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Antenatal screening for Down's syndrome

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Abstract

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows:

To compare different screening methods in isolation, and in various combinations to identify the most sensitive and specific test or tests for Down’s syndrome in the antenatal period.

Screening tests will be compared with respect to the following:

  • proportion of screened fetuses with Down’s syndrome detected by screening before birth;

  • the number of women with a high risk screening test result who subsequently have an unaffected pregnancy;

  • the number of invasive diagnostic procedures in women with fetuses subsequently found to have a normal karyotype;

  • the number of iatrogenic miscarriages in women with fetuses subsequently found to have a normal karyotype; and

  • the number of other adverse effects of screening and diagnosis.

Background

Antenatal screening is used for several reasons (Alfirevic 2004), but perhaps the most important, is to enable maternal or parental choice regarding pregnancy management and outcome.  Women and their partners also have a choice about whether they wish to have a screening test or not.  Before a woman and her partner opt to have a screening test, they need to be fully informed about the risks, benefits and possible consequences of such a test.  This includes the risk of having the test itself, what low‐risk and high‐risk results actually mean and the choices they may have to face should the result show that the woman has a high risk of carrying a baby with Down’s syndrome.  They need to be informed of the risk of a miscarriage due to invasive diagnostic testing, and the possibility that the miscarried fetus may be chromosomally normal.  If, following invasive diagnostic testing, the fetus is shown to have Down’s syndrome, further decisions need to be made about continuation or termination of the pregnancy, the possibility of adoption and finally, preparation for parenthood.  Equally, if a woman has a test that shows she is at a low risk of carrying a fetus with Down’s syndrome, it does not necessarily mean that the baby will be born with a normal chromosomal make up.  This possibility can only be excluded by a diagnostic test.

Down’s syndrome occurs in approximately 1 in 800 live births (Cuckle 1987).  It results from a person having 3 copies of chromosome 21 (also known as trisomy 21), where normally they should have only 2. Down’s syndrome can cause a wide range of physical and mental problems.  It is the commonest cause of mental retardation, and can also cause a number of congenital malformations, notably affecting the heart.  There is also an increased risk of cancers such as leukaemia and numerous metabolic problems including diabetes and thyroid disease.  Some of these problems may be life threatening, or lead to considerable ill health, while some individuals with Down’s syndrome have only mild problems and can lead a relatively normal life.  There is no test which can predict the severity of problems a person with Down’s syndrome will have. 

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.  Having a baby with Down’s syndrome is likely to have a significant impact on family and social life, relationships and parents’ work.  Special provisions may need to be made for education and care of the child, as well as accommodating the possibility of periods of hospitalisation.

There is no cure for Down’s syndrome, and antenatal diagnosis allows for preparation for the birth and subsequent care of a baby with Down’s syndrome, or for the offer of a termination of pregnancy. 

Diagnostic tests for Down’s syndrome

Down’s syndrome can be detected during pregnancy with invasive diagnostic tests such as amniocentesis or chorionic villus sampling (CVS), with or without prior screening (see below). The ability to determine fetal chromosomal make up (also known as a karyotype) from amniotic fluid samples was demonstrated in 1966 by Steele and Breg (Steele 1966), and the first antenatal diagnosis of Down’s syndrome was made in 1968 (Valenti 1968).  Amniocentesis is an invasive procedure which involves taking a small sample of the amniotic fluid (liquor) surrounding the baby, using a needle which goes through the abdominal wall into the uterus, and is usually performed after 15 weeks gestation.  CVS involves taking a sample of the placental tissue using a needle which goes through the abdominal wall and uterus or a cannula through the cervix.  It is usually performed between 10 and 13 weeks gestation.  Amniocentesis and CVS are both methods of obtaining fetal chromosomal material which are then used to diagnose Down’s syndrome.  Both tests use ultrasound scans to guide placement of the needle.  Amniocentesis carries a risk of miscarriage in the order of 1%; transabdominal CVS may carry a similar risk (Alfirevic 2003).

