The future of prenatal diagnosis: rapid testing or full karyotype? An audit of chromosome abnormalities and pregnancy outcomes for women referred for Down's Syndrome testing

Abstract

Objective To assess the implications of a change in prenatal diagnosis policy from full karyotype analysis to rapid trisomy testing for women referred primarily for increased risk of Down's Syndrome. Design Retrospective collection and review of data.Setting The four London Regional Genetics Centres.Population Pregnant women (32,674) in the London area having invasive prenatal diagnosis during a six-year three-month period. Methods Abnormal karyotypes and total number of samples referred for raised maternal age, raised risk of Down's Syndrome following serum screening or maternal anxiety were collected. Abnormal karyotypes detected by molecular trisomy detection were removed, leaving cases with residual abnormal karyotypes. These were assessed for their clinical significance. Pregnancy outcomes were ascertained by reviewing patient notes or by contacting obstetricians or general practioners. Main outcome measures Proportion of prenatal samples with abnormal karyotypes that would not have been detected by rapid trisomy testing, and the outcome of those pregnancies with abnormal karyotypes. Results Results from 32,674 samples were identified, of which 24,891 (76.2%) were from women referred primarily for Down's Syndrome testing. There were 118/24,891 (0.47%) abnormal sex chromosome karyotypes. Of the samples with autosomal abnormalities that would not be detected by rapid trisomy testing, 153/24,891 (0.61%) were in pregnancies referred primarily for Down's Syndrome testing. Of these, 98 (0.39%) had a good prognosis (46/98 liveborn, 3/98 terminations, 1/98 intrauterine death, 1/98 miscarriage, 47/98 not ascertained); 37 (0.15%) had an uncertain prognosis (20/37 liveborn, 5/37 terminations; 12/37 not ascertained) and 18 (0.07%) had a poor prognosis (1/18 liveborn, 2/18 miscarriage, 11/18 terminations, 4/18 not ascertained). Conclusions For pregnant women with a raised risk of Down's Syndrome, a change of policy from full karyotype analysis to rapid trisomy testing would result in the failure to detect chromosome abnormalities likely to have serious clinical significance in approximately 0.06% (1 in 1659) cases. However, it should be noted that this figure may be higher (up to 0.12%; 1 in 833) if there were fetal abnormalities in some of the pregnancies in the uncertain prognosis group for which outcome information was not available.

QF‐PCR as a stand‐alone test for prenatal samples: the first 2 years' experience in the London region

“…In the case of de novo translocations, a risk of 5-6% of abnormal phenotype is quoted (Gardner and Sutherland, 2004); the retrospective review of >32 000 pregnancies by Ogilvie et al (2005) found that 3 out of 98 pregnancies with a good prognosis were terminated apparently based on this risk. Chitty et al (2006) reported that abnormal nonaneuploidy karyotypes have a low prevalence in samples with NT < 4 mm at <14 weeks' gestation.…”

“…An aliquot from each sample was then sent to the cytogenetics laboratory at Guy's Hospital, where QF-PCR testing using a single multiplex of polymorphic microsatellite markers for chromosomes 13, 18 and 21 was carried out as described previously (Mann et al, 2001;Ogilvie et al, 2005) and in line with the current CMGS/ACC (2007) Best Practice Guidelines (http://www.cytogenetics.org.uk/prof standards/ professional standards.htm).…”

“…Samples from pregnancies with ultrasound abnormalities indicative of Turner syndrome (cystic hygroma, hydrops, NT > 4 mm, specific cardiac defects) or with a history of sex chromosome aneuploidies or sex-linked disease were additionally tested using a multiplex containing markers for the sex chromosomes (Donaghue et al, 2003;Ogilvie et al, 2005).…”

“…Published audits of chromosome abnormalities found by karyotyping at prenatal diagnosis have consistently shown a prevalence of between 0.07% and 0.1% for clinically significant abnormalities that would not be detected by QF-PCR in samples from pregnancies without fetal ultrasound Copyright  2010 John Wiley & Sons, Ltd. abnormalities (Thein et al, 2000;Lewin et al, 2000;Ryall et al, 2001;Ogilvie et al, 2005), although a more cautiously interpreted audit concluded that approximately 1 in 100 samples referred with a Down syndrome risk which received QF-PCR only would have an undetected autosomal chromosome abnormality and that 33% of these would have a substantial risk of serious phenotypic consequences, equivalent to a prevalence of 0.33% (Caine et al, 2005). The anxiety, distress and potentially unnecessary pregnancy terminations that can follow equivocal karyotype results, plus the resource implications, especially for laboratories and counselling services, were put forward as an argument for replacing the traditional approach to prenatal diagnosis for women in this specific referral group.…”

“…Since the development and availability of molecular methods, such as QF-PCR for assessing chromosome copy number, the suitability of full karyotype analysis for samples referred solely for raised risk of trisomy has been questioned (Ogilvie, 2003;Nicolini et al, 2004;Leung et al, 2004;Ogilvie et al, 2005;Sparkes et al, 2008;Cirigliano et al, 2009). Published audits of chromosome abnormalities found by karyotyping at prenatal diagnosis have consistently shown a prevalence of between 0.07% and 0.1% for clinically significant abnormalities that would not be detected by QF-PCR in samples from pregnancies without fetal ultrasound Copyright  2010 John Wiley & Sons, Ltd. abnormalities (Thein et al, 2000;Lewin et al, 2000;Ryall et al, 2001;Ogilvie et al, 2005), although a more cautiously interpreted audit concluded that approximately 1 in 100 samples referred with a Down syndrome risk which received QF-PCR only would have an undetected autosomal chromosome abnormality and that 33% of these would have a substantial risk of serious phenotypic consequences, equivalent to a prevalence of 0.33% (Caine et al, 2005).…”