UOG Journal Club: Fetal fraction in maternal plasma cell-free DNA at 11–13 weeks’ gestation

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  • 1. UOG Journal Club: January 2013Fetal fraction in maternal plasma cell-free DNA at 11–13 weeks’gestation: relation to maternal and fetal characteristicsG Ashoor, A Syngelaki, LCY Poon, JC Rezende and KH NicolaidesVolume 41, Issue 1, Date: January 2013, pages 26–32Journal Club slides prepared by Dr Asma Khalil(UOG Editor for Trainees)
  • 2. Chiu RW et al., BMJ 2011; Chen EZ et al., PloS One 2011; Ehrich M et al., AJOG 2011; Palomaki GE et al., Genet Med 2011; Palomaki GE et al., Genet Med 2012;Ashoor G et al., AJOG 2012; Bianchi D et al., Obstet Gynecol 2012; Norton ME et al., AJOG 2012; Sparks AB et al., AJOG 2012Trisomy 21 Trisomy 18 Trisomy 13DR FPR DR FPR DR FPRChiu et al. 2011 100% 2.1%Chen et al. 2011 91.9% 2% 100% 1.1%Ehrich et al. 2011 100% 0.2%Palomaki et al. 2011 98.6% 0.2%Palomaki et al. 2012 100% 0.3% 91.7% 1%Ashoor et al. 2012 100% 0% 98% 0% 80% 0.05%Bianchi et al. 2012 98.9% 0% 92.1% 0% 68.8% 0%Norton et al. 2012 100% 0.03% 97.4% 0.07%Sparks et al. 2012 100% 0% 100% 0%DR, detection rate; FPR, false positive rateScreening by cell-free (cf) DNA testing of maternal blood in high-risk populations:Background
  • 3. Nicolaides KH et al., AJOG 2012Ashoor G et al., UOG 2013Detection rate False positiverateTrisomy 21 99.5% 0.1%Trisomy 18 92–100% 0–0.3%Trisomy 13 68–100% 0–1.1%Screening by cfDNA testing of maternal blood in low-risk populations:Background
  • 4. Strengths• Highly accurate in the detection oftrisomies 21 and 18 and to a lesserdegree trisomy 13• The screening performance fortrisomies 21 and 18 is far superior tothat of all currently availablescreening methods (DR>99% andFPR <1%)Limitations•The main limiting factor currently isthe high cost• Fails to provide results if the fetalfraction < 4%BackgroundNon-invasive prenatal testing (NIPT)
  • 5. Fetal fraction in maternal plasma cell-free DNA at 11–13 weeks: relation tomaternal and fetal characteristicsAshoor et al., UOG 2013Objectives• Examine the possible effects of maternal and fetal characteristics onthe fetal fraction in maternal plasma cfDNA at 11–13 weeks• Estimate the proportion of pregnancies at high risk of NIPT failurebecause the fetal fraction is < 4%
  • 6. Fetal fraction in maternal plasma cell-free DNA at 11–13 weeks: relation tomaternal and fetal characteristicsAshoor et al., UOG 2013• Prospective first-trimester screening for aneuploidies andadverse pregnancy outcomes in singleton pregnancies(n=1,949)• Stored maternal plasma at −80 °C• Collected in ethylenediamine tetraacetic acid BD vacutainer TM tubes• Centrifuged at 2000g for 10min and subsequently at 16 000g for10min, within 15min of collectionMethodology
  • 7. 0501001502002.3 4.0 6.3 9.0 12.3 16.0 20.3 25.0 30.3Fetal fraction (%)Frequency• The median fetalfraction was 10.0%•  with weight•  in Afro-Caribbean•  with fetal CRL•  7.5% in smokers•  25.0% in trisomy 21Results
  • 8. 0510152025Fetalfraction(%)40 50 60 70 80 90 100 110 120 130Maternal weight (kg)140 150 160 170 18099th75th50th25th97th95th90th10th5th3rd1st4Weight(kg)Failure(%)40 0.460 1.580 4.7100 12.1120 25.1140 43.1160 62.8180 79.5Results
  • 9. Fetal fraction in maternal plasma cell-free DNA at 11–13 weeks: relation tomaternal and fetal characteristicsAshoor et al., UOG 2013ResultsNo significant contribution to fetal fraction from:• Maternal age• Fetal gender• NT thickness• Method of conception• Linear association with free β-hCG and PAPP-A
  • 10. Fetal fraction in maternal plasma cell-free DNA at 11–13 weeks: relation tomaternal and fetal characteristicsAshoor et al., UOG 2013DiscussionThe inverse association between fetal fraction and maternalweight could be attributed to:• Dilutional effect• Accelerated turnover of adipocytes (releases cfDNA of maternalorigin into the circulation thereby lowering the proportion of fetalcfDNA)
  • 11. Fetal fraction in maternal plasma cell-free DNA at 11–13 weeks: relation tomaternal and fetal characteristicsAshoor et al., UOG 2013• NIPT is far superior to currently available screening methods. Thegreatest risk factor for low fetal fraction and failure is obesity. Theopportunity for testing and counseling in the same visit is missed whenNIPT fails.• Alternatively, NIPT can be performed along with the combined screeningblood test at 10-11 weeks. Hence results are available at the scanassessment, where CVS can be performed if high risk. Where NIPT fails,the parents would still have the first trimester combined test result.• This policy might exaggerate the problem of low fetal fraction because it isdone earlier when the CRL and fetal fraction are smallerImplications for practice
  • 12. Fetal fraction in maternal plasma cf-DNA is affected by Maternal characteristics (weight, ethnicity, smoking) Fetal characteristics (CRL, aneuploidy)Fetal fraction in maternal plasma cell-free DNA at 11–13 weeks: relation tomaternal and fetal characteristicsAshoor et al., UOG 2013Conclusions
  • 13. Discussion points• What maternal characteristics would influence the fetal fraction in maternal plasma cell-free fetal DNA test after 14 weeks’ gestation?• Apart from trisomy 21, what other fetal chromosomal abnormalities would influence thefetal fraction in maternal plasma cell-free DNA in multiple pregnancies?• Can we offer the non-invasive prenatal testing (NIPT) using cell-free fetal DNA to twinpregnancies or pregnancies conceived using IVF with egg donation?• What sort of NIPT result would be expected with placental mosaicism?• Could invasive prenatal diagnosis be avoided with a low-risk NIPT result where the fetushas an isolated increased nuchal translucency?• What impact would the introduction of NIPT as a screening tool have on the numbers ofprenatal invasive tests performed?• Would there be a role for first-trimester combined nuchal plus biochemistry testing if NIPTwere used universally as a routine screening tool.• What would be the management options for a woman that had fetal DNA in maternalplasma test when first seen at 11 weeks’ gestation, and who received a ‘failed’ result at 13weeks?