Historical developments in screening tests for Down’s syndrome

Initially, screening was determined solely by using maternal age to classify a pregnancy as high or low risk for trisomy 21, as it was known that older women had a higher chance of carrying a baby with Down’s syndrome (Penrose 1933).  At 20 years old the age related risk at term is 1:1500, at 30 years it is 1:800, at 35 1:270 and at 45 the risk is in excess of 1:50.  If a woman was deemed to be high risk (for example, over the age of 35), amniocentesis was offered. 

Further advances in screening were made in the early 1980’s, when Merkatz et al. investigated the possibility that low maternal serum alpha‐fetoprotein (AFP), obtained from maternal blood in the second trimester of pregnancy could be associated with chromosomal abnormalities in the fetus.  Their retrospective case‐control study showed a statistically significant relationship between fetal trisomy, such as Down’s syndrome, and lowered maternal serum AFP (Merkatz 1984).  This was further explored by Cuckle et al in a larger retrospective trial using data collected as part of a neural tube defect (NTD) screening project (Cuckle 1984).  This work was followed by calculation of risk estimates using maternal serum AFP values and maternal age, which ultimately led to the introduction of the two screening parameters in combination (Alfirevic 2004).

In 1987 in a small case‐control study of women carrying fetuses with known chromosomal abnormalities, Bogart and colleagues investigated maternal serum levels of human chorionic gonadotrophin (hCG), as a possible screening tool for chromosomal abnormalities in the second trimester (Bogart 1987).  This followed the observations that low hCG levels were associated with miscarriages, which are commonly associated with fetal chromosomal abnormalities.  They concluded that low hCG levels were associated with Down’s syndrome and because hCG levels plateau at 18‐24 weeks that this would be the most appropriate time for screening.  Later work suggested that the ß sub‐unit of hCG was a more effective marker than total hCG (Macri 1990; Macri 1993).

Second trimester unconjugated oestriol (uE3), produced by the fetal adrenals and the placenta, was also evaluated as a potential screening marker.  In another retrospective case‐control study, uE3 was shown to be lower in Down’s syndrome pregnancies compared with unaffected pregnancies.  When used in combination with AFP and maternal age, it appeared to identify more pregnancies affected by Down’s syndrome than AFP and age alone (Canick 1988).

Further work suggested that all 3 serum markers (AFP, hCG and uE3) showed even higher detection rates when combined with maternal age (Wald 1988a; Wald 1988b) and appeared to be a cost‐effective screening strategy (Wald 1992).

Two other serum markers, produced by the placenta, have been linked with Down’s syndrome, namely pregnancy associated plasma protein A or PAPP‐A, and inhibin A.  PAPP‐A has been shown to be reduced in the first trimester of Down’s syndrome pregnancies, with its most marked reduction in the early first trimester (Bersinger 1995). Inhibin A is high in the second trimester in pregnancies affected by Down’s syndrome (Cuckle 1995; Wallace 1995). There are some issues concerning the biological stability and hence reliability of this marker, and the effect this will have on individual risk. 

Sonographic tests

In 1992, Nicolaides and colleagues demonstrated an association between increased nuchal translucency (NT) and chromosomal abnormalities (Nicolaides 1992).  Nuchal translucency measurement requires an ultrasound scan of the fluid at the fetal neck between 10 and 13+6 weeks gestation.  If the amount is large it suggests an increased risk of Down’s syndrome. This study was small (827 women), but led to further research into the use of NT scanning and its value when combined with serum tests.

Other first trimester ultrasound markers have been investigated; they include absent nasal bone, abnormal ductus venosus flow velocity and tricuspid regurgitation.

Urine tests

In addition to serum and ultrasound markers for Down’s syndrome, work has been carried out looking at urinary markers.  These markers include invasive trophoblast antigen, ß‐core fragment, free ßhCG and total hCG (Cole 1999). There is controversy about their value (Wald 2003).

It is notable that both measured values of serum and ultrasound markers will change with increasing gestation. Therefore, it is important to be aware of the gestational age of the pregnancy when interpreting results so that a precise an estimation of risk as possible can be made.  This may be difficult where the woman is unsure of her dates, and highlights the importance of dating a pregnancy accurately by ultrasound, where such facilities exist.

