopreservation. The efficiency of cryopreservation has improved dramatically since older slow-freezing methods were replaced by ‘snap freezing’ or vitrification. The process requires ovarian stimulation and egg collection as in routine IVF, followed either by cryopreservation of oocytes or fertilization and later cryopreservation of embryos. This approach was first developed for use with young women with cancer who were facing chemotherapy or radiotherapy. This treatment would be likely to lead to significant loss of ovarian reserve and later infertility. Storage of eggs or embryos would allow them the chance of having children after successful treatment of their cancer even if their natural ovarian reserve was completely depleted by their treatment. Many pregnancies and births have now been reported in this group of patients and oncofertility preservation is widely practised (24, 25).
The technology of egg freezing is also increasingly being utilized by healthy young women who are anxious about their loss of ovarian reserve before they are in a position to start their family (26). Some have a strong family history of early menopause, while others have left a long-term relationship and are worried because of advancing age. A third group are in a long-term relationship but wish to defer pregnancy for career or family reasons. As IVF becomes safer and more socially acceptable, and as vitrification of oocytes has significantly improved survival and subsequent viability of frozen-thawed oocytes, this approach is being more widely advocated although some fertility specialists remain sceptical about the chances of pregnancy from vitrified oocytes.
Egg freezing has also been widely applied in the creation of ‘donor egg banks’ (27). These are used by women who have poor or no ovarian reserve, either due to advanced age or premature menopause, and who wish to have a family with donor oocyte. Use of cryopreservation allows for effective screening for infectious diseases since donors can be tested for seroconversion for HIV and hepatitis before the oocytes are released from the bank. Donors are younger women who either wish to donate altruistically or who are paid to donate. While this latter practice is permitted in many jurisdictions, including the United States and many European countries, others, including Australia, permit payment of expenses only. As with children born after sperm donation, modern practice encourages transparency with identification of the donor to the child when he or she reaches maturity. This allows the child to learn about their biological origins by way of a meeting or meetings with their donor ‘parent’.