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Non-Invasive Prenatal Testing (NIPT) following IVF or IVF+PGT-A, beneficial or not?

Roy Pascal Naja, PhD, DipRCPath
Laboratory Director, Eurofins Clinical Genetics UK

Category:
Genetics PGS / PGT-A

Roy Pascal Naja examines the question "Is NIPT worth it?". The accompanying image depicts a smiling man dressed in a suit.
From this video you will find out:
  • What factors should patients consider when deciding whether to opt for NIPT? Are there specific scenarios where NIPT is highly recommended following IVF?
  • For couples undergoing IVF, how does the decision to pursue Non-Invasive Prenatal Testing (NIPT) impact the overall fertility treatment process?
  • What are the benefits of Non-Invasive Prenatal Testing (NIPT) when combined with Preimplantation Genetic Testing for Aneuploidies (PGT-A) during IVF? How does this combination contribute to a more informed and successful pregnancy?
  • Are there any specific trisomies or genetic conditions that NIPT is particularly effective at detecting?

What is NIPT - Non-Invasive Prenatal Testing?

Have you ever wondered about the benefits and potential of Non-Invasive Prenatal Testing (NIPT) following IVF or IVF+PGT-A? During this session, Roy Pascal Naja, PhD, DipRCPath, Laboratory Director at Eurofins Clinical Genetics in the UK explained how it works, its main benefits, and how this advanced testing can provide peace of mind during a crucial phase in your journey to parenthood.

Chromosomal inheritance and trisomies

Humans have chromosomes containing our genetic material. We inherit 22 pairs of chromosomes numbered 1 to 22 and an additional pair of sex chromosomes (XX for females, XY for males). Normally, we inherit one chromosome from each parent through either sperm or egg transmission. However, errors may occur during the creation of sperm and egg, leading to a condition called a trisomy, where a fetus has three chromosomes instead of the normal two.

Why is a trisomy important in pregnancies? The most relevant cause of miscarriage is chromosomal abnormalities, specifically trisomies. A graph from a significant work in Nature Genetics shows an increasing percentage of trisomies in clinically recognized pregnancies with advancing maternal age. Over 25% of clinically recognized pregnancies in women above 38 are trisomies.

Notably, trisomies like 21 (Down syndrome), 18 (Edwards syndrome), and 13 (Patau syndrome) can lead to adverse outcomes. While modern science allows some children with trisomy 21 to lead relatively normal lives, trisomies 18 and 13 often result in severe consequences, including death.

Evolution of Prenatal Screening

Prenatal screening for trisomies traces back to 1959 when Jerome Lejeune identified trisomy 21 as the genetic cause of Down syndrome. In the 1990s, the first trimester screening, involving maternal age, serum bio markers, and ultrasound findings, became the gold standard. In 1997, the discovery of fetal DNA in maternal blood led to the development of non-invasive prenatal testing (NIPT).

Non-Invasive Prenatal Testing (NIPT)

NIPT, implemented in the UK in recent years, uses maternal blood to detect trisomies and defects in fetal DNA. Fetal DNA released by trophoblasts in the placenta enters the bloodstream, making it detectable from as early as five weeks, with concentrations sufficient for testing from week 10 onward.

Types of NIPT

There’s more than one type of NIPT. You’ve got a basic NIPT, which is the test that screens for common chromosomal trisomies – T21, T18, and T13. There is also an expanded NIPT, which is a test that checks for abnormalities in all of your chromosomes, including your sex chromosomes and all the autosomes (chromosomes 1 to 22). It also detects certain segments of these chromosomes if they are lost or gained.

Who Should Consider NIPT?

NIPT testing should be recomended to all pregnant women. As Roy emphasized, this is not just hiw recommendation; it’s in the guidelines of several national societies, including the Maternal and Fetal Medicine Society, the American College of Obstetricians and Gynecologists, and the American College of Medical Geneticists. While it is recommended for all pregnant women, it is highly recommended for women of advanced maternal age, those with repeated miscarriages, and those with previous conceptions.

Advanced Maternal Age and Repeated Miscarriages

Advanced maternal age and repeated miscarriages, forms of infertility, increase the risk of chromosomal abnormalities. IVF, or in vitro fertilization, has been a successful treatment for infertility since the birth of the first IVF baby, Louise Brown, in 1978. Over the years, IVF has advanced, with morphology and morphokinetics being crucial in embryo selection.

Prenatal Genetic Testing in IVF

Morphology and time-lapse monitoring are significant in IVF. Morphokinetics, observing the embryo’s development in real-time, added a new dimension to embryo selection. However, neither morphology nor time-lapse monitoring can predict aneuploidy. Therefore, non-invasive prenatal testing (NIPT) is highly recommended for IVF patients, especially those in the advanced maternal age category.

Pre-Implantation Genetic Testing (PGT)

Pre-implantation genetic testing for aneuploidies (PGT-A) is an early stage of NIPT applied to pre-implantation embryos. PGT-A is done using the same technology as NIPT, checking for whole chromosomes gained or lost and even pieces of chromosomes gained or lost. Transferring a euploid embryo, tested by PGT-A, lowers the risk.

PGT-A is not foolproof. It has challenges, including human error, sample mix-up, contamination, and the occurrence of mosaicism. Mosaicism is when an embryo has both normal and trisomic cells, making it challenging to predict aneuploidy accurately.