Timing of screening tests

Historically, screening for Down’s syndrome has been undertaken in the second trimester of pregnancy, usually at 15 to 19 weeks gestation, as this is the period during which biochemical screening for neural tube defects was carried out.  If first trimester screening tests are effective and safe, however, they carry the advantage of allowing earlier termination of pregnancy, where appropriate.  It could also be argued that due to the significant spontaneous miscarriage rate of pregnancies affected by trisomy 21, earlier detection may result in unnecessary intervention, for example termination of pregnancies that are likely to have miscarried anyway.

There are subgroups of women in whom screening results may present particular challenges of interpretation.  An example is those with multiple pregnancies, where most serum markers will be altered due to the presence of multiple fetuses, and not necessarily because of the presence of a fetus with trisomy 21. 

Risk scores and test combinations

Improved diagnostic performance can be obtained by using several tests in combination, such as maternal age and serum marker combinations (e.g. the triple test), or combinations of maternal age, serum markers and sonographic measurements. Computation of probabilities of Down’s syndrome for each combination of tests needs to use statistical methods to take into account the correlations between the markers separately for Down’s syndrome fetuses and unaffected fetuses.  

A likelihood ratio can be computed for each observed value of a single marker as the ratio of the height of probability distribution in affected compared to unaffected fetuses.  If the probability distributions can be assumed to have a normal shape, or converted to a normal shape by transformation, the likelihood ratio can be computed simply knowing the means and standard deviations of the distributions. This likelihood ratio combined with data on age‐standardised risk can be used to compute the probability of a fetus having Down’s syndrome using Bayesian updating, given maternal age and the marker value.   When there are multiple markers, each of which can be transformed to a normal distribution, the method can be extended to model multivariate normal distributions for affected and unaffected fetuses, given the means, standard deviations and correlations between markers (Royston 1992).

The transformation of values requires both standardisation to marker levels in unaffected fetuses of the same gestational age (usually achieved by expressing all values as a multiple of the median level in the unaffected fetuses) and transformation to a normal distribution by removal of outliers and application of a log‐transformation to remove skewness.  Consideration needs to be made as to whether the median value for each marker in unaffected fetuses is obtained from the study data, from standard published values, or from records kept in the local laboratory, along with how frequently such values are updated and the sample size upon which they are based.

The equations generated by these processes are often coded into software to produce 'risk score' computations, which will provide a predicted individual probability of Down’s syndrome.  For purposes of evaluation the equation which generates a risk score can be treated as a test, and its sensitivity and specificity noted when dichotomised at some standard high risk value.  Caution is needed to ascertain whether an assessment of performance of a risk score is based on evaluation in the dataset from which it was created, or in a separate validation dataset.  The former will produce an over‐optimistic assessment of the performance of the test.

Interpreting the results

In most instances, women deemed to be at high risk for Down’s syndrome according to their screening test result are then offered definitive testing.  The definition of a high risk result varies from centre to centre but is often in the region of 1 in 200 to 1 in 300.  This means, for example, that if a woman has a 1 in 200 chance of having a baby with Down’s syndrome, she also has 199 in 200 chances of having a baby without Down’s syndrome.  Definitive testing by amniocentesis carries a 1 in 100 chance of miscarriage (Alfirevic 2003).  This means that screening can cause more pregnancies without Down’s syndrome to miscarry than Down’s syndrome pregnancies to be identified. 

At present there are many different screening tests available, incorporating different combinations of serum and urine markers, and ultrasound techniques.  Each test may have a different sensitivity (the chances of a test being positive in a Down’s syndrome pregnancy) and specificity (the chances of a test being negative in an unaffected pregnancy). Tests may be performed at varying stages of pregnancy, or involve screening at two different stages.  Which one of these tests, or combination of tests, is the most effective at picking up Down’s syndrome at the earliest possible gestation, while causing the least possible distress to the expectant parent(s), is still a matter of considerable debate.

Some studies have largely drawn conclusions from modelled data, based on relatively small patient samples.  In recent years there have been reports of several large multicentre studies, which have looked at a wide variety of tests in the same populations of women.  These include the SURRUS trial (Wald 2003), the FASTER trial (Malone 2005), a Scottish multicentre study (Crossley 2002) and a multicentre study conducted from the Harris Birthright centre (Nicolaides 2005).  As yet there is no agreed gold standard screening test, and as a consequence the tests offered to women are many and varied.

