First Trimester Screening: Combined Test for Down Syndrome

What Is First Trimester Screening?

First trimester screening (combined screening test) is a prenatal test that combines an ultrasound measurement of the fluid at the back of the baby's neck (nuchal translucency) with blood tests measuring pregnancy hormones. Together, these results calculate the probability that the baby has certain chromosomal abnormalities such as Down syndrome.

First trimester screening, also known as combined screening, nuchal translucency (NT) screening, or combined test, is one of the most common prenatal screening tests offered to pregnant women worldwide. The test is designed to identify pregnancies that have an increased probability of chromosomal abnormalities, allowing parents to make informed decisions about further testing and pregnancy management.

Unlike diagnostic tests such as amniocentesis or chorionic villus sampling (CVS), first trimester screening is a screening test that provides probability estimates rather than definitive diagnoses. A screening test cannot tell you with certainty whether your baby has a chromosomal abnormality; it can only indicate whether the risk is higher or lower than average. This distinction is crucial for understanding what the results mean.

The test has been used clinically since the 1990s and has become a standard part of prenatal care in many countries. Its widespread adoption is due to its non-invasive nature, relatively early timing in pregnancy, and reasonable detection rates when combined with appropriate follow-up testing.

How does the test work?

First trimester screening works by combining multiple markers to calculate a personalized risk estimate. The ultrasound component measures the nuchal translucency, which is a collection of fluid under the skin at the back of the baby's neck. Babies with chromosomal abnormalities often have increased nuchal translucency measurements. However, increased nuchal translucency alone does not confirm an abnormality, as many babies with increased measurements turn out to be perfectly healthy.

The blood test component measures two pregnancy hormones: pregnancy-associated plasma protein-A (PAPP-A) and human chorionic gonadotropin (hCG), specifically the free beta subunit (free beta-hCG). Abnormal levels of these hormones, combined with the ultrasound findings and maternal factors such as age, are entered into a specialized algorithm that calculates the overall risk.

What Conditions Does First Trimester Screening Detect?

First trimester screening primarily screens for trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome). These are the three most common chromosomal abnormalities that are compatible with live birth, though Edwards and Patau syndromes are much rarer and often more severe.

Chromosomes are structures in every cell that contain our genetic information. Most people have 46 chromosomes arranged in 23 pairs. During cell division after fertilization, errors can occur that result in an extra chromosome (trisomy) or a missing chromosome. Some chromosomal abnormalities are so severe that they cause miscarriage early in pregnancy, while others are compatible with live birth but cause varying degrees of developmental differences.

Down Syndrome (Trisomy 21)

Down syndrome is the most common chromosomal abnormality detected by first trimester screening. It occurs when there is an extra copy of chromosome 21, resulting in 47 chromosomes instead of 46. Down syndrome affects approximately 1 in 700 live births, though the risk increases with maternal age. People with Down syndrome typically have intellectual disability of varying degrees, characteristic facial features, and may have heart defects and other health conditions. With appropriate support and medical care, many individuals with Down syndrome live fulfilling lives well into adulthood.

Edwards Syndrome (Trisomy 18)

Edwards syndrome occurs when there is an extra copy of chromosome 18. It is much rarer than Down syndrome, occurring in approximately 1 in 5,000 live births. Edwards syndrome causes severe developmental abnormalities, and most affected pregnancies result in miscarriage or stillbirth. Among babies born with Edwards syndrome, the majority do not survive past their first year of life due to severe organ abnormalities.

Patau Syndrome (Trisomy 13)

Patau syndrome results from an extra copy of chromosome 13 and occurs in approximately 1 in 16,000 live births. Like Edwards syndrome, Patau syndrome causes severe developmental abnormalities and is associated with very poor prognosis. Most affected pregnancies end in miscarriage, and survival beyond the first few weeks of life is uncommon.

When Is First Trimester Screening Done?

The blood test can be taken after week 9 of pregnancy, while the ultrasound is performed between weeks 11+2 and 13+6. The timing is crucial because the nuchal translucency measurement is only accurate during this specific window when the fetus is between 45mm and 84mm in crown-rump length.

The timing of first trimester screening is carefully chosen to optimize accuracy. The blood test component can be performed from week 9 onwards, though ideally it is done at least a few days before the ultrasound to allow time for laboratory analysis. Some healthcare systems perform the blood test at the same time as the ultrasound for convenience.

