Why You Should Get Genetic Testing During Pregnancy

Pregnancy is a series of milestones and stages that each come with their own set of choices.  At the end of the first trimester, pregnant individuals must decide whether to have genetic testing and what kind of testing to do.

When my patients have done pre-implantation genetic testing (PGT), essentially a form of per-pregnancy genetic testing done during IVF, where the embryo transferred underwent genetic screening before it was frozen, they often assume that the PGT covers them and no other tests are required. At every discharge visit, I make it a point to talk to my patients about the need for genetic screening/testing, in some form, during pregnancy.

Pregnancy genetic testing options

Prenatal genetic tests can be broken down into screening tests and diagnostic tests.

Screening Tests

Screening tests indicate if you are at an increased risk of having a child with the wrong amount of DNA (ie. missing or gained chromosomes). In general, screening tests are non-invasive (blood work markers and/or ultrasound features). A newer non-invasive form of prenatal screening for the first trimester involves the analysis of free, or cell-free, fetal DNA which is found in the mom’s circulation – it can be analyzed for the number of chromosomes from a blood draw taken from a pregnant patient. In general, screening tests may point to a need for further testing which is more definitive and can confirm whether or not an actual problem exists. Screening tests can also miss things – it will not always flag that there is a problem – so there is a chance that something could be missed. The chance of this is lower in patients who are known to be at lower risk in general (ie. younger patients – since age is a major risk factor for having the wrong number of chromosomes in the egg/embryo). Further, screening tests can only tell us about the amount of DNA in a pregnancy and to detect some markers on ultrasound for certain types of birth defects) – they cannot test whether an embryo carries a type of mutation that can lead to a specific disease (ie. cystic fibrosis). Screening tests that point to an increased risk of genetic abnormality or in patients who want to get definitive information about the genetics of their pregnancy can opt for DIAGNOSTIC tests. Some patients may decide to forgo some screening tests and go straight to diagnostic testing.

Diagnostic Tests

Diagnostic testing is always invasive and requires a sample of cells, either from the placenta or fetus itself. These tests can be done in the first trimester, as chorionic villus sampling between 11-14 weeks or in the second trimester, as an amniocentesis starting as early as 15-16 weeks. 

Chorionic villus sampling (CVS): 

CVS is done between 11 to 14 weeks. A sample of chorionic villi (cells from the placenta) is removed using a needle (through the abdomen or cervix, depending on the position of the placenta in the uterus) and sent off for testing. When embryos are tested with PGT, a very small number of cells (4-10) from the trophectoderm, the part of the embryo that will one day become the placenta, is what is tested. When sampling cells from the placenta during a CVS, many more cells can be removed for analysis. This allows for the technology to be higher resolution and to detect smaller deletions or duplications in the DNA that would otherwise not be picked up by PGT.  The downside to a CVS is that it is invasive and can lead to cramping, spotting/bleeding, and there is a very small risk of miscarriage. In experienced hands, the risk of miscarriage may be as low as 1 in 500 to 1000 cases. There is also a very small risk of the procedure leading to infection in the placenta/uterus. In rare cases the cells that make up the placenta do not reflect the cells that make up the fetus – this is called ‘confined placental mosaicism’.

Amniocentesis:

Amniocentesis involves the removal of a small amount of amniotic fluid from the uterus, to be sent off for genetic testing – to quantify the amount of DNA in a pregnancy and/or to diagnose whether a pregnancy is affected by a genetic mutation/disease. Amniocentesis for the purpose of genetic testing can be done from 15 to 20 weeks of pregnancy. The amniotic fluid which surrounds the baby contains many cells shed from the fetus itself – therefore the genetic testing results from this sample will reflect the genetic makeup of the fetus, not a limited component of the pregnancy (ie. the placenta). The amniotic fluid is drawn up using a long needle which passes through the abdominal wall and into the uterus and amniotic sac. Because this is an invasive procedure, there can be complications, albeit rare. Amniocentesis can result in leaking amniotic fluid – in most cases this is transient and will stop within 1 week. Miscarriage can also occu with rates of about 0.1-0.3%. There is also a risk of introducing an infection into the uterus. Very rarely, the needle itself could lead to injury of the baby or structures around the uterus. 

Why you should always genetic test during pregnancy

Now that we’ve reviewed the types of prenatal genetic testing available, let’s get back to why I recommend genetic testing- even in pregnancies from PGT-normal embryos:

PGT errors:

While PGT has been validated and is known to have a low error rate (~less than 2%), no test is perfect and can be fully trusted. It makes sense to do prenatal genetic testing as a confirmatory step. This is particularly true in cases where PGT has been used to rule out a specific genetic mutation/disease. 

Mosaicism:

Mosaicism is a normal biological phenomenon whereby cells with differing numbers of chromosomes can exist within the same embryo/person. Because PGT involves only sampling 4-10 cells of the part of the embryo that one day becomes the placenta, and confined placental mosaicism can occur – sometimes the cells being tested for PGT might not be representative of the overall embryo and future pregnancy. Nobody knows the true incidence of mosaicism in embryos – this is being actively researched and explored and is a major hot topic in our field. More on mosaicism to come in a future post…stay tuned!

Limited resolution of PGT:

The technology used for PGT to count the number of chromosomes can only go so deep. The resolution of this test is limited to 5 million base pairs of DNA. This means there can be smaller portions of DNA missing or duplicated, some of which may have significant clinical consequences (ie. implantation failure, miscarriage, disease etc). Prenatal diagnostic testing such as CVS and amniocentesis can detect these smaller abnormalities using a technology called microarray. 

PGT is a great tool that fertility doctors use to aid in the selection of the best possible embryo for transfer – but no tool is perfect – and every tool has its limitations.

My advice to patients is to pretend as though they never used PGT and to proceed with the type of genetic testing they would have if they hadn’t undergone IVF with PGT in the first place.

This is in line with recommendations from the American College of Obstetricians and Gynecologists, who recommend some form of testing in pregnancy, regardless of PGT.  

The decision of whether to do screening or diagnostic genetic testing of a pregnancy is a highly personalized decision dependent on one’s value system, potential future decisions (ie. would you terminate an abnormal pregnancy?), how prepared one wants to be to understand the health of any future pregnancies, and the level of risk that is acceptable, and the amount of information one wants about their unborn child. These decisions are complex and can be aided by speaking with your fertility doctor, obstetrician, and a genetic counselor.