Antenatal Screening for Down's Syndrome

The risk of Down's syndrome varies with maternal age:

• 1:1500 at 20 years
• 1:800 at 30 years
• 1:270 at 35 years
• 1:100 at 40 years
• > 1:50 at 45 years and over¹

The risk also increases after a previously-affected pregnancy:

• With regular trisomy 21, the recurrence risk is 0.75% at 12 weeks; 0.42% during the middle trimester and 0.34% at term.²
• Following trisomy due to a translocation, the recurrence risk is dependent on the type of translocation and which partner carries the translocation.³
• People with Down's syndrome rarely reproduce. Of maternal offspring, less than half have Down's syndrome.³

• There is a national screening programme for Down's syndrome.
• The aim of this screening programme is to identify those women at a higher risk of having a baby with Down's syndrome and offer them diagnostic testing using either chorionic villus sampling (if less than 13 weeks' gestation) or amniocentesis (if beyond 15 weeks gestation). These procedures carry a risk of miscarriage (0.5-1% excess miscarriage risk for amniocentesis; 1-2% for chorionic villus sampling).³
• Women found to be carrying a baby with Down's syndrome may be offered a termination of pregnancy or they may choose to continue with the pregnancy.
• The challenge of an antenatal screening programme is to identify women in whom a risk of Down's syndrome is sufficiently high to justify such an invasive test and to minimise the risk of miscarrying a healthy baby.⁴
• A target was set by the National Screening Committee that by April 2007, Down's syndrome screening tests should achieve a detection rate of at least 75% with a false positive rate of 3% or less.⁵

• There are two methods of screening for Down's syndrome: serum screening and ultrasound screening. These can be used in combination.
• Once a screening test has been performed, the chance of the fetus having Down's syndrome is calculated using software that takes into account maternal age and gestation.
• The screening test is positive if this probability is equal to, or greater than, a nationally agreed cut-off level.
• The current cut-off level in the UK is a 1 in 250 chance that the pregnant woman is carrying a baby with Down's syndrome. These women are offered diagnostic testing.

Serum markers for Down's syndrome³

These include:

• Pregnancy Associated Plasma Protein A (PAPP-A): produced by placental syncytiotrophoblasts; levels reduced in pregnancies affected by Down's syndrome.
• Beta-human chorionic gonadotrophin (β-HCG): produced by placental syncytiotrophoblasts; raised levels in pregnancies affected by Down's syndrome.
• Alpha-fetoprotein (AFP): produced by fetal yolk sac and liver; reduced levels in pregnancies affected by Down's syndrome.
• Unconjugated oestriol (uE₃): produced by placenta and fetal adrenals; reduced levels in pregnancies affected by Down's syndrome.
• Inhibin-A: produced by placenta; raised levels in pregnancies affected by Down's syndrome.

Factors that can affect these serum markers include:³

• Weight: marker levels are higher in lighter women and lower in heavy women.
• Ethnic group: Afro-Caribbeans have higher levels of AFP and HCG compared to Caucasians.
• Twins and multiple pregnancy: increased levels if serum markers are present.
• Assisted conception: if a donor egg is used, Down's risk should be calculated using age of donor; HCG levels can be increased in assisted conception.
• Previous pregnancy history
• Bleeding: recent bleeding increases AFP levels.
• Smoking
• Insulin dependent diabetes mellitus
• Gestational age

Nuchal translucency scanning

• Fetal nuchal translucency (NT or FNT) screening uses ultrasound to measure the size of the nuchal pad at the nape of the fetal neck.
• It should be performed between 11 weeks and 13 weeks + 6 days.³
• Increased nuchal translucency reflects fetal heart failure, and is typically seen in any serious anomaly of the heart and great arteries, and strongly associated with a chromosomal abnormality. In one study, 84% of karyotypically proven trisomy 21 fetuses had a nuchal translucency >3mm at 10-13 weeks' gestation (as did 4.5% of chromosomally normal fetuses).
• The greater the extent of FNT, the greater the risk of abnormality.
• It is a straightforward test but will have a 20% false positive rate (FPR) if the thresholds are set to detect 85% (if used alone and maternal age adjusted).
• Adding nasal bone screening during the same examination may increase sensitivity further and reduce the FPR.^6,7 One study concluded that an absent nasal bone should be considered as a highly predictive marker of Down's syndrome.⁸
• Specific standards have been set for nuchal translucency measurement.⁹

