Antenatal care guidelines review Public consultation draft 22 May 2017 Contents

62.1Tests for chromosomal anomalies

62.1.1Effectiveness of tests

Offering testing for fetal chromosomal anomalies to all women in the first trimester — regardless of maternal age — is recommended in the United Kingdom (NICE 2008), the United States (ACOG 2007) and Australia (RANZCOG 2015).

Summary of the evidence

Combined first trimester tests

Combined first trimester tests identify factors that are known to be associated with fetal chromosomal anomalies and that are independent of each other.

The probability of chromosomal and other anomalies and fetal and postnatal death increases with nuchal translucency thickness. Favourable outcomes have been observed in 92% of babies with nuchal translucency of 3.4 mm (95^th centile) compared to 18% of those with nuchal translucency of ≥6.5 mm (Ayras et al 2013). In some situations, the ultrasound component of first-trimester testing may be difficult or impossible (eg due to high BMI, fetal positioning).

Combining nuchal translucency assessment with testing of maternal serum increases the predictive value (Alexioy et al 2009). Recent evidence on the sensitivity of the combined test had the following findings.

A systematic review (65 studies) found detection rates of 91.9% for trisomy 18 (false positive rate 3.5%), 83.1% for trisomy 13 (false positive rate 4.4%) and 70.1% for monosomy X (false positive rate 5.4%) (Metcalfe et al 2014).

Cohort studies found detection rates of:

92.2% for trisomy 21 (false positive rate 8.0%) (n=675,332) (Kagan et al 2015b).

91.3% for trisomy 21, 97.1% for trisomy 18, 92.3% for trisomy 13, 80% for sex chromosome aneuploidies and 87% for atypical aneuploidies (n=21,052) (Kagan et al 2015a)

87% for trisomy 21, 91.8% for trisomies 13 and 18, 86.0% for monosomy X, 8.1% for other sex chromosome aneuploidies, 89.3% for triploidy and 13.0% for other high-risk outcome (n=14,684) (Syngelaki et al 2014)

The pooled rate of invasive procedures was 59 per 1,000 pregnancies tested (Susman et al 2010; Syngelaki et al 2014; Kagan et al 2015a).

As fetal nuchal translucency thickness increases with crown-rump length (Pandya et al 1995; Edwards et al 2003) and the detection rate in serum is influenced by maternal age (Grati et al 2010), these factors are included in assessment algorithms. The inclusion of age in the calculation, either alone or in combination with serum test results, increases identification of the probability of chromosomal anomalies (Wapner et al 2003; Scott et al 2004; Centini et al 2005; Soergel et al 2006; Gebb & Dar 2009; Hagen et a 2010; Schmidt et al 2010). The maternal serum variables are also influenced by gestational age, maternal weight, ethnicity, smoking, in vitro fertilisation, parity and diabetes, the background risk for each being calculated and then included in the algorithm with nuchal transluceny and maternal age. A history of a previous trisomy 21 pregnancy increases the chance of an abnormal screening test result for trisomy 21.

Offering the combined ultrasound and biochemistry tests reduces the number of women offered diagnostic testing (Saltvedt et al 2005; Marsk et al 2006; Philipson et al 2008; Zournatzi et al 2008; Nadel & Likhite 2009; Lo et al 2010), although some women still opt to have diagnostic testing following a normal result (Caughey et al 2007; Hagen et al 2010) and others choose to go directly to the diagnostic test. The combined test may lead to fewer losses of normal pregnancies (Chasen et al 2004) and is cost-effective (Chou et al 2009).

Consensus-based recommendation

63.If a woman chooses to have the combined test (nuchal translucency thickness, free beta-human chorionic gonadotrophin, pregnancy-associated plasma protein-A), make arrangements so that blood for biochemical analysis is collected between 9 weeks to 13 weeks 6 days gestation and ultrasound assessment takes place between 11 weeks and 13 weeks 6 days gestation.

Cell-free DNA testing

As a replacement for combined first trimester testing, cfDNA testing would have a higher detection rate for the more common trisomies — relative risk of detection 1.13 (1.08 to 1.18) for trisomy 21 and 1.22 (1.18 to 1.26) for trisomies 18 and 13 (Petersen et al 2014; Syngelaki et al 2014; Gyselaers et al 2015; Kagan et al 2015a; Kagan et al 2015b; McLennan et al 2016). Fewer invasive procedures would be required (10 per 1,000 women tested) (Susman et al 2010; Syngelaki et al 2014; Kagan et al 2015a) and rates of procedure-related miscarriage would be lower (Morris et al 2014; Gyselaers et al 2015; Mersy et al 2015).

However, cfDNA testing may not detect less common chromosomal anomalies identified through ultrasound assessment — relative risk of detection 0.23 (0.16 to 0.33) for sex chromosome aneuploidies (Syngelaki et al 2014; Kagan et al 2015a; McLennan et al 2016) and 0.01 (0.00 to 0.04) for atypical aneuploidies (Petersen et al 2014; Syngelaki et al 2014; Kagan et al 2015a). As well, the economic costs of incorporating cfDNA testing for trisomy 21 into practice in Australia are currently higher than those for combined first trimester testing (costs associated with cfDNA testing for other chromosomal anomalies have not been investigated in Australia) (O'Leary et al 2013; Ayres et al 2014).

As cfDNA testing is available in Australia, it is important that health professionals counsel women who request the test. The following points are of importance in ensuring informed consent:

the test may be conducted from 10 weeks onwards (Gil et al 2015)

the test is not diagnostic — a positive result requires confirmation by invasive procedures (Gil et al 2015; Meck et al 2015; Neufeld-Kaiser et al 2015; McLennan et al 2016)

while, the test has a higher detection rate for common chromosomal anomalies than combined first trimester testing, it may not detect other, less common, chromosomal anomalies (see above)

diagnosis of fetal structural or genetic anomalies may be delayed or missed if the 11–13 week ultrasound is not performed in conjunction with cell-free DNA testing (RANZCOG 2015)

although the false positive rate is lower than for combined first trimester testing, both false positives and false negatives occur (Gil et al 2015b; Mackie et al 2016; Taylor-Phillips et al 2016)

low fetal fraction of DNA in the maternal circulation (Benachi et al 2015, Gil et al 2015b, Neufeld-Kaiser et al 2015, McLennan et al 2016), which is common among women with a BMI >30 kg/m² (Benachi et al 2015, Gil et al 2015b, Neufeld-Kaiser et al 2015, McLennan et al 2016) may be reported as a failed test or increase the false negative rate of the result — depending on the timing of the test, this may mean that women with a test failure miss the window for combined first trimester testing

in rare circumstances, the test may raise suspicions of maternal or fetal conditions other than the fetal anomalies for which the test is being performed (Sachs et al 2015)

the test is not currently covered by Medicare or private health insurance — costs to women are $400–$500, depending on location.