The ultrasound component must be performed during a specific window between 11 weeks and 2 days (11+2) and 13 weeks and 6 days (13+6) of pregnancy. This timing is based on the crown-rump length (CRL) of the fetus, which should be between 45mm and 84mm. Before this window, the fetus is too small for accurate nuchal translucency measurement. After this window, the lymphatic system develops and the nuchal fluid naturally decreases, making the measurement less meaningful.

If you miss the window for first trimester screening, you may be offered second trimester screening instead, which uses different blood markers and is performed between weeks 15 and 20. However, second trimester screening has a slightly lower detection rate for Down syndrome and provides results later in pregnancy.

Availability and access

First trimester screening is widely available in most developed countries, though access may vary depending on your healthcare system and location. In some regions, the test is offered to all pregnant women, while in others it may be offered only to those in higher-risk categories or those who specifically request it. Some healthcare systems cover the cost of the test, while others require out-of-pocket payment.

You typically need a referral from your healthcare provider (midwife, obstetrician, or general practitioner) to schedule first trimester screening. The referral ensures that the test is performed at the appropriate time and that you receive proper counseling about what the test involves and what the results mean.

How Is First Trimester Screening Done?

First trimester screening consists of two parts: a blood test that measures pregnancy hormones (PAPP-A and hCG), and an ultrasound examination that measures the nuchal translucency and confirms gestational age. The procedures are simple, safe, and typically take about 30 minutes for the ultrasound portion.

The blood test

The blood test component of first trimester screening involves a simple blood draw from a vein in your arm, similar to any other blood test. No special preparation is required; you do not need to fast beforehand. The blood sample is sent to a specialized laboratory where it is analyzed for two specific markers:

• PAPP-A (Pregnancy-Associated Plasma Protein-A): A protein produced by the placenta. Lower than expected levels are associated with increased risk of chromosomal abnormalities.
• Free beta-hCG (Human Chorionic Gonadotropin): A hormone produced during pregnancy. In Down syndrome pregnancies, levels tend to be higher than average, while in Edwards and Patau syndrome, levels tend to be lower.

You may experience mild discomfort or slight soreness at the blood draw site, but there are no other side effects from the blood test itself. Results are typically available within a few days to a week, depending on the laboratory.

The ultrasound examination

The ultrasound examination is performed abdominally (on your belly) using a handheld probe called a transducer. Gel is applied to your abdomen to help transmit sound waves, and the sonographer moves the transducer over your belly to obtain images of the fetus. The examination is painless and typically takes 15-30 minutes.

Having a moderately full bladder can help push the uterus into a better position for imaging, especially earlier in the screening window. However, do not worry if you need to empty your bladder before the examination; good images can usually still be obtained.

During the ultrasound, the sonographer will:

• Confirm the number of fetuses (single pregnancy vs. twins)
• Measure the crown-rump length (CRL) to confirm gestational age
• Measure the nuchal translucency (NT) - the fluid-filled space at the back of the baby's neck
• Check for the presence of the nasal bone (absence can be an additional marker)
• Assess basic fetal anatomy

You are welcome to bring a support person to the ultrasound appointment. However, it is generally recommended not to bring young children, as the examination requires concentration and the room may need to be darkened for optimal imaging.

What Do the Results Mean?

First trimester screening results are expressed as a probability ratio, such as "1 in 1,000" for Down syndrome. A result below a certain cutoff (commonly 1 in 150 or 1 in 250) is considered "screen positive" or high-risk, indicating that further testing is recommended. A "screen negative" result indicates lower risk but does not guarantee an unaffected pregnancy.

Understanding first trimester screening results requires careful interpretation. The test does not simply say "yes" or "no" to chromosomal abnormalities. Instead, it provides a personalized risk estimate based on your specific measurements and factors. This risk is expressed as a ratio or probability.

For example, a result of "1 in 10,000 for Down syndrome" means that out of 10,000 women with similar results, statistically one would have a baby with Down syndrome and 9,999 would not. This is considered a low-risk result. Conversely, a result of "1 in 50" means that out of 50 women with similar results, one would have an affected baby and 49 would not. This is considered a high-risk result, but it is important to recognize that even with this result, there is a 98% chance the baby is unaffected.