• Maternal age alone (30% detection rate; 5% false positive rate)
• 1st trimester tests (11-14 weeks)
  • Nuchal translucency alone
  • Combined test: nuchal translucency scanning plus serum measurement of free β-HCG and PAPP-A
• 2nd trimester tests (15-20 weeks)
  • Double test: measures uE₃ and β-HCG
  • Triple test: measures AFP, HCG and uE₃
  • Quadruple test: measures free β-HCG, AFP, inhibin A and uE₃
• 1st and 2nd trimester tests
  • Integrated test: a combined test is carried out at 11-14 weeks PLUS AFP, uE₃ and inhibin A are measured at 15-20 weeks; results not available until after 15 weeks
  • Serum integrated test: PAPP-A and HCG are measured at 11-14 weeks but no nuchal scan is performed PLUS AFP, uE₃ and inhibin A are measured at 15-20 weeks

A key study in Down's syndrome screening was the Serum Urine and Ultrasound Screening Study (SURUSS).^11,12 It compared the different antenatal screening tests available for Down's syndrome. It was a prospective study of about 47,000 singleton pregnancies conducted in 25 maternity units. It concluded that:

• The Integrated test offers the most effective and safe method of screening for women who attend in the first trimester.
• The next best is the Serum integrated test.
• The Quadruple test is the best test for women who first present in the second trimester.
• The Double test (AFP and HCG), the Triple test, or nuchal translucency alone (with or without maternal age) should no longer be retained in antenatal screening for Down's syndrome.

The current NICE guidelines for antenatal care¹⁰ have looked at all available evidence for Down's syndrome screening. NICE found that:

• The Integrated test has a higher detection rate and lower false positive rate when compared with other screening tests.
• It is cost effective and results in the fewest losses of normal fetuses after invasive diagnosis.
• There are concerns regarding the practicality of this test. Up to 25% of women fail to attend for the second component of the test.
• There is also evidence that women prefer a one-stage test.

This lead NICE to the conclusion that the combined test should be the screening test offered to women in the first trimester. This has good diagnostic accuracy for Down's syndrome and other chromosomal abnormalities.

NICE also concluded that the Quadruple test has the best screening performance in the second trimester. However, NICE notes that the measurement of inhibin A is not generally available in the UK.

NICE guidelines on antenatal care, published in March 2008, include guidelines on screening for Down's syndrome. They cover the following points:

• Who should be offered screening?
  • All pregnant women should be offered screening for Down's syndrome.
  • They should understand that it is their choice, after informed discussion, whether or not to proceed with the screening programme.
• Timing of screening
  • Screening should be performed by the end of the first trimester (13 weeks 6 days).
  • However, screening should be offered up to 20 weeks gestation for women booking later in pregnancy.
• What screening tests should be offered?
  • The 'combined test' (nuchal translucency, beta-human chorionic gonadotrophin (β-HCG) and pregnancy-associated plasma protein-A) should be the screening test offered to women between 11 weeks 0 days and 13 weeks 6 days.
  • For women who book later, the most clinically and cost-effective serum screening test (triple or quadruple test) should be offered between 15 weeks 0 days and 20 weeks 0 days.
  • When it is not possible to measure nuchal translucency (because of fetal position or maternal raised BMI), women should be offered serum screening (triple or quadruple test) between 15 weeks 0 days and 20 weeks 0 days.
• Providing information: women should be given information regarding Down's syndrome screening at their first appointment with a healthcare professional. This should include:
  • Balanced and accurate information about Down's syndrome.
  • The fact that screening does not give a definite diagnosis.
  • An explanation of the risk score obtained following screening.
  • The screening pathway and next steps for screen-positive and screen-negative results, including information about the decisions that need to be made at each step and their consequences.
  • Information about amniocentesis and chorionic villus sampling.
• Screen-positive results
  • All women with screen-positive results should have rapid access to counselling by trained staff.
• Other points
  • The routine anomaly scan should not be routinely used as a screening tool for Down's syndrome using soft markers.
  • The presence of an isolated soft marker, with the exception of increased nuchal fold, on the routine anomaly scan, should not be used to adjust the a priori risk for Down's syndrome.
  • If there is an increased nuchal fold (≥ 6mm) or two or more soft markers for Down's syndrome on the routine anomaly scan, a referral to a fetal medicine specialist should be offered.

• Around 2% of pregnancies affected by Down's syndrome are twins.¹³
• If the twins are dizygotic, the risk of Down's syndrome for each baby individually is the same as for a single baby (around 1 in 800 pregnancies).
• If the twins are monozygotic, the risk to both of having Down's syndrome is around 1 in 800.
• Serum markers are affected by the presence of more than one baby.
• Recent studies have shown that a combination of nuchal translucency scanning and serum screening may be beneficial in the risk assessment of Down's syndrome for twin pregnancies.^14,15

Use of fetal cells in the maternal circulation for prenatal diagnosis is being investigated, and may negate the need for amniocentesis.