Introduction to NIPD / NIPT

A guide for patients and healthcare professionals

What is NIPD and NIPT?

Non-invasive prenatal diagnosis (NIPD) or testing (NIPT) is based on a maternal blood test.

In some cases, such as testing for the genetic condition achondroplasia, it is diagnostic (NIPD) and will mean that an invasive test is not required to confirm a NIPD result.

In other circumstances, such as testing for Down syndrome, an invasive test (chorionic villus sampling or amniocentesis) will still be necessary to confirm an abnormal result, and it is then referred to as NIPT.

This guide covers the basic information that patients and health professionals need to know about NIPD and NIPT. This is a new and rapidly evolving technology, so it is important to check back regularly for the latest information and guidance.

How is NIPD / NIPT possible?

NIPD and NIPT work by analysing the DNA fragments present in the maternal plasma during pregnancy. This is known as cell-free DNA. Most of this cell-free DNA comes from the mother (cell-free maternal DNA), but around 10%-20% of it comes from the placenta, which is representative of the unborn baby (cell-free fetal DNA).

Cell-free fetal DNA (cffDNA) is first detectable from about 4 -5 weeks’ gestation, however the level of cffDNA is not high enough for analysis. The cffDNA reaches a level suitable for analysis at different gestations according to what is being tested for.

The cffDNA is cleared from the maternal circulation within the first hour after birth. Therefore, we know that it is specific to the woman’s current pregnancy. However, it is important to remember that NIPD and NIPT analyses both the baby’s and the mother’s cell-free DNA.

View the video below to see Stephanie Allen, clinical scientist at Birmingham Women’s Hospital, explain NIPT.

‘Cell-free fetal DNA comes from the placenta’

What can NIPD and NIPT be used for?

Fetal sex determination

NIPD is offered in the UK to determine fetal sex in pregnancies at risk of serious X-linked conditions, such as Duchenne muscular dystrophy, and those at risk of congenital adrenal hyperplasia (CAH).

In the case of X-linked conditions, there is a 50% chance of a male fetus inheriting the condition from the mother. If a male fetus is detected by NIPD, then invasive testing for definitive molecular diagnosis of the condition can be offered. If NIPD shows the fetus is female, an invasive test is not usually required, as females are not generally seriously affected by X-linked conditions as they have two copies of the X chromosome. 

Fetal sex determination in pregnancies at risk of CAH is useful to determine management of the pregnancy. The fetus can be treated with dexamethasone from 6-7 weeks’ gestation to prevent the abnormal development of the external genitalia (virilisation) in a female fetus.  Dexamethasone treatment can then be discontinued if NIPD shows the fetus is male.

For more details, see our guide to NIPD for fetal sex determination.

For academic studies and papers on NIPT for fetal sex determination, see our Library section.

Fetal Rhesus D typing in Rhesus D negative mothers

NIPD has been used in the UK for the past decade for RhD- women who have been sensitised and have a history of haemolytic disease of the newborn (HDN) or have elevated levels of anti-D antibodies in pregnancy.

When the mother has a RhD- blood type, NIPD can be used to detect whether the fetus has inherited the RHD gene from the father. If the woman is found to have a RHD- fetus, there is no risk of HDN and they can have standard antenatal care. Women carrying an RHD+ baby need to be closely monitored throughout pregnancy to determine optimum management, such as intrauterine transfusions or early delivery if necessary.

Research has shown that fetal RHD typing in RhD- mothers is highly accurate from around 11 weeks’ gestation. In the future it may be possible to test all RhD- mothers in early pregnancy to determine the fetal RHD type. This will allow the administration of anti-D prophylaxis to be targeted to only those women who are carrying a RHD+ fetus.

For academic studies and papers on NIPT for fetal blood types, see our Library section.

Fetal blood genotyping in other situations (Kell, HPA etc)

It is possible to analyse cffDNA for Kell and HPA (human platelet antibodies) and other genes predicting blood antibody status.

However, the accuracy of these tests varies, and if you need more information about these other tests it is best to consult your local obstetrician or haematologist. Further information is available from the IBGRL Blood Group Genotyping Service.

Single gene disorders

NIPD is available for some single gene disorders that are inherited in a dominant fashion from the father or arise de novo. In these situations, cffDNA will contain altered alleles that are not present in the high background of maternal cfDNA. NIPD is currently available for achondroplasia, thanatophoric dysplasia and Apert syndrome (ie FGFR 2 and 3 alterations). For details about these tests, see our factsheets on skeletal dysplasias and Apert syndrome. To request a test from the North East Thames Regional Genetics Service Laboratory at Great Ormond Street Hospital, download this form.

