NIPT utility in clinical setting - critical overview and the first two years of implementation experience in Helsinki Fetal surgery- reality or utopia? Lab Quality Days 2017 Vedran Stefanovic Associate Professor Fetomaternal Medical Center, Dept of OB/GYN Helsinki, Finland Vedran.stefanovic@hus.fi
Agenda Basic fact about NIPT Accuracy and performance Incidental findings Costs The importance of pre-and post-test counselling Implementation worldwide Implementation in HUCS Challanges
NIPT basic facts cell-free fetal DNA detectable in maternal plasma from 5th gestational week half-time few hours to obtain interpretable result, at least 4% of fetal cff-dna fraction required (for twins at least 10%) first report almost 20 years ago Duodecim, 2015 used worldwide for non-invasive determination of fetal Rhesus D antigene (NIPD)
Current use of NIPT Considerable experience of using NIPT in mainstream clinical practice Test performance in clinical settings is consistent Main use is in screening for T13,18 and 21 Some use of fetal sex determination for X-linked disorders Isolated cases at present of screening for single gene disorders such as achondroplasia in women at high risk
Nicolaides et al: Analysis of cell-free DNA in maternal blood in screeningnfor fetal aneuploidies: updated meta-analysis, UOG, 2015 There is now conclusive evidence that cfdna analysis of maternal blood in screening for trisomy 21 in singleton pregnancies is superior to all previous methods in achieving both of these objectives. Performance of screening in twins by cfdna testing requires further evaluation. The DR of screening by cfdna testing for trisomies 18 and 13 and sex chromosome aneuploidies is lower than that for trisomy 21. Indeed, the reported DR for these aneuploidies in this meta-analysis is likely to have been overestimated; trisomies 18 and 13 are over-represented in the cases of a failed result and sex chromosome aneuploidies are ascertained inadequately in some of the studies. Additionally, expansion of the indications of cfdna testing to include trisomies 18 and 13 and sex chromosome aneuploidies would increase the cumulative FPR eight-fold, from 0.09% to 0.72%.
100 000 SIC! McCullough et al, PlosONE 2014
Jama, 2016 If multiple aneuploidies detected on NIPT 20-44% risk of maternal cancer BUT Preliminary results, small number of patients
Implementation statements ACOG 2015 Not to be offered to low risk women Indications AMA, ultrasound features, previous affected child (high risk women) SOGC 2013 Offer to high risk women as an alternative to amniocentesis BUT amniocentesis to confirm positive results before TOP International Society of Prenatal Diagnosis Offer to high risk women as a second line screen Local economic resources and access to ultrasound, invasive testing and counselling should be taken into account.
1.1.2015 alkaen 1.Seula UÄ tutkimus + seeruminäyte = yhdistelmäseulonta (FTS) riski 1:250 2.Sikiön niskaturvotus 3-3.9 mm 3.Poikkeava tulos keskiraskauden seulonnassa 4. Ensimmäinen seula tekemättä + ikä yli 40 v 5. Aiempi poikkeava kromosomilöydös (21-trisomia ja muut tavanomaiset aneuploidiat) Poikkeava NT 4 mm Rakennepoikkeavuus Neuvonta (potilas valitsee: invasiivinen tutkimus tai NIPT) NIPT * Neuvonta Istukkabiopsia (ad H14 +6 ) TAI Lapsivesinäyte (H15 +0 alkaen) 21,18, ja 13-trisomia sekä sukukromosomi PCR Normaali tulos Poikkeava tulos tai vastaus eiinformatiivinen Istukkabiopsia (ad H14+6) TAI lapsivesinäyte (H15 +0 alkaen)-karyotyyppi ( + tarv. molekyylikaryotyypitys) Neuvonta Poikkeava tulos Ei jatkotoimenpiteitä Lapsivesipunktio 21,18, ja 13-trisomia sekä sukukromosomi PCR Neuvonta * NIPT= Non-Invasive Prenatal Testing Taulukko: Vedran Stefanovic 12/2014 Neuvonta
