With a genetic diagnosis, the counseling ophthalmologist should outline the options available for family planning. Some people may accept a high statistical risk and choose to have children. This decision is based on how they perceive the social and psychological challenges of the disorder. Attitude toward reproduction may be considerably different, for instance, for a female carrier of protanopia than for a female carrier of X-linked RP or choroideremia, even though the statistical risk for an affected son is the same for each carrier. Some may elect to delay childbearing in the hope of future medical advances. For a variety of personal and ethical considerations, others may opt for contraception, termination of pregnancy, sterilization, and/or adoption.
Artificial insemination by a donor is a useful option in family planning if the father has a dominant disease or if both parents are carriers of a biochemically detectable recessive disorder. However, it is clearly not applicable if the mother is the carrier of an X-linked or mitochondrial disorder or if the mother is the individual affected by an autosomal dominant mutation. Finally, donor eggs, donor embryos, and surrogate motherhood—where these options are available—may be alternatives for some families.
In some circumstances, an individual or a couple may use the results of genetic testing and consider prenatal testing or in vitro fertilization (IVF) technology with preimplantation genetic diagnosis (PGD) to avoid recurrence in their children. Knowledge of these options and of the potential ethical, social, and cultural issues they raise is important for clinicians.
Prenatal diagnosis (PND) with amniocentesis or chorionic villus sampling (CVS) for biochemically identifiable disorders (eg, Tay-Sachs disease, many mucopolysaccharidoses, and more than 100 other diseases) is useful in the proper genetic scenarios.
Other possible indications for PND include
advanced maternal age or positive results from prenatal screening, which both carry an increased risk of chromosomal abnormalities
elevated maternal serum α-fetoprotein, suggesting a neural tube defect
presence of soft markers or fetal abnormalities that could suggest a chromosomal abnormality or a genetic disease
presence of a familial disease detectable by DNA analysis
Amniocentesis is usually performed at 15–16 weeks of gestation, when enough fluid and cells can be obtained for culture and the maternal risk of abortion is relatively low. The risk of spontaneous abortion or fetal morbidity from the procedure is approximately 0.5%. Earlier PND of chromosomal abnormalities, at about 10 weeks of gestation, is available through the use of CVS. In this procedure, tissue from the placenta is obtained under ultrasound visualization. It is then cultured and karyotyped in a manner similar to that used for amniocentesis. As a first-trimester procedure, CVS allows earlier diagnosis and can lead to earlier and thus safer pregnancy termination. The rate of spontaneous abortion associated with this procedure is estimated at 1%–2%.
Cell-free fetal DNA (cffDNA), sometimes called noninvasive prenatal screening, is a new technique to examine fetal DNA in the maternal bloodstream. CffDNA is being developed to allow PND without the risks associated with CVS or amniocentesis.
Couples who elect PND in the form of either CVS or amniocentesis may face considerable anxiety about complications, such as pregnancy loss, waiting time to obtain the genetic results, and, potentially, the difficult decision of whether to terminate an affected pregnancy—a dilemma that couples are aware they may face repeatedly with each consecutive pregnancy.
Preimplantation genetic diagnosis
Preimplantation genetic diagnosis (PGD) has the advantage of enabling selection of unaffected embryos through testing prior to implantation. Embryos are created using intracytoplasmic sperm injection (ICSI), in which a single sperm is injected into each egg in an attempt to achieve fertilization. On day 3, when each embryo consists of 6–8 cells, 1 cell (blastomere) is removed per embryo. DNA is extracted from these cells and amplified using fluorescent polymerase chain reaction (F-PCR) to make millions of copies of the relevant region of DNA. This region is then sequenced to provide a reliable diagnosis of the status of the genetic mutation in each embryo. Unaffected embryos are transferred to the uterus on day 4 or 5. Usually, no more than 1 or 2 embryos can be transferred, to avoid the possibility of multiple births.
PGD is acceptable to many couples and, for some, it represents a valuable alternative to PND. For some couples with a moral or religious objection to pregnancy termination and who are at risk of having a child with a genetic condition, this technique may provide the opportunity to have an unaffected child. However, PGD may be associated with stress and anxiety for couples similar to that discussed earlier. Other concerns include the high cost of IVF and genetic testing (often not covered by insurance) and the low IVF pregnancy rates. PGD has raised ethical issues about embryo destruction and sex selection. Furthermore, the issue of eugenics (selection for perceived favorable nonmedical traits) has also been debated. Just as diseases differ among individuals, so do the concerns and beliefs of different parents; thus, the acceptability of different reproductive technologies should be discussed with each couple.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.