These tests are proving to be highly accurate and it is not recommended that invasive tests are needed to confirm the NIPD result. In the future it is hoped that NIPD will become available for other paternally inherited autosomal dominant conditions and de novo alterations.

NIPD is also able to direct the management of pregnancies at risk of autosomal recessive conditions, such as cystic fibrosis, when the mother and father carry different altered genes. In this situation NIPD can be used to determine if the paternal alteration has been inherited by the fetus.

If the fetus does inherit the paternal alteration, an invasive test could be offered to determine if the fetus has also inherited the maternal altered gene and is therefore affected by the condition.  If the paternal alteration is not inherited by the fetus, it would not be at risk of developing the condition, although it may be a carrier if it inherits the maternal alteration. NIPD for cystic fibrosis to exclude paternal inheritance of the altered gene is available on a research basis – see our factsheet.

For more details, see our guide to NIPD for single gene disorders.

For academic studies and papers on NIPD for single gene disorders, see our Library section.

Down syndrome

We know that there is a small amount of the baby’s DNA in the mother’s blood. NIPT for Down syndrome works by counting the number of DNA fragments present in the maternal plasma during pregnancy.

Each chromosome has sequences of DNA that are specific to that particular chromosome. Thus, to detect Down syndrome, all the DNA sequences that link or map to each individual chromosome must be analysed and counted. The total amount of chromosome 21 sequences in the mother’s blood can be compared with the amount of the other chromosomes sequences. If the baby has Down syndrome, there will be slightly more sequences that map to chromosome 21 than expected, indicating that there is more chromosome 21 present than normal.

This allows very accurate prediction of pregnancies where the fetus is likely to have Down syndrome. However, false positives can occur because this approach tests all the cell-free DNA in the mother’s blood, the majority of which comes from the mother, not just the cffDNA that comes from the placenta. An invasive test is therefore needed to confirm a NIPT result that predicts the baby is affected. For this reason, testing cfDNA for aneuploidy is considered to be an advanced screening test and is generally referred to as NIPT. For more details, see our guide to NIPT for Down syndrome.

For academic studies and papers on NIPT for aneuploidy, see our Library section.

NIPT for Down syndrome is not currently available through the NHS. However, many private clinics are offering the test to pregnant women. ARC UK has more information on this.

Research is being done to evaluate the technology and assess how it may be introduced in the NHS. Find out more about RAPID’s evaluation study of NIPT for aneuploidy.

How are NIPD and NIPT carried out?

Although testing is usually reliable after 7 weeks’ gestation, the timing of the test depends on what is being testing for.

An ultrasound scan must be offered before NIPD or NIPT, to confirm the precise gestation of the pregnancy, to check for multiple pregnancies, and to make sure the baby(ies) are alive. The placenta continues to shed fetal DNA after the death of the fetus and this can be the cause of inaccurate results.

Testing requires a sample of blood, taken from the mother’s arm, as with a regular blood test.

Each laboratory may have different requirements for the type of collection tubes, so it is important that you know how and when to take the sample(s).

Limitations of NIPD and NIPT

There are some constraints with NIPD and NIPT, which should be understood and explained to the patient:

  • It is not possible to tell which fetus the DNA is from in multiple pregnancies.
  • The relative proportion of cell-free fetal DNA is reduced in women with a high BMI as they have more of their own cell-free DNA circulating in their blood. This may increase the chance of getting an inconclusive result.
  • Detailed counselling and discussion with the mother before having the test will be needed. Although it is just a blood test, it can provide the same kinds of information as an invasive test, and women must think through the potential consequences of the results, and whether they really do want the information.
  • In some situations, an invasive test may still be required to confirm an abnormal result.
  • There may be other limitations, depending on the reason for testing.

See also our guides for patients and healthcare professionals for more information.

‘Women must think through the potential consequences of the results, and whether they really do want the information’

Benefits of NIPD and NIPT

There are also clear benefits to NIPD and NIPT:

  • The number of invasive tests carried out is likely to reduce as a result of NIPD and NIPT.
  • There is no increased risk of miscarriage through the use of NIPD and NIPT.
  • Less expertise is required to perform a blood test than an invasive test.
  • Invasive testing is considered more uncomfortable for women than a blood test.
  • In many cases we can offer NIPD /NIPT earlier than traditional invasive testing.