A few months ago a young couple, Michele and Dan, came to my office for a mid-trimester fetal anatomic survey at 21 weeks’ gestation. They were excited to see their fetus in 3D-4D ultrasound, and were wowed by the 3D image of their baby’s face. During the scan the couple related that they were sure their baby was OK “because the blood test came back negative,” and had decided to forego first trimester screening, despite their OB strongly recommending it.
The blood tests, nuchal translucency measurement, and other sonographic parameters evaluated in first trimester screening are considered together to provide a risk profile for fetal chromosomal anomaly, particularly the risk of Down syndrome. If there is an increased risk, the parents may be advised to undergo invasive testing, such as chorionic villus sampling (CVS) or amniocentesis. In addition, first trimester screening can raise warning flags for structural anatomic malformations in the fetus, as well as other problems for the pregnancy. If first trimester screening includes a full fetal anatomic survey, it can spot about 40% of fetal malformations at a very early stage.
While I was reassured that Michele and Dan’s results on noninvasive prenatal testing (NIPT) meant the risk of their baby having Down syndrome and certain other aneuploidies was extremely low, I explained that structural malformations were still a much more common concern than chromosomal anomalies, and that a negative NIPT result did not rule out other conditions. Michele protested, “On the Internet it said that the blood test rules out Down syndrome 100%, that we didn’t have to worry.”
“The screening tests only give you a risk profile,” Dan insisted, “they don’t tell you if the baby is really affected. So we thought the blood test was the way to go.”
“I don’t want to have an amnio,” Michele continued, “I had a miscarriage in my last pregnancy,” she continued, as I proceeded to the echocardiography portion of the examination.
“Your baby appears to have a heart defect,” I said, as gently as I could, and began to explain the nature of transposition of the great arteries (TGA).
NIPT is the name applied to new techniques that use a sample of a pregnant woman’s blood to examine her fetus’s chromosomes. As early as 10 weeks of pregnancy there is sufficient fetal genetic material, called cell-free DNA, found in the maternal serum to allow analysis. A negative result from NIPT is a very good test to rule out Down syndrome in the fetus: it is highly specific, meaning that in almost all cases, a negative result is truly negative. NIPT is also highly sensitive, which means that in almost all cases, a positive result is truly positive. However, because there is a chance (however small) of a false positive (a healthy fetus may have a result showing him/her to have Down syndrome), a positive test result always needs to be confirmed with invasive testing, such as CVS or amniocentesis, before any decisions are made regarding the further management of the pregnancy. NIPT has also been found useful in identifying fetuses with other chromosomal anomalies and certain other genetic conditions. NIPT can also be used to determine the fetal sex.
However, while NIPT does a very good job at what it is designed for: looking at fetal chromosomal complement in specific conditions, it does not examine all the fetal chromosomes, nor does it look at the anatomy of the fetus. Fetal anatomy is examined in detail by ultrasound scanning. There is some debate among practitioners regarding the optimal week of pregnancy when full early fetal anatomy scanning should be performed. Some practitioners prefer performing the scan at the time of nuchal translucency screening, 11-13 weeks, while others prefer 14-16 weeks, when the fetal organs are more developed. The important point to remember: a fetus with a normal (negative) NIPT result can have an anatomic structural malformation. It has been shown that while fetuses with malformations may be at increased risk of chromosomal anomaly, the majority have healthy chromosomes. The diagnosis of a malformation by ultrasound should prompt invasive testing such as CVS or amniocentesis. In some centers, more detailed investigation by chromosomal microarray analysis (CMA), which may discover subtle anomalies, will also be ordered. CMA detects duplicated or deleted chromosomal segments and translocations—rearrangements of chromosomal structure, which may not be evident on traditional karyotyping.
NIPT is a very reliable test. But patients may have a false sense of security regarding their baby’s well-being. A negative NIPT result cannot rule out anatomic structural malformations in the fetus, nor does it rule out all chromosomal anomalies. There is ongoing debate surrounding the integration of NIPT into existing screening programs.
I continued to follow Michele and Dan in the weeks and months that followed. They were, of course, shocked and dismayed by their diagnosis. With Michele at 21 weeks, we immediately arranged multidisciplinary consultation with the cardiologists, who explained the procedures the baby would have to undergo, and how Michele’s plans for the birth would have to change. Prenatal diagnosis of TGA can improve the baby’s surgical outcome, and with prompt intervention, prognosis is excellent. They met with a genetic counselor, and despite Michele’s fears, underwent amniocentesis. CMA is performed in all such cases in our center. Testing ruled out genetic syndromes that we suspected based on the anatomic malformation, none of which could have been diagnosed by NIPT.
With comprehensive information in hand about their baby’s prognosis and the options open to them, Michele and Dan decided to continue the pregnancy, despite the difficult road they knew was ahead. They made arrangements for delivery in the tertiary care center where the baby would undergo surgery, so she would not have to be transferred from their community hospital and would be under constant surveillance. “I fell in love when I first saw the baby’s face in 3D,” she told me. “Whatever comes, we’ll handle it together.”
How do you think NIPT should be integrated into prenatal care? How do you advise your patients who ask about NIPT? Have you encountered patients with negative NIPT results whose fetus has a structural anomaly? Have you encountered patients with false negative or false positive NIPT? Comment below or let us know on Twitter: @AIUM_Ultrasound.
Simcha Yagel, MD, is Head of the Division of Obstetrics and Gynecology Hadassah-Hebrew University Medical Centers, Jerusalem, Israel, and Head of the Center for Obstetric and Gynecological Ultrasound at the Hadassah-Hebrew University Medical Centers, Mt. Scopus, Jerusalem. He served as moderator for a panel discussion, “Noninvasive Prenatal Testing and Fetal Sonographic Screening,” that appeared in the March 2015 issue of the Journal of Ultrasound in Medicine.