Previous reviews

A systematic review of second trimester ultrasound markers in the detection of Down’s syndrome fetuses was published in 2001 which concluded that nuchal fold thickening may be useful in detecting Down’s syndrome, but that it was not sensitive enough to use as a screening test.  It concluded that the other second trimester ultrasound markers did not usefully distinguish between Down’s syndrome and pregnancies without Down’s syndrome (Smith‐Bindman 2001).

There has yet to be a systematic review and meta‐analysis of the observed data on serum, urine and first trimester ultrasound markers, in order to draw rigorous and robust conclusions about the diagnostic accuracy of available Down’s syndrome screening tests.

Objectives

To compare different screening methods in isolation, and in various combinations to identify the most sensitive and specific test or tests for Down’s syndrome in the antenatal period.

Screening tests will be compared with respect to the following:

  • proportion of screened fetuses with Down’s syndrome detected by screening before birth;

  • the number of women with a high risk screening test result who subsequently have an unaffected pregnancy;

  • the number of invasive diagnostic procedures in women with fetuses subsequently found to have a normal karyotype;

  • the number of iatrogenic miscarriages in women with fetuses subsequently found to have a normal karyotype; and

  • the number of other adverse effects of screening and diagnosis.

Secondary objectives

To consider whether there is a uniform test suitable for all women, or whether different screening methods are more applicable to different groups (i.e. higher risk groups or different ethnic groups).

Methods

Criteria for considering studies for this review

Types of studies

We will include:

  • retrospective case‐control studies recruiting a group of women with known Down’s syndrome pregnancies and a group of women with unaffected pregnancies, where the index test(s) are analysed and compared between the two groups;

  • prospective and retrospective cohort studies including direct (head to head) studies in which all women from a given population have one or more index test(s) and reference standard, and in whom a pregnancy outcome is recorded; and

  • randomised controlled trials in which women are randomised to one of several index tests / package of index tests and all receive a reference standard.

We will exclude studies in which no useful data can be extracted from the paper.

Participants

Pregnant women at less than 24 weeks gestation confirmed by ultrasound, who have not undergone previous testing for Down’s syndrome in this pregnancy, and those in special groups which pose either increased risk of Down’s syndrome or difficulty with conventional screening tests including:

  • maternal age greater than 35 years old;

  • multiple pregnancy;

  • diabetes Mellitus; and

  • family History of Down’s syndrome.

Index tests

Tests will be divided into serum tests, urine tests and sonographic tests and categorised by timing with regard to gestation.

  • Serum tests at less than 24 weeks gestational age which may include, amongst others:

    • ßhCG / free ßhCG;

    • total hCG;

    • AFP;

    • uE3;

    • PAPP‐A;

    • Inhibin‐A; and

    • ADAM‐12.

  • Urine tests which may include, amongst others:

    • invasive trophoblast antigen;

    • ß‐core fragment;

    • free ßhCG; and

    • total hCG.

  • Sonographic tests at less than 14 weeks gestational age which may include, amongst others:

    • nuchal translucency;

    • absent nasal bone;

    • ductus venosus studies;

    • tricuspid regurgitation/A‐V regurgitation; and

    • abnormalities such as cyctic hygroma, as defined by individual studies.

We will look at comparisons of tests in isolation and in various combinations, including those which form part of tests involving more than one stage.  These may include tests such as double/triple/quadruple tests, first trimester and second trimester screening, combined test, integrated screening and sequential screening (i.e. independent, step‐wise, contingent and repeated measures screening).

Where tests are used in comparison we will look at the performance of test comparisons according to predicted probabilities computed using a risk equation.  Where individual patient data is available we will compute risks using a standardised equation.

Target conditions

Down’s syndrome in the fetus due to trisomy, translocation or mosaicism.

Reference standards

We will consider one of several reference standards.  The primary reference standards will be genetic verification using the following:

  • amniocentesis;

  • chorionic villus sampling;

  • postnatal karyotyping; and

  • miscarriage with cytogenetic testing of the fetus.

