By Blair Stevens
Uncertain genetic testing results are not an unusual event in the field of genetic counseling. Obstetricians routinely refer patients to genetic counselors to help them navigate unclear prenatal genetic testing results by reviewing the complexities of genetic information and discussing the benefits, risks, and limitations of additional testing.
In 2019, I met with a pregnant patient who faced unclear prenatal genetic testing results and was desperately seeking more information. Little did we know that her confusing prenatal testing results had nothing to do with her pregnancy. This patient was concerned because her non-invasive prenatal testing (NIPT), also known as non-invasive prenatal screening (NIPS) or cell-free DNA screening (cfDNA), screening results were “uninformative.” NIPT is a common prenatal screening test that assesses a pregnancy’s risk for conditions like Down syndrome and can predict the sex of the baby. A pregnant person has DNA floating in their bloodstream that comes from their own cells as well as cells from the baby’s placenta. So while this NIPT is not 100% accurate, it is quite good at predicting the risk for certain genetic conditions in pregnancy. Certain prenatal screening tests like NIPT are very accurate for conditions such as Down syndrome, but less so for rare genetic conditions. Patients having this testing should know that NIPT results do not diagnose a genetic condition or give a yes/no answer, and should seek follow-up testing if appropriate.
When a pregnancy is flagged for a genetic condition included on the NIPT screen, results are typically reported as “increased risk” or “positive.” When a pregnancy is not flagged for one of these conditions, results are typically “low risk” or “negative.” In the case of my patient, her first NIPT screen could not produce a result because there was too little fetal DNA in her blood sample, an issue we call “low fetal fraction.” This happens sometimes. A repeat sample was submitted, but the second NIPT screen results were “uninformative.” Unfortunately, it was difficult to obtain information from the performing lab as to why these results were uninformative.
Understanding the test results
During our genetic counseling session, we discussed the possibility that these results may be due to a genetic condition in the baby, may be a maternal health problem, or could be due to something that is considered “normal variation.” My patient was healthy, so we were less suspicious of a maternal condition. In order to test the baby to know for sure about a genetic condition, we would need to insert a long, thin needle in her tummy to take out amniotic fluid from around the baby. This procedure is called amniocentesis and is safe for the baby over 99% of the time when it is performed after 16 weeks of pregnancy. My patient was only 14 weeks pregnant at the time of our consultation, so she was forced to wait two more weeks for information. She was incredibly anxious and pleaded for another option that could be pursued immediately.
We sent a new blood sample to a different lab that uses a different NIPT technology and includes more genetic conditions in its NIPT. Unfortunately, we received another uninformative result. When the second testing lab was contacted, they informed me that the DNA results were “erratic” and not consistent with a genetic condition in the pregnancy, although this possibility could not be ruled out. Given this uncertainty, the patient elected to undergo an amniocentesis. Normal results came back within a couple of weeks and my patient could finally sleep at night.
Here, the focus shifted from the pregnancy’s health to my patient’s health. While there have been numerous reports of pregnant individuals diagnosed with cancer after having atypical or uninformative NIPT results, the lab reassured me that my patient’s DNA pattern did not match cases of cancer they had seen in the past. However, I did warn my patient that there is still a great deal that we did not know, and she should have a low threshold to visit a doctor if she noticed early signs of cancer such as persistent pain, coughing, fatigue, or headache. My patient subsequently enjoyed her pregnancy, had normal ultrasounds, and delivered a perfectly healthy baby.
The importance of follow-up testing
A few months after delivery, my patient suffered from constant fatigue that was easily attributed to caring for a newborn baby. However, when she continued to feel unwell and could not shake a nagging cough, she asked her doctor for further evaluation. She was comforted by her doctor that it was common for new mothers to feel this way and was brushed off. After pleading with her doctor to order a chest X-ray, she finally discovered why she had so many inconclusive genetic test results during her pregnancy: she was diagnosed with Hodgkin’s lymphoma. Lymphoma is a type of cancer that starts in the white blood cells (lymphocytes). Cancer cells have abnormal DNA that causes them to grow out of control and can release their cfDNA into the blood stream, similar to cfDNA from the placenta (and the basis for NIPT).
Fortunately for this patient, after six months of chemotherapy, she was declared cancer free and has had multiple clean scans since then. I have spoken to my patient several times throughout this journey and she is incredibly grateful that she listened to her instincts and advocated for herself. Although she was overcome with worry during her pregnancy due to these results, the anxiety proved worthwhile as it motivated her to be more aware of her symptoms and to push back when she did not feel heard by her medical team. She also informed me that several members of her online cancer support group had atypical NIPT (cfDNA) results before getting their cancer diagnoses.
Cancer and pregnancy do not often overlap, but when they do, NIPT screening may provide the first signs of malignancy. Controversy persists on how to manage these results — they can be life-saving, as in this case, but they may also cause unnecessary concern in cases where the NIPT results are unclear and parental cancer is not the underlying explanation.
How genetic counselors can help you understand your results
Genetic counselors must frequently balance information that maximizes benefits and minimizes harm for patients in unclear circumstances. We are trained to work together with our patients to inform them of the necessary facts, be their copilot through the uncertain detours, and promote patient independence with the aid of expert guidance. If you have received an unclear result from NIPT screening, you likely have more questions than answers. If you do not feel you have received enough information about your results, genetic counselors are available to help you through these difficult times.
The ability to detect more conditions in pregnancy is increasing with the ever-expanding menu of genetic testing options, and so too are uncertain test results. For this reason, genetics expertise should be accessible to all patients through providers such as genetic counselors. You can find a genetic counselor at findageneticcounselor.nsgc.org.
Blair Stevens, MS, CGC, is the National Society of Genetic Counselors’ Prenatal Expert and a genetic counselor at University of Texas Health Science Center.