Beyond the Needle: From Invasive Risks to the New Standard in Prenatal Care

Edited by Nabiha Kashfee

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This blog post serves to simplify this scholarly article:

• Advancements of non-invasive prenatal testing: the role of obstetricians, published in the Journal Frontiers in Medicine

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For many parents, the first ultrasound is a core memory, but sometimes, the most profound information about your baby comes from a simple blood draw. Non-Invasive Prenatal Testing (NIPT), a blood test that screens for chromosomal abnormalities using fetal DNA in the mother’s bloodstream, has become increasingly popular for its ability to detect chromosomal abnormalities at an early stage of gestation. That being said, informing patients in depth about NIPT and its potential risks is essential. There are many misunderstandings surrounding NIPT which can lead to unnecessary testing, confusion about results, and increasing maternal anxiety. It is crucial for obstetricians and primaries to implement NIPT appropriately in their clinics to avoid unfavorable possibilities.

Prenatal Testing Before NIPT

Figure 1: What did Prenatal testing look like before NIPT?

Before the introduction of NIPT in 2011, prenatal testing relied heavily on invasive technology. Since the 1960s, amniotic fluid cytology has been considered to be the “gold standard” prenatal genetic test involving inserting an uncomfortable needle into the womb to extract fetal skin or respiratory cells in the amniotic fluid. By the 1980s, prenatal genetic testing had advanced to chorionic villi sampling which takes tissue straight from placenta via catheter or needle. Both methods are highly invasive and involve physical discomfort such as cramping. Even worse, it can cause miscarriages in around 1 out of 1000 to 1 out of 100 women.

In 1988, a larger step towards non-invasive procedures was made with a biochemical screening for human chorionic gonadotropin (hGC) levels. hGC is a hormone produced in the placenta when a woman becomes pregnant and its concentration can be used to predict the possibility of Down Syndrome. By the 1990s, nuchal translucency, a simple ultrasound that involves looking for fluids behind the fetus’ necks, became a routine screening in pregnant women for Down Syndrome and heart defects. Lastly, 1997 marks the year that cfDNA in maternal plasma was discovered. This breakthrough paved the way for a new era of screening, leading to the development of the non-invasive prenatal test (NIPT) which is way more safer for mothers and their babies.

What is NIPT?

Figure 2: Genosalut. (2022, July 4), Cell free fetal DNA test, [Digital Artwork], Google Images,

At 9 weeks, blood is drawn from the mother’s arm to extract and analyze placental DNA circulating throughout her body. Placental DNA, also known as cell-free DNA (cfDNA), originates from the fertilized egg itself. By taking a look at the cfDNA, researchers can view any aneuploidies and the gender of the child. However, it is important to note that even with its accuracy, NIPT is a screening tool rather than a diagnostic one. 

Specifically, it is 99.2% accurate in detecting trisomies 13, 18, and 21 (Down Syndrome). To ensure accuracy, the Fetal Fraction (FF) is also taken into the analysis. Fetal Fraction is the ratio of the fetal cfDNA to the mother’s DNA in the blood, and it is expressed as a percentage. At 9-10 weeks, the Fetal Fraction is typically around 6 to 20%, but to confirm NIPT accuracy, a minimum value of 4% FF is needed. Success is thankfully common as the failure rate of FF is 0.32%, meaning that the probability of FF being unable to confirm genetic results is very low. Out of the 0.32% of unsuccessful NIPT, 16.4% were caused by maternal malignancy which is a rare occurrence where NIPT actually detects cancer in the mother, mistaking cfDNA caused by a tumor rather than cfDNA from the fetus. Additionally, 20% of failures are due to a low percentage of FF. This Fetal Fraction exhibits low levels during the first 8 weeks of gestation, which makes NIPT very reliant on timing to be effective. Lower FFs can also possibly be attributed to older ages and greater BMIs.

NIPT metrics:

Detection Accuracy	99.2%
Average Fetal Fraction at 9-10 Weeks	6% - 20%
Fetal Fraction to Confirm NIPT Accuracy	4% or more
Failure Rate of Fetal Fraction	0.32%

Within the Failures of Fetal Fraction:

Caused by Maternal Malignancy	16.4%
Caused by Low Fetal Fraction	20%

Results are classified into two categories; high probability or low probability. Fetal Fraction predicts mainly trisomies. Specifically, a high probability of trisomy 21 is shown as an increase in Fetal Fraction. Conversely, high probability of trisomy 13 and 18 decrease it. False positives happen frequently in twins, triplets, and so on, making NIPT unsuitable for these populations. Additionally, false positives often happen in cases of placental mosaicism, where there are chromosomal differences between the placenta and the fetus in certain cells.

The Role of Providers

There are many cautious steps to be taken by providers before and after this procedure occurs. This responsibility lies within providers, whether that be obstetricians (OB), primary doctors, or even a genetic counselor. While NIPT isn’t suitable for every mother, it is important to be able to suggest this option correctly for soon-to-be mothers, especially those who are in their forties or have a family history of hereditary diseases. As there is no formal guide, obstetricians should still provide a comprehensive overview of all screening options (not just NIPT) including the place of concern, the testing process, and the associated risks and benefits. If unable, the OB should refer the mother to a genetic counselor who can potentially go more in depth and guide the family to a choice best fit if screening is desired. Pre-test counseling may be expanded beyond the ACOG 15-visit standard to include extended care for patients with specific risk factors, such as maternal age over 35, a family history of hereditary disease, incest, or a previous pregnancy involving aneuploidy. During this process, the provider should not pressure any parents to choose a specific screening tool and instead lend an ear to any concerns or questions they may have. 

  This guidance and support should continue after the results of NIPT especially when a failure occurred or results are abnormal. Some mothers may feel anxious or even depressed after learning or waiting for results. OBs should know how to recognize this and comfort the family or refer them to a mental health professional if needed. Additionally, mothers with unexpected abnormalities in their results may need to make a decision regarding elimination if permitted in the region. Informing without bias and showing care are necessary steps for the mother to feel safe in her choice. When patients feel empowered by provider’s support, they can better weigh the advantages of prenatal screening, most notably the shift towards safer, non-invasive methods. 

Clinical and Social Impact

Both invasive and non-invasive genetic tests are typically done during the same time-frame during the pregnancy. But, NIPT, as a whole, has reduced the need for invasive techniques which can even cause miscarriages, thus improving early detection. Additionally, while most mothers are able to make their own informed decisions about genetic screening thanks to obstetricians and further counseling, it is still important to note drawbacks to NIPT in implementation. For instance, some mothers are not able to be fully informed due to religious beliefs, disinterest, and language barriers. Socioeconomic factors also create a barrier for mothers to access NIPT. Women in low income areas already have a harder time accessing reproductive health. Some locations have laws banning abortion, which correlates with societal stigma for NIPT.  Even if NIPT is implemented in these areas, it is important for mothers to have access to safe termination if needed.

Future Directions for NIPT

Prenatal genetic screenings have come a long way from invasive practices that often meant the risk of miscarriages and discomfort. Today, a simple blood draw at nine weeks can relieve parents of any worries without any harmful risks. Nevertheless, the focus becomes less rooted in the science, but rather providing better support when implementing NIPT in clinical settings. However, the next discoveries being made for this science are already emerging within the field of In-Vitro Fertilization (IVF), where clinics may be able to screen embryos using the fluid in which they grow in instead of a mother’s womb. Ultimately, the heart of NIPT remains the same: empowerment. By bridging the gaps in access and providing unbiased support, providers can ensure that every family has the tools to make the choices best fit to their special journey.