Secondary reference standards will include birthing registers and Down’s syndrome registers, and diagnosis based on postnatal macroscopic inspection.  It is expected that most studies will suffer differential verification as they will only use genetic testing on fetuses considered high risk according to the screening test; the reference standard for most unaffected infants being observing a phenotypically normal baby.

Types of outcome

The following outcomes will be considered:

  • cross‐classifications of index test results against reference standards at standard multiple of the median cut‐points (for individual tests) and risk values (for test combinations);

  • summary statistics for distributions of index test results in affected and unaffected fetuses for individual tests; and

  • harms of testing:

    • need for further testing;

    • side effects of test;

    • interventions and side effects;

    • process outcomes; and

    • other abnormalities detected by testing.

  • spontaneous Miscarriage;

  • miscarriage subsequent to invasive procedure with or without normal karyotype;

  • fetal karyotype;

  • termination of pregnancy:

    • prior to definitive testing or in a karyotypically normal pregnancy;

    • following confirmation of Down’s Syndrome; and

    • following detection of other chromosomal abnormalities.

  • stillbirth;

  • livebirth of affected and unaffected fetus; and

  • uptake of definitive testing by women

Included studies must report relevant and interpretable data.  The search will identify all studies of diagnostic accuracy.  Studies of the additional outcomes which do not include diagnostic accuracy will not be included.

Categories such as women’s experience of screening, economic evaluation of screening and caregiver satisfaction are outside of the scope of this review of diagnostic accuracy.  However if studies of diagnostic accuracy report this information it will be considered.

Search methods for identification of studies

Electronic searches

We will apply a sensitive search strategy to search the following databases using the text words and MeSH terms listed below, adapting the search strategy for each different database.

Databases to be searched include:

  • MEDLINE via OVID (1980 to current date);

  • EMBASE via Dialog Datastar (1980 to current date);

  • BIOSIS via EDINA (1985 to current date);

  • CINAHL via OVID (1982 to current date);

  • the Database of Abstracts of Reviews of Effectiveness (The Cochrane Library);

  • MEDION (http://www.mediondatabase.nl/);

  • Database of Systematic Reviews and Meta‐Analyses in Laboratory Medicine (http://www.ifcc.org/);

  • the National Research Register (http://www.nrr.nhs.uk/); and

  • Health Services Research Projects in Progress database (http://www.nlm.nih.gov/hsrproj/).

The search strategy will combine three sets of search terms (see Appendix 1). The first set will be made up of named tests, general terms used for screening/diagnostic tests and statistical terms. Note that the statistical terms are used to increase sensitivity and are not used as a methodological filter used to increase specificity. The second set will be made up of terms that encompass Down’s syndrome and the third set made up of terms to limit the testing to pregnant women. All terms within each set will be combined with the Boolean operator OR and then the three sets will be combined using AND.  The terms used will be a combination of subject headings and free text terms.  The search strategy will be adapted to suit each database searched.

We will attempt to identify cumulative papers which report data from the same dataset, and contact authors to obtain clarification of the overlap between data presented in these papers, in order to prevent data from the same women being analysed more than once. 

Searching other resources

In addition, we will examine references cited in studies identified as being potentially relevant, and those cited by previous reviews.  We will contact authors of studies where further information is required.  We will not apply a diagnostic test filter, and we will not apply language restrictions to the search. 

We will carry out forward citation searching of relevant items, using the search strategy in ISI citation indices, Google scholar and Pubmed ‘related articles’.

Data collection and analysis

We will use the methods suggested by the Cochrane Collaboration Screening and Diagnostic Tests Methods Group.

Selection of studies

Two review authors will screen the titles and abstracts, where available, of all studies identified by the search strategy.  We will obtain full text versions of all studies identified as being potentially relevant, and they will be independently assessed by two review authors for inclusion, using a study eligibility screening proforma a based on pre‐specified inclusion criteria.  Any disagreement between the two review authors will be settled by consensus, or by a third party where necessary.

