Down's syndrome occurs when a person has three, rather than two copies of chromosome
21; or the specific area of chromosome 21 implicated in causing Down's syndrome. It
is the commonest congenital cause of mental disability and also leads to numerous
metabolic and structural problems. It can be life‐threatening, or lead to considerable
ill health, although some individuals have only mild problems and can lead relatively
normal lives. Having a baby with Down’s syndrome is likely to have a significant impact
on family life. Noninvasive 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.
However, no test can predict the severity of problems a person with Down’s syndrome
will have. The aim of this review was to estimate and compare the accuracy of first
trimester serum markers for the detection of Down’s syndrome in the antenatal period,
both as individual markers and as combinations of markers. Accuracy is described by
the proportion of fetuses with Down’s syndrome detected by screening before birth
(sensitivity or detection rate) and the proportion of women with a low risk (normal)
screening test result who subsequently had a baby unaffected by Down's syndrome (specificity).
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), Health Services Research Projects
in Progress database (25 August 2011). We did forward citation searching ISI citation
indices, Google Scholar and PubMed ‘related articles’. We did not apply a diagnostic
test search filter. We also searched reference lists and published review articles.
We included studies in which all women from a given population had one or more index
test(s) compared to a reference standard (either chromosomal verification or macroscopic
postnatal inspection). Both consecutive series and diagnostic case‐control study designs
were included. Randomised trials where individuals were randomised to different screening
strategies and all verified using a reference standard were also eligible for inclusion.
Studies in which test strategies were compared head‐to‐head either in the same women,
or between randomised groups were identified for inclusion in separate comparisons
of test strategies. We excluded studies if they included less than five Down's syndrome
cases, or more than 20% of participants were not followed up. We extracted data as
test positive or 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 (Quality Assessment of Diagnostic
Accuracy Studies) criteria. We used hierarchical summary ROC meta‐analytical methods
or random‐effects logistic regression methods to analyse test performance and compare
test accuracy as appropriate. Analyses of studies allowing direct and indirect comparisons
between tests were undertaken. We included 56 studies (reported in 68 publications)
involving 204,759 pregnancies (including 2113 with Down's syndrome). Studies were
generally of good quality, although differential verification was common with invasive
testing of only high‐risk pregnancies. We evaluated 78 test combinations formed from
combinations of 18 different tests, with or without maternal age; ADAM12 (a disintegrin
and metalloprotease), AFP (alpha‐fetoprotein), inhibin, PAPP‐A (pregnancy‐associated
plasma protein A, ITA (invasive trophoblast antigen), free βhCG (beta human chorionic
gonadotrophin), PlGF (placental growth factor), SP1 (Schwangerschafts protein 1),
total hCG, progesterone, uE3 (unconjugated oestriol), GHBP (growth hormone binding
protein), PGH (placental growth hormone), hyperglycosylated hCG, ProMBP (proform of
eosinophil major basic protein), hPL (human placental lactogen), (free αhCG, and free
ßhCG to AFP ratio. Direct comparisons between two or more tests were made in 27 studies.
Meta‐analysis of the nine best performing or frequently evaluated test combinations
showed that a test strategy involving maternal age and a double marker combination
of PAPP‐A and free ßhCG significantly outperformed the individual markers (with or
without maternal age) detecting about seven out of every 10 Down's syndrome pregnancies
at a 5% false positive rate (FPR). Limited evidence suggested that marker combinations
involving PAPP‐A may be more sensitive than those without PAPP‐A. Tests involving
two markers in combination with maternal age, specifically PAPP‐A, free βhCG and maternal
age are significantly better than those involving single markers with and without
age. They detect seven out of 10 Down's affected pregnancies for a fixed 5% FPR. The
addition of further markers (triple tests) has not been shown to be statistically
superior; the studies included are small with limited power to detect a difference.
The screening blood tests themselves have no adverse effects for the woman, over and
above the risks of a routine blood test. However some women who have a ‘high risk’
screening test result, and are given amniocentesis or chorionic villus sampling (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. Screening tests for Down’s syndrome in first
three months of pregnancy Background
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 during pregnancy to
assist them in making decisions. If a mother is carrying a baby with Down’s, 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 Down’s child.
The most accurate tests for Down’s 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. Both these tests involve inserting needles through the mother's
abdomen and are known to increase the risk of miscarriage. Thus, the tests are not
suitable for offering to 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, they can miss cases of Down’s and also give
a ‘high risk’ test result to a number of women whose babies are not affected by Down’s.
Thus, pregnancies identified as ‘high risk’ using these screening tests require further
testing using amniocentesis or CVS to confirm a diagnosis of Down’s. What we did
The aim of this review was to find out which of the blood screening tests done during
the first three months of pregnancy are the most accurate at predicting the risk of
a pregnancy being affected by Down's. We looked at 18 different blood markers that
can be used alone or in combination, taken before 14 weeks gestation, thus creating
78 screening tests fro Down’s. We found 56 studies, involving 204,759 pregnancies
of which 2113 had pregnancies affected by Down's. What we found
For the first 14 weeks of pregnancy, the evidence supports the use of the double test
of two blood markers; pregnancy‐associated plasma protein A (PAPP‐A) and free beta
human chorionic gonadotrophin (βhCG), in combination with the mother's age. This test
detects around seven out of every 10 (68%) pregnancies affected by Down's. It is common
practice to offer amniocentesis or CVS to women with a high risk test result. About
one in 20 women (5%) having this test will have a ‘high risk’ result but most of these
women will not be carrying a baby with Down’s. We found for tests in the first 14
weeks of pregnancy, there is little evidence to support the use of serum tests made
up of more than two blood markers.
Other important information to consider
The blood tests themselves have no adverse effects for the woman, over and above the
risks of a routine blood test. 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.