Eligible for NIPT at FMC (1.1.-31.12.2015) (high-risk for aneuploidy according to the HUS protocol) N=422 Declined N=111 Normal result N= 290 Accepted N=311 (uptake 73,6%) No further examinations N=13 Invasive N=98 17 abnormal results 21-trisomy (N=16) confirmed by invasive procedure TOP N=13, 2 continued pregnancy ongoing pregnancy (declined invasive) N=1 1 case of 21-trisomy + XXY > TOP Normal N=86 Miscarriage N=1 Abnormal N=12 8 x 21-trisomy all TOP 3 x 18-trisomy all TOP 1 x XXY ongoing pregnancy No-call (less than 4% cfdna N=4 (1.28% of all) No further examinations (2) Invasive (2) 21-trisomy TOP
N/A 80 N/A 5 5 3.75 598 578 69.7 26 26 2.52
1.FTS risk 1:11-1:250 2.NT 3-3.4 mm 3.Mid-trimester screen positive 4. Maternal age > 40 yrs and FTS not performed 5. Common trisomy in previous pregnancy HELSINKI _February 2016 1. NT 3.5 mm 2. Any structural abnormality (excluding SMs) 3. FTS 1:10 4.IUGR on the 2nd trimester screening Counselling NIPT * Counselling CVS (up to 14+6)or Amnio (from 15+0) Normal Abnormal or no-call CVS (ad H14+6) Or amnio (H15 +0 ) Primarily trisomy PCR if normal acgh Counselling No further follow up 2ns trimester genetic sonogram Abnormal Amniocentesis Counselling Counselling * NIPT= Non-Invasive Prenatal Testing Taulukko: Vedran Stefanovic 11/2015
HELMIKUU 2016 alkaen 1.Seula UÄ tutkimus + seeruminäyte = yhdistelmäseulonta (FTS) riski 1:11-1:250 2.Sikiön niskaturvotus 3-3.4 mm 3.Poikkeava tulos keskiraskauden seulonnassa 4. Ensimmäinen seula tekemättä + ikä yli 40 v 5. Aiempi poikkeava kromosomilöydös (21-trisomia ja muut tavanomaiset aneuploidiat) 1. Niskaturvotus 3.5 mm (noin 100/vuosi) 2. Rakennepoikkeavuus (noin 100 vuosi) 3. Yhdistelmäseulontariski 1:10 (noin 75/vuosi) 4.IUGR rakenne UÄ tutkimuksessa (noin 10/vuosi) Neuvonta (potilas valitsee: invasiivinen tutkimus tai NIPT) Istukkabiopsia (ad H14 +6 ) TAI Lapsivesinäyte (H15 +0 alkaen) 21,18, ja 13-trisomia sekä sukukromosomi PCR Normaali tulos NIPT * Poikkeava tulos tai vastaus eiinformatiivinen Äiti ei haluaa invasiivista/ei halua Keskeyttää missään olosuhteeissa Jos NIPT positiivinen ei varmistusta Neuvonta Istukkabiopsia (ad H14+6) TAI lapsivesinäyte (H15 +0 alkaen) Ensin trisomia + sukukrom. PCR,jos normaali acgh Neuvonta Poikkeava tulos Ei jatkotoimenpiteitä Lapsivesipunktio 21,18, ja 13-trisomia sekä sukukromosomi PCR Neuvonta Neuvonta * NIPT= Non-Invasive Prenatal Testing Taulukko: Vedran Stefanovic 11/2015
The consequences of NIPT (mis)use worldwide? Abandonment of ultrasound in fetal screening Unprofessional counselling Misuse of NIPT in screening for microdeletions Unneccessary rise in invasive prodecures
NIPT and ethical issues Potential to undermine informed consent just another blood test Risk of normalising test as routine impact on informed consent Increased societal pressure to test and terminate Misuse of NIPT for minor conditions Autonomy allows women to exercise reproductive autonomy by removing risk of miscarriage, but also threatens autonomy is the ease of the test results in pressure to take it. Use of NIPT for information only justice and equitable distribution of funds. Private access vs access to all Privacy of partner s rights
Discussion Equal access to NIPT as the second-tier screening to all pregnant HIGH-RISK (!) women in public sector No NIPT for twin pregnancies Private sector offers to anyone who pays The problem is aggressive offering of NIPT-plus 6 microdeletion pannel to low-risk pregnancies National register?
DISCUSSION Very high FPR for sex chromosome aneuploidies (revealed in private clinics, sent for counselling and further evaluation to University hospitals) No in-house NIPT analysis Insufficient implementation follow up in some university hospitals NIPT not yet implemented in national screening guidelines
Conclusions NIPT has changed the concept of fetal screening However, expectations (misinterpretaions?) are still too high Implementation should be monitored in each institution with NIPT as a screening method Cost are high and the universial screening is not cost-effective Pre- and post-test counselling are essential and there is a room for improvement