Data extraction and management

We will develop a data extraction form, to aid collection of relevant and important data from included studies.  One review author will independently extract the data, and where difficulty or uncertainty exists, a second review author will validate the extracted information.

Whenever possible, data will be treated as dichotomous, with a high‐risk result (as defined by each individual study) being regarded as test positive (suggestive or diagnostic of Down’s syndrome), and a low‐risk result being regarded as test negative (suggestive of absence of Down’s Syndrome).  Where data are available at several cut‐points we will record these.  In addition, where combinations of tests are used, the overall result, from combining the test into a risk score, will be used to determine whether a test is positive or negative, and not the individual components that make up the test.

We will differentiate between data based on observation of test performance in patients in study groups, and data derived from statistical models (calculations of expected screening performance of tests).  Where possible we will extract summaries of distributions of markers and correlations of distributions of markers.  Individual patient data will be obtained, wherever possible, in order to compute classifications of risk in a standardised way.

Assessment of methodological quality

We will use a modified version of the QUADAS tool (Whiting 2003), which is a quality assessment tool for use in systematic reviews of diagnostic accuracy studies, to assess the methodological quality of included studies.  Two review authors will separately assess each included study.  Any disagreement between the two review authors will be settled by consensus, or by a third party where necessary. Each item in the QUADAS tool will be marked as ‘yes’, ‘no’ or ‘unclear’, and scores will be presented graphically and in tables.  We will not use a summary quality score.

QUADAS criteria will include the following questions.

  1. Was the spectrum of patients representative of the patients who will receive the test in practice?

    1. Was the sample selected from a wide range of ages (i.e. childbearing age)? 

    2. Was the sample selected from a specified ‘high‐risk’ group? That is:

      • over 35;

      • family history of Down’s syndrome;

      • multiple pregnancy;

      • diabetes mellitus.

    3. Was the sample taken from a select or unrepresentative group of patients (i.e. private practice)/atypical screening population?

    4. Were all affected and unaffected fetuses included that could be tested at the time point when the screening test would be applied, or did recruitment occur at a later time point when selection could be affected by selective fetal loss?

  2. Is the reference standard (amniocentesis, chorionic villus sampling, postnatal karyotyping, miscarriage with cytogenetic testing of the fetus or phenotypically normal baby) likely to correctly classify the target condition?

  3. Did the whole sample or a random selection of the sample receive verification using a reference standard of diagnosis?

  4. Did patients receive the same reference standard regardless of the index test result?

  5. Was the reference standard independent of the index test result (i.e. the index test did not form part of the reference standard)?

  6. Were the index test results interpreted without knowledge of the results of the reference standard?

  7. Were the reference standard results interpreted without knowledge of the results of the index test?

  8. Were the same clinical data (i.e. maternal age and weight, ethnic origin, gestational age) available when test results were interpreted as would be available when the test is used in practice?

  9. Were uninterpretable/intermediate test results reported?

  10. Were withdrawals from the study explained?

  11. Were all patients found to be at high risk offered definitive testing/reference standard?

  12. Other unspecified quality concerns include:

    1. source of medians used for age and laboratory standardisation? How frequently they are updated; are they based on retrospective data or study data; are they generated locally or published value?

    2. for evaluation of risk scores, was assessment made on a separate validation sample or using appropriate methods to correct for over‐optimism?

Statistical analysis and data synthesis

The methods used for meta‐analysis will be contingent on the data obtained.  Where dichotomised data are available, we will combine studies using bivariate hierarchical methods to obtain direct estimates or detection rates (sensitivity) and false positive rates (1‐specificity) and the associated uncertainty.  We will compare tests and test combinations by including co‐variates in the model.  Data on studies which make direct comparisons between tests will be analysed separately. 

Additional analyses will be undertaken for individual markers comparing distributions between unaffected and Down’s syndrome fetuses after appropriate transformation of parameters, using standard mean difference meta‐analytical methods.

Data on event rates, such as harms of testing, will be displayed using forest plots and pooled using standard meta‐analytical methods, taking account of heterogeneity between studies.

Investigations of heterogeneity

We will compare results between studies which derive risk scores and those that validate them; and between studies which report actual observed results and those in hypothetical standardised populations. 

