Overview of screening programmes

There are a range of antenatal screening programmes. Most include tests to diagnose a variety of genetic and infectious conditions, including Down’s syndrome, spina bifida, sickle-cell anaemia, thalassaemia, HIV, hepatitis B, syphilis and rubella. In general they may be considered in three groups:

In addition, women are offered screening for HIV, hepatitis B, syphilis and rubella early in pregnancy.

Screening for Down’s syndrome

In the UK, all pregnant women are offered screening for trisomy 21 (Down’s syndrome) either in the first or second trimester. The first screening test is used to estimate a risk or probability of a fetus being affected. If the risk is higher than a pre-determined cut-off then a second diagnostic test is offered, which provides a definite result. The tests are optional and women may choose to refuse or opt out of the process at any stage. Screening tests are not foolproof. A proportion of cases are missed (false negatives) and most of the ‘screen positive’ cases turn out not to have the abnormality (false positives).

First trimester screening

Although second trimester screening has been common practice, combined first trimester screening is currently considered to be best practice as it provides a higher detection rate and lower false positive rate. It uses a combination of ultrasound measurement of fetal nuchal translucency (NT), and measurement of the maternal serum markers free beta HCG (FβHCG) and pregnancy-associated plasma protein A (PAPP-A), to derive a combined risk for Down’s syndrome. Each of these markers, including NT, varies with gestation and an accurate measurement of fetal maturity is required for accurate interpretation of results. For first trimester screening, ultrasound measurement of fetal crown rump length (CRL; Fig 77.1), carried out at the same time as the NT measurement, is used as the basis of the calculation of gestation for conversion of marker concentrations into a multiple of the median (MoM). An MoM is a measure of how far an individual test result deviates from the median. MoM is commonly used to report the results of medical screening tests, particularly where the results of the individual tests are highly variable.

Nuchal translucency

Nuchal translucency (Fig 77.2) is the fluid-filled area that is present at the back of the fetal neck and measures around 1.0 mm in unaffected pregnancies at 11–13 weeks’ gestation. It tends to be increased in Down’s syndrome and can be measured accurately by ultrasound (to the nearest 0.1 mm). The NT measurement is converted to a multiple of the median NT size at the appropriate CRL and a risk estimated.

For combined screening, NT measurements should be taken only when the fetal CRL falls within the range of 45–84 mm (equivalent to 11+2 – 14+1 weeks of gestation). Before this, the fetus is too small to allow accurate NT measurement, and after 14 weeks the strength of the association between NT and fetal chromosome abnormalities is not strong enough to be used in this respect.

Biochemical tests

In Down’s syndrome, the maternal serum FβHCG is increased to levels approaching twice those in unaffected pregnancies (2.0 MoM), whereas PAPP-A levels are reduced to around half the normal level (0.5 MoM); the magnitude of the change is maximum at earlier gestations.

Risk calculation

The results (MoM) of NT and biochemical markers are used to calculate the risk of Down’s syndrome. A cut-off of 1 in 150 is used to define whether a pregnancy is ‘low risk’ or ‘high risk’ on combined screening. All screening risk results equal to or greater than 1 in 150 are considered high risk, and these women are offered further counselling and diagnostic testing. About 2% of results fall into this category. All screening risk results less than 1 in 150 are considered low risk and no further action is usually indicated in these cases. It is also worth noting that as maternal age is a component of the screening risk calculation, there are a higher proportion of ‘positive’ tests in older women and the test detects an increasing proportion of Down’s syndrome pregnancies as maternal age advances. Multi-stage testing is strongly discouraged. Women who have had first trimester combined screening should not subsequently go on to have a second trimester biochemical screening test for Down’s syndrome.

Diagnostic tests

Women whose first trimester screening results fall in the high-risk category are offered chorionic villus sampling which, in the first trimester, carries a miscarriage rate of about 1–2%.

Second trimester screening

Although all women, who wish to be screened, should be encouraged to do so in the first trimester, second trimester screen provides an opportunity for those who present too late for first trimester screening. Maternal blood sample should be taken between 14+2 weeks and 20+0 weeks for measurement of alpha fetoprotein (AFP), human chorionic gonadotrophin (HCG), unconjugated oestriol (UE3) and Inhibin A. Pregnancies affected by Down’s syndrome have elevated levels of hCG and Inhibin A to around twice the levels found in unaffected pregnancies (2.0 MoM), while AFP and UE3 are reduced to around three-quarters of normal levels (0.75 MoM). These results along with maternal age are used to calculate the risk of Down’s syndrome. As with first trimester, a cut-off of 1 in 150 is used to define risk. All screening risk results equal to or greater than 1 in 150 (around 3–4% of pregnancies fall in this category) are high risk and these women are offered further counselling and diagnostic testing.

Diagnostic tests

Women whose second trimester screening results fall in the high-risk category are offered amniocentesis in order to exclude or identify a chromosome abnormality. Amniocentesis is associated with a risk of miscarriage of around 1%.

Other factors affecting interpretation of biochemical markers

Several factors have been identified which affect serum marker concentrations and therefore the risk estimate derived from them. Corrections, to take account of these variables, can be made to provide a more accurate estimate of risk for individual women.