Screen positive (high-risk) results

A screen positive or high-risk result does not mean your baby definitely has a chromosomal abnormality. It means that the calculated risk is above a certain threshold (cutoff), and further testing is recommended to provide more information. The cutoff varies by institution but is commonly set at 1 in 150 or 1 in 250.

If you receive a screen positive result, you will be offered genetic counseling and the opportunity for further testing. Your options typically include:

• NIPT (Non-Invasive Prenatal Testing): A more accurate blood test that analyzes cell-free fetal DNA in maternal blood. Detection rate for Down syndrome exceeds 99% with a very low false-positive rate.
• Amniocentesis: A diagnostic test performed after 15 weeks that samples amniotic fluid. Provides a definitive diagnosis with 99.9% accuracy but carries a small risk of miscarriage (approximately 1 in 300-500).
• Chorionic Villus Sampling (CVS): A diagnostic test performed between 11-14 weeks that samples placental tissue. Also provides a definitive diagnosis with similar accuracy and miscarriage risk to amniocentesis.

Screen negative (low-risk) results

A screen negative or low-risk result indicates that the calculated risk is below the cutoff threshold. While this is reassuring, it is important to understand that it does not guarantee an unaffected pregnancy. First trimester screening detects approximately 85-90% of Down syndrome cases, meaning that 10-15% of affected pregnancies will have "normal" screening results (false negatives).

Most women with screen negative results can proceed with their pregnancy with reasonable reassurance, while remaining aware that no screening test is perfect. Additional testing is generally not recommended for low-risk results unless there are other concerning findings or you have a strong preference for diagnostic certainty.

How Accurate Is First Trimester Screening?

First trimester combined screening detects approximately 85-90% of Down syndrome cases with a false-positive rate of about 5%. This means that 5 out of 100 women screened will receive a high-risk result even though their baby does not have a chromosomal abnormality. Detection rates for Edwards and Patau syndromes are similarly high.

The accuracy of first trimester screening is typically described using two key metrics: the detection rate (sensitivity) and the false-positive rate. The detection rate is the percentage of affected pregnancies that the test correctly identifies as high-risk. The false-positive rate is the percentage of unaffected pregnancies that the test incorrectly identifies as high-risk.

For Down syndrome, first trimester combined screening has a detection rate of approximately 85-90% with a false-positive rate of about 5%. This means that out of every 100 pregnancies with Down syndrome, approximately 85-90 will be correctly identified as high-risk, while 10-15 will be missed (false negatives). Meanwhile, out of every 100 pregnancies without Down syndrome, approximately 5 will incorrectly receive a high-risk result (false positives).

Factors affecting accuracy

Several factors can affect the accuracy of first trimester screening:

• Quality of ultrasound: Accurate nuchal translucency measurement requires specialized training and certification. Results from accredited centers tend to be more reliable.
• Gestational age: The test is most accurate when performed at the optimal time (11-14 weeks). Testing outside this window may reduce accuracy.
• Maternal factors: Certain factors such as maternal weight, smoking status, and ethnicity can affect hormone levels and are accounted for in risk calculations.
• Multiple pregnancies: Screening in twin pregnancies is more complex and may have different detection rates.

Is First Trimester Screening Safe?

Yes, first trimester screening is completely safe for both mother and baby. The blood test involves a routine blood draw, and ultrasound uses sound waves with no known harmful effects. Unlike diagnostic tests such as amniocentesis, first trimester screening carries absolutely no risk of miscarriage or harm to the pregnancy.

One of the major advantages of first trimester screening over diagnostic tests is its safety profile. The test is entirely non-invasive, meaning nothing enters the uterus or comes in contact with the baby. The blood test is a standard venipuncture with minimal discomfort, and ultrasound has been used in obstetrics for decades with an excellent safety record.

Ultrasound works by emitting high-frequency sound waves that bounce off tissues to create images. These sound waves do not use radiation (unlike X-rays or CT scans) and have not been shown to cause any harm to the developing fetus when used appropriately in medical settings. Major medical organizations including the American College of Obstetricians and Gynecologists (ACOG), the World Health Organization (WHO), and the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) support the use of ultrasound in pregnancy when medically indicated.