Sensitivity analyses

We will consider the impact of age standardisation, improvements in technology and adjustment for fetal loss in sensitivity analyses.

Revision of the protocol

It may be necessary to revise this protocol following preliminary data collection, to adapt for data handling and inclusion criteria.  We will document any change in the protocol.

Table 1. Glossary of terms (adapted in part from the UK National Screening Committee Glossary)

Abnormal ductus venosus flow velocity

The ductus venosus is a vessel in the fetus which allows oxygenated blood from the placenta to bypass the fetal liver and flow straight to the heart.  In conditions such as Down’s syndrome the pressure in this vessel can be abnormally high.

Absent nasal bone

Absence of the bone that forms the bridge of the nose, which may be detected at ultrasound scan during early pregnancy.

Affected individuals

Those individuals who are affected by the disorder for which they are being screened.

Amniocentesis

Amniocentesis is an invasive procedure which involves taking a small sample of the amniotic fluid (liquor) surrounding the baby, using a needle which goes through the abdominal wall into the uterus, and is usually performed after 15 weeks gestation.

Chorionic villus sampling (CVS)

Chorionic villus sampling involves taking a sample of the placental tissue using a needle which goes through the abdominal wall and uterus or a cannula through the cervix.  It is usually performed between 10 and 13 weeks gestation.

Combined test

First trimester test (up to 13+6 weeks of pregnancy) based on combining nuchal translucency measurement with free beta‐hCG, pregnancy‐associated plasma protein A (PAPP‐A) and the woman’s age.

Diagnostic accuracy

The amount of agreement between the information from the index test and the reference standard (see below).

Diagnostic test

A definitive test, performed after a positive screening test result that gives a diagnosis (i.e. yes or no)?

Double test

Second trimester test (from 13+6 up to 24 weeks of pregnancy) based on the measurement of alpha‐fetoprotein (AFP), human chorionic gonadotrophin (hCG ß either free beta‐hCG or total hCG), together with the woman’s age.

First trimester

Pregnancy from conception up to 13 weeks and 6 days.

Iatrogenic

A disease or condition in a patient occurring as a result of treatment.

Index test

A test or group of tests being evaluated in a systematic review.

Integrated test

Measurements performed at different times of pregnancy combined into a single test result. Unless otherwise specified, 'integrated test' refers to the combination of nuchal translucency measurement and PAPP‐A in the first trimester, with the quadruple test (see below) in the second.

Mosaicism

This is a condition in which person has some cells containing a normal number of chromosomes, and some containing an abnormal number.  The more abnormal cells there are, the greater the effect.

Multiple of the median (MOM)

The serum test concentration for a pregnant woman divided by the average (median) for unaffected pregnancies in a defined population at the same stage of pregnancy.

Quadruple test

Second trimester test (from 13+6 up to 24 weeks of pregnancy) based on the measurement of AFP, uE3, free beta‐hCG (or total hCG), and inhibin‐A together with the woman’s age.

Reference Standard

The best available method for establishing the presence or absence of the target disease or condition.

Second trimester

Pregnancy from 14 weeks to 28 weeks gestation.  Note that for the purposes of this Cochrane review, second trimester testing refers to the period of 14 to 24 weeks gestation.

Tricuspid regurgitation

Leakiness of or backflow of blood through the tricuspid valve of the heart.  The tricuspid valve separates the upper and lower chambers of the right side of the heart.

Triple test

Second trimester test (from 14 up to 24 weeks of pregnancy) based on the measurement of AFP, unconjugated oestriol (uE3), and hCG (either total hCG or free beta‐hCG) together with the woman's age.

Trisomy

The presence of an extra chromosome resulting in three copies of a particular chromosome instead of the normal two.

Translocation

Part of one chromosome is broken off and attached to another chromosome.  This does not usually cause the individual any problems as they have a normal amount of chromosomes, but in an abnormal arrangement.  It can be passed on as an extra chromosome to offspring, resulting in conditions such as Down's syndrome.

Figuras y tablas -
Table 1. Glossary of terms (adapted in part from the UK National Screening Committee Glossary)