Down's syndrome (also known as Down's or Trisomy 21) is an incurable genetic disorder that causes significant physical and mental health problems, and disabilities. However, there is wide variation in how Down's affects people. Some individuals are severely affected whilst others have mild problems and are able to lead relatively normal lives. There is no way of predicting how badly a baby might be affected.
Expectant parents are given the choice to be tested for Down’s syndrome during pregnancy to assist them in making decisions. If a mother is carrying a baby with Down’s syndrome, then there is the decision about whether to terminate or continue with the pregnancy. The information offers parents the opportunity to plan for life with a child with Down’s syndrome.
The most accurate tests for Down’s syndrome involve testing fluid from around the baby (amniocentesis) or tissue from the placenta (chorionic villus sampling (CVS)) for the abnormal chromosomes associated with Down’s syndrome. Both these tests involve inserting needles through the mother's abdomen and are known to increase the risk of miscarriage. Thus, the tests may not be suitable for all pregnant women. Rather, tests that measure markers in the mother’s blood, urine, or on ultrasound scans of the baby are used for screening. These screening tests are not perfect as they can miss cases of Down’s syndrome and also give high risk test results to a number of women whose babies are not affected by Down’s syndrome. Thus, pregnancies identified as high risk using these screening tests require further testing using amniocentesis or CVS to confirm a diagnosis of Down’s syndrome.
What we did
We assessed combinations of first trimester (up to 14 weeks' gestation) and second trimester serum screening tests (up to 24 weeks' gestation), with or without first trimester ultrasound screening tests, Our aim was to identify the most accurate test(s) for predicting the risk of a pregnancy being affected by Down's syndrome. We looked at one ultrasound marker (nuchal translucency) and seven different serum markers (PAPP-A, total hCG, free βhCG, uE3, AFP, inhibin A, ADAM 12) that can be used alone, in ratios or in combination, taken before 24 weeks' gestation, thus creating 32 screening tests for Down’s. We found 22 studies, involving 228,615 pregnancies (including 1067 fetuses affected by Down's syndrome).
What we found
For Down's syndrome screening, where tests were carried out in the first and second trimester and combined to give an overall risk, we found that a test comprised of first trimester nuchal translucency and PAPP-A, and second trimester total hCG, uE3, AFP and Inhibin A was the most sensitive test, detecting nine out of 10 pregnancies affected by Down's syndrome. Five per cent of pregnant women receiving a high risk test result based on this combination would not be affected by Down's syndrome. There were relatively few studies assessing these tests and therefore we cannot make a strong recommendation about the best test.
Other important information to consider
The ultrasound tests themselves have no adverse effects for the woman, and blood tests can cause discomfort, bruising and, rarely, infection. However, some women who have a high risk screening test result, and are given amniocentesis or CVS have a risk of miscarrying a baby unaffected by Down’s. Parents will need to weigh up this risk when deciding whether or not to have an amniocentesis or CVS following a high risk screening test result.
Tests involving first trimester ultrasound with first and second trimester serum markers in combination with maternal age are significantly better than those without ultrasound, or those evaluating first trimester ultrasound in combination with second trimester serum markers, without first trimester serum markers. We cannot make recommendations about a specific strategy on the basis of the small number of studies available.
Down's syndrome occurs when a person has three copies of chromosome 21 (or the specific area of chromosome 21 implicated in causing Down's syndrome) rather than two. It is the commonest congenital cause of mental disability. Non-invasive screening based on biochemical analysis of maternal serum or urine, or fetal ultrasound measurements, allows estimates of the risk of a pregnancy being affected and provides information to guide decisions about definitive testing.
Before agreeing to screening tests, parents need to be fully informed about the risks, benefits and possible consequences of such a test. This includes subsequent choices for further tests they may face, and the implications of both false positive (i.e. invasive diagnostic testing, and the possibility that a miscarried fetus may be chromosomally normal) and false negative screening tests (i.e. a fetus with Down’s syndrome will be missed). The decisions that may be faced by expectant parents inevitably engender a high level of anxiety at all stages of the screening process, and the outcomes of screening can be associated with considerable physical and psychological morbidity. No screening test can predict the severity of problems a person with Down's syndrome will have.
To estimate and compare the accuracy of first and second trimester serum markers with and without first trimester ultrasound markers for the detection of Down’s syndrome in the antenatal period, as combinations of markers.
We conducted a sensitive and comprehensive literature search of MEDLINE (1980 to 25 August 2011), Embase (1980 to 25 August 2011), BIOSIS via EDINA (1985 to 25 August 2011), CINAHL via OVID (1982 to 25 August 2011), the Database of Abstracts of Reviews of Effectiveness (the Cochrane Library 25 August 2011), MEDION (25 August 2011), the Database of Systematic Reviews and Meta-Analyses in Laboratory Medicine (25 August 2011), the National Research Register (Archived 2007), and Health Services Research Projects in Progress database (25 August 2011). We did not apply a diagnostic test search filter. We did forward citation searching in ISI citation indices, Google Scholar and PubMed ‘related articles’. We also searched reference lists of retrieved articles
Studies evaluating tests of combining first and second trimester maternal serum markers in women up to 24 weeks of gestation for Down's syndrome, with or without first trimester ultrasound markers, compared with a reference standard, either chromosomal verification or macroscopic postnatal inspection.
Data were extracted as test positive/test negative results for Down's and non-Down's pregnancies allowing estimation of detection rates (sensitivity) and false positive rates (1-specificity). We performed quality assessment according to QUADAS criteria. We used hierarchical summary ROC meta-analytical methods to analyse test performance and compare test accuracy. Analysis of studies allowing direct comparison between tests was undertaken. We investigated the impact of maternal age on test performance in subgroup analyses.
Twenty-two studies (reported in 25 publications) involving 228,615 pregnancies (including 1067 with Down's syndrome) were included. Studies were generally high quality, although differential verification was common with invasive testing of only high risk pregnancies. Ten studies made direct comparisons between tests. Thirty-two different test combinations were evaluated formed from combinations of eight different tests and maternal age; first trimester nuchal translucency (NT) and the serum markers AFP, uE3, total hCG, free βhCG, Inhibin A, PAPP-A and ADAM 12. We looked at tests combining first and second trimester markers with or without ultrasound as complete tests, and we also examined stepwise and contingent strategies.
Meta-analysis of the six most frequently evaluated test combinations showed that a test strategy involving maternal age and a combination of first trimester NT and PAPP-A, and second trimester total hCG, uE3, AFP and Inhibin A significantly outperformed other test combinations that involved only one serum marker or NT in the first trimester, detecting about nine out of every 10 Down's syndrome pregnancies at a 5% false positive rate. However, the evidence was limited in terms of the number of studies evaluating this strategy, and we therefore cannot recommend one single screening strategy.