Preimplantation genetic diagnosis

Pregnant women whose babies are at risk of having a genetic condition serious enough to warrant consideration of termination of pregnancy may be offered prenatal diagnostic tests such as amniocentesis and chorionic villus biopsy. For some couples, however, such tests are not acceptable, and preimplantation genetic diagnosis is an alternative.

Preimplantation genetic diagnosis involves testing the early embryo after in vitro fertilisation. One or two cells (blastomeres) are removed at biopsy from the preimplantation embryo at the 6-10 cell stage (day 3 of development), thus allowing replacement into the uterus of unaffected embryos.

Preimplantation genetic diagnosis can be offered for three major categories of disease. Firstly, it can be used to determine the sex of the embryo for sex linked disorders where the specific genetic defect at a molecular level is unknown, highly variable, or unsuitable for testing on single cells—for example Duchenne muscular dystrophy.¹ Secondly, it can be used to identify single gene defects such as cystic fibrosis, where the molecular abnormality is testable with molecular techniques after polymerase chain reaction (PCR) amplification of DNA extracted from single cells.² Thirdly, it can be used in chromosomal disorders, where fluorescence in situ hybridisation has been developed to detect a variety of chromosomal rearrangements, including translocations, inversions, and chromosome deletions.³ Some potential parents who carry a chromosomal rearrangement may never have achieved a viable pregnancy before requesting preimplantation genetic diagnosis if each previous conception resulted in a chromosomally unbalanced embryo which miscarried spontaneously.

Preimplantation genetic screening for aneuploidy (Down's syndrome and other trisomies) is not licensed by the Human Fertilisation and Embryology Authority in the United Kingdom, though it is offered elsewhere, including the United States and Italy.

It has taken over 10 years for preimplantation genetic diagnosis to become established, and only five UK centres are licensed. A preimplantation diagnosis cycle is a major undertaking for any couple, and the psychological, medical, and financial costs are considerable. A single cycle costs £4000-7000 (US$6000-10 500) (including drugs). About half of British patients obtain some NHS funding.

Recently the European Society of Human Reproduction and Embryology published results on 886 couples undergoing 1318 cycles of preimplantation genetic diagnosis over seven years.⁴ Most couples had already had pregnancies, but fewer than 25% had healthy children. Over a quarter had one or more children affected with a genetic condition and a similar proportion had a spontaneous abortion or underwent termination after prenatal diagnosis. In about a third of cases the genetic indication for preimplantation genetic diagnosis was combined with subfertility, necessitating in vitro fertilisation or intracytoplasmic sperm injection. The reported pregnancy rate was only 17% (detection of fetal heart beat per cycle started), but this is improving: in our centre, established in 1998, the rate is 33%.⁵ The European study reported four misdiagnoses after tests using PCR; these were detected at prenatal diagnosis, which was performed on 116 of the 236 fetal sacs (49%).⁴

The high incidence of multiple pregnancies after preimplantation genetic diagnosis is a concern (33% from the European data). Probably a maximum of two embryos should be transferred. Data so far suggest that children born after preimplantation genetic diagnosis do not have a higher incidence of congenital malformations or neonatal problems than children born after “regular” intracytoplasmic sperm injection, but they need to be followed up systematically through childhood.⁴

In the United Kingdom the Human Fertilisation and Embryology Authority has a central role in regulating preimplantation diagnosis, and each centre must obtain a licence for every test offered. The submission of multiple applications is time consuming and there is a debate in the UK about whether over-regulation is stifling service development. The authority's strong guidance is important, however, in such a new and controversial area. The virtually unregulated provision of preimplantation diagnosis in other countries, where sex selection for “family balancing” and HLA typing is performed, risks bringing the whole technique into disrepute.

To offer a safe effective service, a multidisciplinary team needs to be established, including specialists in in vitro fertilisation, clinical geneticists, genetic counsellors, cytogeneticists, and molecular biologists. Laboratories should participate in external quality assessment. The UK's tight regulation should reassure people worried that preimplantation diagnosis might lead to “designer babies.” Establishing a similar degree of regulation internationally will depend on the motivation of individual governments and clinicians.