When nuchal translucencies set off an alarm in early pregnancy
DAVID H. BARAD, MD, MS, Is a Senior Scientist and Head of Clinical IVF and Clinical Research at the Center for Human Reproduction (CHR) in NYC.
September 9, 2024, revised with permission from the September 2024 issue of the CHR VOICE.
Briefing: In another contribution from his article series “Testing the Tests,” Dr. Barad here reviews nuchal translucency testing (NTT) by ultrasound in early pregnancy. This is a widely used test which at very early stages of pregnancy can raise suspicion of certain chromosomal and/or morphological abnormalities of the fetus. As a screening test any suspicious test, however, still requires further confirmation of diagnosis. This test, therefore, also offers an opportunity to discuss the difference between a screening test and a diagnostic test.
Nuchal translucency (NTT) testing is an early ultrasound test that assesses the risk of chromosomal abnormalities in a pregnancy. An excessively wide measurement raises a strong suspicion of a possibly abnormal pregnancy, most often a chromosomal abnormality called the Down’s syndrome (trisomy of chromosome 21). An excessively wide NTT basically suggests an excessive accumulation of fluid at the back of a fetus's neck. Some fluid accumulation is detectable in this location in all fetuses during the first trimester of pregnancy (see the figure below). Besides Down’s syndrome, an increased NTT measurement can also indicate various fetal pathological conditions, including congenital cardiac anomalies, other chromosomal abnormalities, and other non-chromosomal genetic disorders.
NTT testing was first introduced in the early 1990s. The development of this screening method is credited to Professor Kypros Nicolaides, MD, and his team at King's College Hospital in London, who published pioneering research on the correlation between increased nuchal translucency and chromosomal abnormalities, particularly Down’s syndrome. This research laid the foundation for the widespread use of NT testing in prenatal screening.
The measurement between the 2 calipers +---+ reflects the width of the nuchal translucency
The test is conducted when the fetus is between 11 and 14 weeks old, when the translucency measurements are most accurate. If an abdominal ultrasound is used, the patient may need to have a full bladder, which is not required with a vaginal ultrasound.
To correctly perform the test, the ultrasound image must be a mid-sagittal view. This means the ultrasound image should be a clear, longitudinal view of the fetus, showing a profile that includes the neck, nasal bone and the palate. The fetus's head should be in a neutral position, not tilted too far back (hyperextended) or too far forward (flexed). Moreover, the head should be in line with the spine.
The sonographer then measures the thickness of the nuchal translucency. This measurement is done by placing calipers on the ultrasound image to measure the maximum thickness of the translucent area. At 11 weeks, a normal NT measurement should not exceed 2 mm. At 13 weeks and 6 days, a normal measurement is up to 2.8 mm, though some practices consider normal to be up to 3.5 mm.
NTT testing is a screening test, not a diagnostic test. This is a crucially important distinction, often not properly explained to patients. It helps in estimating the likelihood that the fetus may have a chromosomal abnormality but does not provide a definitive diagnosis. As a screening test, unlike some diagnostic procedures, NTT testing is non-invasive and poses no risk to the fetus. If the NTT test indicates an increased risk of a chromosomal abnormality, further diagnostic testing, such as amniocentesis or chorionic villus sampling (CVS), analyzing fetal chromosomes directly, may be recommended for confirmation or refutation of the NTT diagnosis.
Though originally described as a screen for chromosomal aneuploidies (i.e., Down’s syndrome), it was later discovered that NTT testing can also detect congenital cardiac anomalies due to genetic disorders not associated with chromosomal aneuploidies.
This means that NT testing can be positive even in the presence of a normal chromosome analysis (karyotype). The incidence of both fetal structural abnormalities and chromosomal disorders, however, rises significantly with increasing NT measurements, ranging from 30% for NTT measurements between 3.5 and 4.5 mm to approximately 70% for NTT measurements greater than 6.5 mm.
Karyotype analysis of amniotic fluid (amniocentesis) or of placental tissue (CVS) is then typically the initial step in the further evaluation of fetuses with increased NTT diagnosing chromosomal abnormalities in 30%–40% of cases. When the karyotype is normal, array Comparative Genomic Hybridization (array-CGH) can identify submicroscopic imbalances, such as microdeletions and microduplications, offering an additional diagnostic level with an additional yield of approximately 5%. Non-chromosomal genetic mutations such as Noonan’s syndrome can also demonstrate increased nuchal translucency.
One recent study of 114 pregnancies with increased nuchal translucency and normal karyotype as well as normal array-CGH testing found that there was still a 33% risk of serious fetal morbidity even though the karyotype was normal. Further testing for specific genetic syndromes (like Noonan’s syndrome) and a normal mid-trimester anomaly scan reduced the risk among the remaining cases to 9.4%.1
Since NTT is a screening test, it should not be used as sole indication to terminate a pregnancy. Elevated NTT measurements should be followed up with the direct genetic tests noted above (amniocentesis or CVS) to rule out aneuploidy and other genetic causes. This also, for example, applies to another recently increased screening test, so-called non-invasive prenatal testing of blood (NIPT) if the test suggests a chromosomal abnormality. The risk of major cardiac anomalies increases with the size of the NTT, with over 50% of fetuses with an NTT measurement greater than 6 mm having cardiac anomalies. Many pregnancies with positive NTT tests will, however, prove to be normal, though to be safe extensive further testing is required.
We recently saw a patient who had conceived after she was transferred with a by PGT-A testing chromosomal-normal embryo and on ultrasound was found to be NTT positive. The patient underwent further testing with micro-array CGH and second trimester anatomy screening, and, in the end, it was demonstrated that she carried a perfectly normal female pregnancy. She recently returned for a second pregnancy attempt and, after conceiving, once again, turned out to be again NTT -positive. Her follow-up testing at time of this writing is still pending. If this patient turns out to again carry a normal pregnancy, it must be assumed that false-positive NTTs may also be genetic in nature.
Another recent patient who presented to our center was found to have an NTT of over 9 mm. Her obstetrician unfortunately had advised her to have an immediate D&C without further testing of the pregnancy. Chromosomal testing of the fetal tissue after pregnancy termination, however, revealed a normal karyotype. Chromosomal testing of products of conception cannot rule out that this pregnancy had a cardiac (or other) anomaly. It, however, is also possible that in this case a normal pregnancy was mistakenly terminated.
It, therefore, is worthwhile repeating that any abnormality suggested by NTT screening must be confirmed by more definitive diagnostic testing before final decisions are made about pregnancy termination. And since we are here addressing prenatal fetal testing, we also suggest you visit today’s General Medical News section, where we report on a very interesting interview about the ethics of prenatal genetic testing in the Harvard Medicine magazine with Vardit Ravitsky, PhD, one of the world’s best-known medical ethicists in the reproductive field.
References
1. Spataro et al., Int J Gynaecol Obstet 2023, 161 (3), 1040-1045).