All about NIPT- Non Invasive prenatal testing.

The pregnant woman was 36 years old, in her first pregnancy and was about 12 weeks pregnant,  came for the NT scan. Her NT scan was normal. She got the double marker test and the Down syndrome combined screening risk was 1:1020. She was worried about the risk of Down syndrome and she knew that the risk of Down’s syndrome increases with age. No amount of counselling alleviated her anxiety and fear. Was the baby normal? – was her biggest question. I explained the options of NIPT and the needle test (amniocentesis) also. She wanted to know everything about the NIPT.

 

Why is NIPT performed?

NIPT- Non invasive prenatal testing is a blood test performed for the expectant mother, a relatively new modality of screening for common chromosomal abnormalities in pregnancy.

In this test, the mothers blood sample is taken and the baby’s chromosomes (genetic material) are looked for using advanced DNA technology. The test is based on the fact that the genetic material- the DNA, from the placenta is shed into the mothers blood circulation. The placenta has the same chromosomal make up as that of the baby and testing the placental genetic material would reflect the baby’s genetic material. So, let’s get answers for some commonly asked questions about NIPT.

 

What are chromosomes and chromosomal abnormalities?

The genetic material in the cells of our body are responsible for the structure and functioning of the body. This genetic material is organised into 46 units called chromosomes. Of the 46, 23 comes from the egg(mother) and 23 from the sperm(father).

Sometimes, due to various reasons, there can be additional chromosomes. Most commonly, the additional chromosome is either the 21st, 18th or 13th chromosome. Addition of an extra chromosome is called trisomy. Trisomy 21 is called Down syndrome. Trisomy 18 is called Edwards syndrome, trisomy 13 is called Patau syndrome. So the baby has 47 chromosomes instead of 46. This leads to abnormal structure and functioning of the body. 

 

What is Down’s syndrome?

The most common chromosomal abnormality, the Down’s syndrome is caused due to 3 copies of chromosome 21 rather than the usual 2 copies. It can lead to various degree of structural problems in various organs like heart, intestine, brain and varying degree of learning disability.

What is Edwards syndrome?

Edwards syndrome is caused due to 3 copies of chromosome 18 rather than the usual 2. It causes severe intellectual disability, structural problems of the heart, small head and jaw, clenched fist, to name a few. Most babies with Edwards syndrome die before birth or within a few weeks after birth.

What is Patau syndrome?

Patau syndrome is caused due to 3 copies of chromosome 13 rather than the usual 2. It causes severe structural problems. It causes severe growth restriction for the baby, abnormal structure of brain, small eyes, cleft in the lip and palate, low tone of the muscles, abdominal wall defects to name a few.

 

 

What is the commonly used screening modality for the common chromosomal abnormalities?

The commonly used screening is called the combined screening which is a combination of ultrasound scan of the developing baby and blood test for the expectant mother. The risk for chromosomal abnormalities is assessed which could be Low risk, Intermediate risk or high risk.

When the risk is more than 1 in 150, eg in 60, it is considered high risk. If the risk is less than 1: 1000, eg, 1 in 3000, it is considered low risk. If the risk is between 1:150 to 1: 1000, eg, 1:750,  it is considered intermediate risk. 

 

Can one get a NIPT instead of combined screening?

The answer is NO*. The NIPT checks only for the three common chromosomes namely the 21st, 18th  and 13th chromosomes. There are several structural abnormalities that occur without any chromosomal abnormalities, few others occur due to genetic abnormalities not detectable by NIPT. Therefore, it is important to have scan at 11-13 weeks, that can detect structural abnormalities in the baby. The scan also provides an opportunity to assess the risk of developing high blood pressure in the coming weeks of pregnancy.

 

So, who should get the NIPT test done? 

1. One can get the NIPT test done in addition to the scan when the scan is normal with intermediate risk for chromosomal abnormality and if one is not sufficiently reassured about the risk. The detection rates of Down’s syndrome with combined screening is about 90-92 percent and for NIPT is 99 percent.