NIPT following IVF and PGT-A

The positive predictive value (PPV) of NIPT following IVF and PGT-A was examined in a study of 1,139 patients. The PPV was found to be 12.5%, indicating a relatively high rate of false positives. Despite this, the clinical utility of offering NIPT in this setting is emphasized, with proper genetic counseling crucial for interpretation.

Conclusion and recommendations

In summary, the risk of aneuploidy increases with maternal age. NIPT is highly recommended for the IVF patient population, and NIPT should still be offered to IVF and PGT-A tested embryos that result in a viable pregnancy. However, interpreting positive results should be done with caution, and confirmatory diagnostic tests, such as CVS or amniocentesis, are essential in any screen-positive scenario. Always seek proper genetic counseling for informed decision-making.

- Questions and Answers

Is the prenatal test using circulating fetal DNA done by NGS, as in PGT-A using trophectoderm biopsy, or is this done using a different technique? Can you tell us more about the costs as well? 

There are more than one test of an NIPT; the most widely used one is a test from a company called Illumina. This has become the gold standard test and uses NGS. It’s the same test as the one used in PGT-A. Now, the cost is something I cannot answer; many different clinics offer different costs. Some clinics offer a NIPT test coupled with an ultrasound because, during a NIPT test, you should have had an ultrasound. It’s important to tell the NIPT laboratory whether it’s a single or twin pregnancy, and there is more information needed that can only be obtained from an ultrasound. I always recommend having an ultrasound before coming for a NIPT test or doing it simultaneously.

Can the NIPT test be wrong?

If you go online, you can find many different companies, clinics, and testing laboratories claiming high accuracy percentages. I believe that the two most important parameters to consider are positive predictive value (PPV) and negative predictive value (NPV). Sensitivity and specificity are important, but after getting a test result, PPV helps manage expectations. Always ask about PPV when you have the test and receive a positive screen result. If you get a negative result, ask about NPV. Most platforms have a very high NPV, providing reassurance for negative results. However, for positive results, it’s crucial to consult with a laboratory that can explain the results and guide you on the next steps.  

Is the detection of trisomy 13 in a non-invasive study in a pregnancy of 10 weeks reflective of reality? What percentage, in your experience, is a reflection or a reality?

If you get a trisomy 13 result at 10 weeks, the positive predictive value (PPV) is essential to consider. PPV is affected by sensitivity, specificity, and patient age. For trisomy 13, 18, and 21, PPV is slightly lower than for trisomy 21. Patient age plays a crucial role in determining the accuracy of the test. Always inquire about PPV before making decisions based on test results.  

Could you please clarify the increased maternal age for IVF? Is this the age when the egg cells were collected and embryos were frozen or the age of the embryo transfer?

Increased maternal age for IVF refers to the age when the eggs were collected and the embryos were created, not the age at which the embryo transfer occurs.  

What is your opinion regarding offering NIPT in IVF-PGT-A pregnancies where a mosaic embryo was actually transferred?

If you did PGT-A and received a mosaic result, it can be challenging. In such cases, consider expanded NIPT as a second check for PGT-A results, providing more reassurance. If you have only one mosaic embryo, you may opt to transfer it but also go for expanded NIPT to confirm whether the mosaicism persists and aligns with PGT-A results.  

Are there rare diseases common enough to make the expanded NIPT test worth it?

While the basic NIPT test screens for chromosomal abnormalities, the more advanced NIPT test can include a broader range of rare diseases. Deciding if the expanded test is worth it depends on various factors. Consultation with the laboratory, understanding which disorders are screened for, and examining the laboratory’s internal data on concordance and discordance can help make an informed decision.  

If a lab offers blood collection any day but the NIPT test is a few days later, does this affect the result?

NIPT samples are collected in specialized tubes that stabilize the material for five days. Ensure that the laboratory receives the sample within this timeframe to maintain the validity of the test.  

Can you please explain the significance of PPV in relation to considering having the test or not, like in that study where 87% were false positive?

PPV (positive predictive value) is crucial when considering whether to have the test or not. After receiving a positive NIPT result, inquire about the PPV from the laboratory. This metric helps manage expectations and assess the likelihood of a true positive result. Laboratories should be able to calculate PPV based on their internal data, and a high PPV is essential for making informed decisions.  
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Authors
Roy Pascal Naja, PhD, DipRCPath

Roy Pascal Naja, PhD, DipRCPath

Dr Roy Pascal Naja has more than 20 years of experience in clinical diagnostics and health care management, with a focus in fertility. Before joining Eurofins Clinical Genetics UK in 2023 as Laboratory Director and CSO, Dr Naja was the Laboratory Director at Igenomix UK from 2017 to 2023. Prior to this, Dr Naja held several Principal/Senior Scientist positions in private healthcare, NHS and university settings. Dr Naja is a Clinical Scientist (HCPC) and a “Diplomate” member of the Royal College of Pathologists. Dr Naja is a technical expert with the United Kingdom Accreditation Service (UKAS). Having a strong research background and a PhD in Human Genetics, Dr Naja maintains an Associate Professorship position (Honorary) at the department of Reproductive Health, University College London.
Event Moderator
Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.
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