NIPT or Quad Screen: How Do Prenatal Screening Tests Differ and What Do Results Mean?

NIPT and the quad screen are both prenatal screening tests that use a blood sample to estimate the chance of certain conditions, such as Down syndrome. NIPT analyzes small fragments of placental DNA in your blood and can be done earlier in pregnancy. The quad screen measures four proteins and hormones, usually in the second trimester, and can also flag a higher chance of a neural tube defect. Neither test diagnoses a condition. This article compares them and explains what results may suggest and what follow-up testing involves.

NIPT or quad screen: how the two tests compare

Both tests are screening tests. A screening test sorts pregnancies into "lower chance" and "higher chance" groups for a specific set of conditions. It does not tell you whether your baby has one. MedlinePlus (NIH) describes prenatal testing as falling into two broad groups: screening tests that estimate chance, and diagnostic tests that can identify a condition (Prenatal Testing).

The tests differ in what they measure, when they are done, and what they are best at detecting.

The quad screen is a screening test with a long track record. NIPT is newer and is generally better at detecting the common trisomies than older blood-based screens, though it is still screening. A health technology assessment of NIPT indexed by the NIH, Noninvasive Prenatal Testing for Trisomies 21, 18, and 13, Sex Chromosome Aneuploidies, and Microdeletions, reviews how well it performs for each of these targets and notes that performance differs by condition.

How NIPT works

During pregnancy, small pieces of DNA from the placenta circulate in your blood alongside your own DNA. NIPT counts these fragments and looks for a pattern that suggests an extra or missing piece of a chromosome. Down syndrome (trisomy 21) is the best known result, but trisomy 18 and trisomy 13 are usually included as well.

Some labs also offer optional add-ons, such as sex chromosome conditions or a few small chromosome deletions. These add-ons are generally less well studied than the core trisomy results, and a positive result on them can be less reliable. Ask your clinician or a genetic counselor which conditions your specific test reports.

Why a NIPT result can be wrong

The placenta and the baby usually share the same genetic makeup, but not in every pregnancy. Several factors can contribute to a result that does not match the baby:

• Differences confined to the placenta (sometimes called confined placental mosaicism).
• A twin pregnancy in which one twin stopped developing earlier.
• A chromosome difference in the pregnant person's own DNA, which in uncommon cases can be picked up by the test.
• A low amount of fetal DNA in the sample, which may produce no result at all.

Because of these possibilities, a "higher chance" NIPT result is treated as a reason for more testing, not as a diagnosis.

What a "no result" report may suggest

Sometimes the lab cannot report a result because the sample did not contain enough fetal DNA. This can happen for several reasons, including a very early draw or higher body weight, and in some cases it is associated with a chromosome difference. A no-result report is not a negative result. Your clinician may suggest a repeat draw, a different screening approach or an ultrasound.

How the quad screen works

The quad screen measures four substances in your blood, usually in the second trimester:

• AFP (alpha-fetoprotein): a protein made by the baby. Higher levels can be associated with an open neural tube defect, and lower levels with a higher chance of Down syndrome.
• hCG: a pregnancy hormone made by the placenta.
• Estriol: an estrogen made by the placenta and the baby.
• Inhibin A: a hormone made by the placenta.

A lab combines these values with your age, weight, the stage of pregnancy and other factors to calculate a chance for Down syndrome, trisomy 18 and open neural tube defects. Because the pregnancy dating strongly affects the calculation, an ultrasound that corrects the due date can change the result.

The quad screen has an advantage that matters for some people: the AFP part can point toward a neural tube defect such as spina bifida, which NIPT does not generally screen for. MedlinePlus (NIH) lists neural tube defects among the more common birth defects, and an ultrasound is often used to look at the spine and head when AFP is elevated.

What your result may mean

A lower-chance (screen-negative) result

A lower-chance result suggests the likelihood of the screened conditions is small, but it does not remove it. No screening test catches every affected pregnancy, and these tests do not look for all genetic conditions. They also do not screen for many structural birth defects, which is one reason routine ultrasounds are part of prenatal care.