2. When the risk for downs syndromes shows high risk  without any structural abnormalities* in the fetus. 

 

When a structural abnormality is detected on scan and is suspected be due to chromosomal defect, can NIPT be performed to confirm this? 

When a structural anomaly is detected,  Karyotyping of the chromosomes is recommended, which looks into all the 46 chromosomes and not just the three common ones. In addition, a chromosomal microarray test could be performed to detect submicroscopic changes in the chromosomes. This would be possible by performing an amniocentesis and performing a Karyotype and microarray. In fetuses with structural abnormalities, only 70% of the chromosomal abnormalities are caused due to the common trisomies 21, 18 and 13. Therefore, performance of detailed genetic tests like chromosomal microarray* after amniocentesis could add more clinically relevant genetic information in these fetuses. 

 

Can NIPT be performed in twins? 

Yes** it can be performed to screen for trisomy 21( Down syndrome). Studies have shown that the accuracy of the NIPT in twin pregnancy is similar to singleton pregnancies for screening for Down syndrome. If the NIPT shows low risk, it is reassuring as the detection rates for Down’s syndrome is about 99 percent. If NIPT shows high risk, confirmatory test ( CVS/ amniocentesis) needs to be performed for both the twins to accurately determine which of the twins or if both the twins are affected.

Currently there is insufficient evidence for screening for Edward syndrome and Patau syndrome in twin pregnancy.

Can NIPT be performed in triplets?

Currently there is insufficient evidence for use of NIPT as screening tool for common trisomies in triplet pregnancy.

 

How is NIPT performed?

About 5 ml of blood is withdrawn from mother. The sample is sent for testing for the lab. The results are available within 10 days. The results of the test are expressed as either high risk, where the chance of baby having chromosomal problem is high or low risk where the chance of baby having chromosomal problem is low.

 

If the NIPT shows high risk does that mean that baby really has chromosomal abnormality?

***Once, high risk on NIPT for Down’s syndrome, the probability of that baby really  has Down’s syndrome is about 91 percent and the other 9 percent could be normal.

Once, high risk on NIPT for Edwards syndrome, the probability of that baby really  has Down’s syndrome is 84 percent.

Once, high risk on NIPT for Patau syndrome, the probability of that baby really  has Down’s syndrome is 87 percent.

This is the reason why confirmatory diagnostic tests- either a chorionic villus sampling ( CVS) or amniocentesis needs to be performed.

 

Low risk on NIPT, what next?

When the fetus has no structural abnormalities and the result on NIPT is low risk, then the probability of baby having chromosomal abnormality is very low, therefore it’s reassuring for the couple and treating Doctors.

 

* Salomon LJ, Alfirevic Z, Audibert F, Kagan KO, Paladini D, Yeo G, Raine-Fenning N, ISUOG Clinical Standards Committee. ISUOG consensus statement on the impact of non-invasive prenatal testing (NIPT) on prenatal ultrasound practice. Ultrasound in obstetrics & gynecology: the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2014 Jul;44(1):122-3.

** Stokowski R, Wang E, White K, Batey A, Jacobsson B, Brar H, Balanarasimha M, Hollemon D, Sparks A, Nicolaides K, Musci TJ. Clinical performance of non?invasive prenatal testing (NIPT) using targeted cell?free DNA analysis in maternal plasma with microarrays or next generation sequencing (NGS) is consistent across multiple controlled clinical studies. Prenatal diagnosis. 2015 Dec;35(12):1243-6.

***Taylor-Phillips S, Freeman K, Geppert J, Agbebiyi A, Uthman OA, Madan J, Clarke A, Quenby S, Clarke A. Accuracy of non-invasive prenatal testing using cell-free DNA for detection of Down, Edwards and Patau syndromes: a systematic review and meta-analysis. BMJ open. 2016 Jan 1;6(1):e010002.