NEW YORK (GenomeWeb) – Natera said last week that its Panorama noninvasive prenatal test for chromosomal abnormalities is now available for use in twin pregnancies, where it can also determine zygosity, or whether twins are identical or fraternal, as well as fetal sex.
While the company is the last of the large NIPT providers in the US to offer its test for twin pregnancies, the test's ability to determine zygosity is unique among its competitors, and the zygosity results can help determine clinical management, since monozygotic twins that also share a placenta are at increased risk of complications.
About 3 percent of live births in the US involve twins, and in 2015, there were about 133,000 twin births, a sizable market for NIPT companies to target and position their tests in.
Up until last week, Natera did not accept samples from twin pregnancies – several other NIPT providers have already done so since at least 2013 – but it did report when it found evidence of a so-called "vanished twin" where one of the twins had died early in pregnancy, which happens in up to 30 percent of multifetal pregnancies. In a study published in 2014, the company reported on its ability to detect such unrecognized twins.
Now, the Panorama test, which can be administered from nine weeks' gestation, is available for twin pregnancies and can screen for trisomies 21, 18, and 13. In addition, for identical twins only, it can screen for monosomy X, sex chromosomal trisomies, and 22q11.2 deletion syndrome.
According to Kimberly Martin, senior medical director of Natera's women's health franchise, the company conducted a validation study that involved more than 100 sets of twins, about two thirds of them fraternal and a third identical twins. Natera is currently preparing to publish the results of the study, which included cases with trisomy 21, 18, and 13. The test was more than 99.9 percent sensitive and specific for zygosity – Martin said an outside laboratory validated the results – and more than 99 percent sensitive and more than 99.9 percent specific for the chromosomal abnormalities in combination.
For monozygotic twins only – she said the company did not have enough cases of fraternal twins available – Natera also validated the test for monosomy X or Turner syndrome, sex chromosome trisomies, and 22q11.2 deletion or DiGeorge syndrome.
The reason why the Panorama test but not its competitors can determine zygosity is that it analyzes SNPs in the genome, which allows it to distinguish between DNA from the mother and DNA from the fetuses, and, if they are dizygotic, to distinguish between the twins.
Knowing whether twins are monozygotic or dizygotic can inform clinical management, Martin explained, especially if no ultrasound was conducted by a specialist early in the pregnancy.
Twins that share a placenta, a condition known as monochorionicity that occurs in about two thirds of monozygotic pregnancies, are at increased risk of various complications, such as twin-twin transfusion syndrome, intrauterine growth restriction, and birth defects. As a result, monochorionic pregnancies are monitored more closely than other twin pregnancies. Early during pregnancy, ultrasound can determine with more than 95 percent accuracy whether twins share a placenta, Martin said, but this becomes much more difficult as time goes on, and shared-placenta pregnancies are sometimes incorrectly called as dichorionic. Thus, if a woman only comes in for an ultrasound in her second trimester, and if the fetuses have the same sex, it can be impossible to tell whether they share a placenta.
In such cases, which Martin said are not uncommon at centers that deal with high-risk pregnancies, the Panorama test could help. If it determines that the twins are dizygotic, for example, it is clear that they don't share a placenta and there is no need for increased screening.
Martin said she also remembers a case from her practice as an OB/GYN and clinical geneticist where one of the fetuses of a twin pregnancy was smaller than the other and had features pointing to increased trisomy 21 risk. However, it was not known whether the twins were identical or shared a placenta. Having a noninvasive test to determine zygosity would have helped to counsel the parents, she said, who were reluctant to undergo invasive testing, because monozygotic twins would both be at increased risk for trisomy 21, whereas dizygotic twins would not.
"You can see how this can really change how you would talk to a family and how you would then evaluate the pregnancy," she said, and with a dizygotic result, "maybe you would only do an amniocentesis on the smaller twin, you would not test both."
Having a noninvasive zygosity test early during pregnancy could also help steer patients with monozygotic twins towards receiving a shared placenta scan by a specialist. "All women don't get an ultrasound early in pregnancy," Martin said, and "knowing zygosity early can allow reduced surveillance of a dizygotic pregnancy and can make sure that we get an accurate chorionicity assignment early in pregnancy" for those that are monozygotic.
Another distinguishing feature of the Panorama test is that it reports fetal fraction, or the amount of free fetal DNA in the mother's blood, separately for both twins if they are non-identical. Because results from samples with low fetal fraction are less reliable, this provides a measure of confidence in the results for both twins. For example, the overall fetal fraction could be 10 percent, Martin explained, but it could be 1 percent for one twin and 9 percent for the other, so the test result would only be reliable for one of the twins.
Finally, Natera can distinguish between a twin pregnancy with two boys and a pregnancy with a boy and a girl, which the company said its competitors cannot do because they only determine the presence or absence of a Y chromosome.
According to Glenn Palomaki, a professor of pathology and laboratory medicine at the Alpert Medical School at Brown University and at Women and Infants Hospital of Rhode Island, who is familiar with Panorama, the test had previously had trouble interpreting results from dizygotic twin pregnancies. As a result, the company did not offer it for twin pregnancies at all, and if it received samples from dizygotic twin pregnancies inadvertently, those samples would often fail. "The number one advantage is, that's no longer a failed sample – it's now an interpreted sample," he said.
Being able to provide zygosity is an added benefit, he said, that can be helpful in certain cases. "I'm sure an obstetrician will give you a relatively rare occurrence where it's critical."
Other companies have been offering NIPTs to screen for chromosomal abnormalities in twin pregnancies for several years now. Roche's Ariosa and Illumina's Verinata Health, for example, both said in 2013 that they were expanding the use of their tests – Harmony and Verifi, respectively – to twin pregnancies.
Illumina said at the time that it had validated its test using samples from 115 twin pregnancies, where it correctly detected all cases of trisomy 21 and trisomy 18, as well as all samples that contained a Y chromosome.
Ariosa's Harmony test was validated for twin pregnancies in two published studies. A 2013 study that involved 275 pregnancies found that the test identified 14 out of 15 trisomies correctly, but the test failed in about 7 percent of samples because of low fetal fraction. A larger study published in 2014 that involved 515 twin pregnancies also found a higher failure rate than in singleton pregnancies, and the test detected 11 of 12 trisomy 21 cases and all five trisomy 18 cases.
MaterniT 21 Plus, which is offered by LabCorp's Sequenom, can also detect chromosomal abnormalities in multiple gestations, according to the company's website, though its VisibiliT test is currently confined to singleton pregnancies. The company published a study that determined the performance of the MaterniT 21 Plus test in twin pregnancies in 2012, showing that it correctly determined all seven trisomy 21 and one trisomy 13 sample in a total of 25 twin pregnancies, and correctly identified two triplet pregnancies as euploid.