After the blood test, you may experience mild soreness at the draw site, but this typically resolves within a day. There are no special precautions needed after first trimester screening; you can continue your normal activities immediately.

What Should You Consider Before Testing?

Before having first trimester screening, consider why you want the information, what you would do with different results, and whether you would want diagnostic testing if the result is high-risk. There are no right or wrong answers; the decision should be based on your values, beliefs, and personal circumstances.

First trimester screening is entirely voluntary. No one can or should pressure you into having the test or declining it. The decision is deeply personal and depends on many factors that only you can weigh. Before making your decision, it may be helpful to consider the following questions:

• Why do I want this information? Some parents want to prepare emotionally and practically if their child has special needs. Others may want to consider pregnancy options. Still others find that knowing in advance does not change anything for them.
• How would I feel about a high-risk result? A screen positive result can cause significant anxiety, even though it more often than not means the baby is unaffected. Consider whether you are prepared for this possibility.
• Would I pursue diagnostic testing? If you receive a high-risk result, you will be offered diagnostic tests that carry a small risk of miscarriage. Think about whether you would want these tests and what you would do with the results.
• How do my beliefs and values factor in? Your religious, cultural, or personal beliefs may influence how you view prenatal testing and what choices you would make.

It is often helpful to discuss these questions with your partner, if applicable, and with your healthcare provider. Genetic counselors are also available to help you understand the test, its implications, and your options without pressuring you toward any particular decision.

Emotional considerations

Receiving a high-risk screening result can be emotionally challenging, even when you understand that it does not necessarily mean your baby is affected. Many parents experience anxiety, worry, and distress while waiting for follow-up testing results. Support from healthcare providers, counselors, family, and friends can be valuable during this time.

If your follow-up testing confirms a chromosomal abnormality, you will be offered counseling to discuss what this means for your baby, what support is available, and what options you have. Healthcare providers are there to give you accurate information and support your decisions, not to tell you what to do.

First Trimester Screening in Multiple Pregnancies

First trimester screening can be performed in twin pregnancies, but interpretation is more complex. Each baby is assessed individually, and the overall accuracy may be somewhat lower than in singleton pregnancies. Special counseling is recommended for multiple pregnancies.

If you are pregnant with twins or higher-order multiples, first trimester screening is still possible but requires additional considerations. The nuchal translucency measurement is performed separately for each fetus, allowing individual risk assessment. However, the blood test measures hormones that come from all fetuses combined, which can affect the accuracy of risk calculations.

In twin pregnancies, it is also important to determine whether the twins are identical (monochorionic) or fraternal (dichorionic), as this affects risk calculations and follow-up options. Identical twins share the same genetic makeup, so if one has a chromosomal abnormality, the other will too. Fraternal twins are genetically different and can have different chromosomal compositions.

If you are pregnant with multiples and receive a high-risk result, counseling about follow-up options is particularly important, as the implications of diagnostic testing and any pregnancy decisions are more complex.

What Happens After First Trimester Screening?

After first trimester screening, results are typically available within 1-2 weeks. Low-risk results require no further action. High-risk results lead to counseling and discussion of follow-up options including NIPT (additional blood test) or diagnostic testing (CVS or amniocentesis).

The pathway after first trimester screening depends on your results:

After a low-risk (screen negative) result

If your screening result indicates low risk for chromosomal abnormalities, you will typically continue with routine prenatal care. You will be offered additional ultrasounds during pregnancy, including the anatomy scan at 18-22 weeks, which assesses fetal development in more detail. While the screening result is reassuring, remember that it does not guarantee an unaffected pregnancy.

After a high-risk (screen positive) result

If your screening result indicates higher risk, you will be contacted to discuss the results and next steps. This typically includes:

1. Genetic counseling: A counselor will explain what the results mean, answer your questions, and present your options without judgment.
2. Discussion of follow-up testing options: You may choose NIPT for more accurate screening, or diagnostic testing (CVS or amniocentesis) for a definitive answer.
3. Time to decide: You do not need to make immediate decisions. Take time to process the information and discuss with your partner or support people.

If follow-up testing confirms a chromosomal abnormality, you will receive further counseling about what to expect, available support services, and your options. Whatever you decide, healthcare providers are there to support you.