A higher-chance (screen-positive) result

A higher-chance result means the chance is increased compared with the general group, not that the baby has the condition. Many people who receive a screen-positive result go on to have a baby without the condition, and this is more likely to happen with the quad screen than with NIPT. For that reason, clinicians usually recommend a diagnostic test, a detailed ultrasound and a conversation with a genetic counselor before any decisions are made.

An abnormal AFP result

Raised AFP can come from a neural tube defect, but it can also come from a pregnancy that is further along than expected, a twin pregnancy, or other causes. Your clinician will usually combine the number with ultrasound dating and anatomy findings.

Follow-up testing after a higher-chance screen

Diagnostic tests examine the baby's chromosomes directly. The two commonly used procedures are:

• Chorionic villus sampling (CVS): a small sample of placental tissue is taken, often in the late first trimester or early second.
• Amniocentesis: a small amount of amniotic fluid is removed, usually in the second trimester.

Both involve a small chance of pregnancy loss, and your clinician can explain the current estimate for your situation. Deciding whether to have a diagnostic test is personal. Some people want the certainty, others choose to continue with ultrasound monitoring, and others decline further testing. All of these are reasonable choices.

After CVS or amniocentesis, mild cramping can occur. Fluid leaking from the vagina, fever, or worsening abdominal pain after the procedure need prompt evaluation, and heavy bleeding needs emergency care (see the box below).

Who may want one test over the other

Clinicians often consider your age, personal and family history, whether you are carrying twins, and how early you want information. Some points that commonly shape the conversation:

• NIPT can be done earlier and is generally more accurate for the main trisomies, so some people choose it as a first screen.
• The quad screen may be chosen when someone starts care later in pregnancy, or when a neural tube defect screen is wanted.
• Prior pregnancy with a chromosome condition, an abnormal ultrasound or a known family history may lead a clinician to recommend diagnostic testing directly.
• Pregnancies conceived with assisted reproduction can change how some screening results are interpreted; a systematic review in the NIH-indexed literature, Prenatal screening of Down syndrome in assisted reproductive techniques pregnancies, discusses this.

Screening is optional. You can accept some tests, all of them, or none, and you can ask your clinician to explain what each one can and cannot tell you before you decide.

Cost and insurance questions

Coverage for NIPT varies by insurer, by plan and by your clinical situation, and some plans may not pay for it in every pregnancy. An article in the NIH-indexed literature, The impact of insurance on equitable access to non-invasive prenatal screening (NIPT): private insurance may not pay, describes how coverage differences can affect access. Before testing, it can help to call your insurer and the lab to ask what is covered and whether you could receive a separate bill.

Other screening that may come up

NIPT and the quad screen look at chromosomes and neural tube defects. They do not test for single-gene conditions such as cystic fibrosis or spinal muscular atrophy. Those are usually addressed with separate carrier screening, which looks at whether you or your partner carry a gene change. Other routine prenatal checks, such as Rh status and gestational diabetes testing, have their own tests and are discussed in separate articles.

A genetic counselor can help you sort through these options. MedlinePlus (NIH) explains what genetic counseling involves and how it supports decisions about testing.

Coping with a higher-chance result

Waiting for follow-up can be stressful. Many people feel anxious, guilty or overwhelmed, and those feelings are common. Consider bringing a partner or support person to appointments and writing questions down beforehand. Your care team can connect you with counseling. If distress becomes overwhelming, or you have thoughts of harming yourself, contact the 988 Suicide and Crisis Lifeline by calling or texting 988. If you are in immediate danger, call 911.

Questions to take to your appointment

• Which conditions does this test report, and which does it not?
• If my result is higher chance, what would the next step be?
• How does my age, a twin pregnancy or my conception method affect interpretation?
• Will my insurance cover this test, and what might I be billed?
• Can I see a genetic counselor before or after the result?

Bring any relevant family history, such as a relative with a chromosome condition or a neural tube defect, because it can change which test makes sense.

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