Prenatal Genetic Testing and Counselling

Prenatal genetic testing is used to determine if a fetus has, or is at risk of developing, a genetic disorder. These disorders are caused by changes, often deletions or duplications, in fetal DNA and chromosomes. Two main types of testing often performed are screening and diagnosis. Screening tests typically look for aneuploidy—an abnormal number of chromosomes, such as a trisomy—whereas diagnostic testing is used to determine whether the fetus has a specific disorder—for example, Huntington’s disease. All pregnant women in North America have the option of genetic testing, but counselling is strongly recommended to assess individual needs, risks, benefits, and overall options. Most commonly, testing is recommended for pregnancies at risk for either chromosomal or single-gene disorders, with the goal of helping patients make informed reproductive decisions.[1] Maternal age alone is a poor minimal standard for aneuploidy screening,[2] and therefore multiple factors need to be considered in identifying women at risk of giving birth to an infant with any type of chromosomal abnormality.[3]

Preconception Counselling

A consultation with a genetic counsellor involves multiple areas of assessment and education. Family history and ethnicity are both important considerations when assessing the risk of chromosomal abnormalities.[1] For example, if a certain disorder has been identified in a family as being genetically caused, like cystic fibrosis, parents can be tested to evaluate their risk of giving birth to a child who would also be affected.[1] Parents can also be carriers of specific genetic alleles or mutations and can pass on those traits to their offspring. The difficulty is that a parent who is a carrier is often asymptomatic, but “carries” the gene that can be passed on to their children. Then either the child can also be a carrier, or they could present with the disorder if both parents are carriers. This is also where ethnicity plays a role in risk assessment, as some ethnicities have higher carrier rates and different types of mutations than others.[1] Genetic counsellors collect all this information from both partners, and discuss the range of testing options with the risks, benefits, and limitations of each.[4] It’s also important that the counsellor understands their patient’s values regarding prenatal testing options.[4] The overall goal is to provide not only risk assessment for a couple, but also support and education to help them make the best decisions for them.[4]

Prenatal Testing

Two types of testing can be done prenatally, typically between weeks 11 and 14 of pregnancy. A mother’s first ultrasound on her baby is conducted to measure and observe any structural anomalies that may indicate Down syndrome, congenital heart defects, and other growth issues.[5] Bloodwork can also be performed in the late first trimester and in the second trimester to screen for Down syndrome, trisomy 18, and neural-tube defects.[6] An ultrasound in the second trimester may be scheduled either as a follow-up to the first, or on its own as a screening for physical abnormalities at this stage in development.[6] Normally, humans have 23 pairs of chromosomes. Having too many or too few chromosomes can lead to major developmental changes. For example, a trisomy means that there are three chromosomes instead of the normal paired chromosomes. The number that follows “trisomy,” for example, 21 or 18, indicates which human chromosomes are affected. There is no control over preventing these issues, and we don’t fully know why they happen. Chromosomal microarray is one means of testing which can be used to detect small deletions or duplications of the genetic material within chromosomes. The material (cells) tested is taken either from an amniocentesis, removing a small portion of amniotic fluid from around the fetus, or from what we call chorionic villus sampling or “CVS,” where cells are taken directly from the placenta.[4] A microarray will often be recommended if something structurally abnormal is found on a previous ultrasound; however, the results can be complicated. Interpreting some of the variants on a microarray comes with a degree of uncertainty. Some results may be clearer, whereas others may leave couples, and even their genetic counsellor, more unsure than anything.

The problem is that it can be extremely difficult to see microarray results and be able to know exactly what the increased risk of a disorder is.[7] Even if a change is found in the results, there could be very limited information available, or limited documented cases on that one change. In such cases, some infants found with these changes can grow up completely unaffected, while others with that same genetic change could have a drastically different presentation with severe neurodevelopmental delays.[7] We can find these changes, but they can manifest in different ways,[7] and for some women and couples, that fact alone can be more distressing because the information gathered from the test results really doesn’t provide the answers they were looking for.[4] More recently, noninvasive prenatal screening is being used in practice. It’s noninvasive in nature because, unlike CVS and amniocentesis, the fetus and placenta stay undisturbed, while blood is only taken from the mother. In fact, the use of invasive tests has decreased over the past five years, as these more advanced screening tests have improved.[4] In noninvasive prenatal screening, laboratories use fetal cell-free DNA found in the plasma of pregnant women, often taken in the late first trimester.[4][8] This sample can be used to determine the gender of the fetus as well as fetal Rh blood group genotype in Rh-negative women.[8]

Several studies have shown a high sensitivity, high specificity, and low false-positive rates using cell-free DNA testing to detect trisomy 13, 18, and 21. As well, there is a high detection rate for sex chromosome abnormalities.[1] Specific testing using these methods can also be applied to diagnose hemophilia, beta-thalassemia, and sickle-cell anemia.[8] The downside is that, as of current, it cannot detect neural tube defects, and should not be considered a complete substitute for our routine first and second trimester screening (bloodwork and ultrasound).[1]

Pre- and Post-IVF Transfer Testing

A history of recurrent pregnancy loss will often prompt the testing of both partners for chromosomal abnormalities. Chromosomal aneuploidy has been identified as a major factor in failure for an embryo to implant, as well as spontaneous abortions (miscarriage).[1] Preimplantation genetic screening (PGS) is performed on all embryos obtained from an IVF cycle and is used to detect aneuploidy.[1] A sample of cells is taken from the embryo after fertilization, but before uterine transfer. Over the past few years, many changes have occurred in PGS. First, advances have allowed labs to provide fast turnaround times for results and with higher accuracy. When the test originated, only 9–12 chromosomes could be evaluated at a time; however, significant advances now allow us the ability to evaluate all 23 chromosome pairs.[9] As well, the biopsy used to occur on day 3 after fertilization, during the cleavage stage when the embryo is in the blastomere phase. Now, we can use trophectoderm biopsy further into the cleavage stage around day 5, which decreases the risk of a developmental lag in the embryo.[9] Similarly, preimplantation genetic diagnosis (PGD) can be used to assess for specific conditions such as cystic fibrosis, Huntington’s disease, achondroplasia, and many others.[1] However, these types of tests are only run when the condition has been identified as genetic within the family history.

What to Consider with Regards to Genetic Testing

Women and their partners need to understand that testing is optional and should be considered only if in line with their personal beliefs as well as their family history and/or risk of genetic disorders.[4] As technology advances, testing procedures and options may change, so it is best to understand all options with the risks and benefits of each. As well, there are limitations to any results obtained from testing. Many women and couples go into testing hoping for a simple “yes” or “no” answer, but this may not always be the case. In fact, many cases have been documented where results are unclear or the implications of a specific abnormality are currently unknown.[4] This can leave patients more distressed and unsure of their future reproductive steps. As far as screening goes, more is not necessarily better. Before deciding on having a test done, ask yourself what you would do with the results. Would it change or influence any of your decisions? Would you be able to live with uncertainty? Unfortunately, we must address these concerns, as our means of testing are not 100% accurate or clear. However, with time and technological advances, that could—and likely will—change.