A contingent model for cell-free DNA testing to detect fetal aneuploidy after fi rst trimester combined screening
Carmen Cotarelo-Pérez
a,*, Raluca Oancea-Ionescu
a, Eloy Asenjo-de-la-Fuente
b, Dolores Ortega-de-Heredia
c, Patricia Soler-Ruiz
b, Pluvio Coronado-Martín
b, María Fenollar-Cortés
aaClinicalGeneticsUnit,HospitalUniversitarioClínicoSanCarlos,Madrid,Spain
bDepartmentofObstetricsandGynaecology,HospitalUniversitarioClínicoSanCarlos,Madrid,Spain
cDepartmentofBiochemistry,HospitalUniversitarioClínicoSanCarlos,Madrid,Spain
ARTICLE INFO
Articlehistory:
Received3May2018
Receivedinrevisedform20December2018 Accepted22December2018
Availableonline15January2019
Keywords:
Cell-freefetalDNAtest Chromosomalabnormalities Aneuploidy
Firsttrimestercombinedscreening Contingentmodel
ABSTRACT
Objective:Toassesstheresultsofthefirsttrimestercombinedtesttodesignaprenatalprotocolforthe introductionofthecell-freefetalDNAtestasacontingentscreeningmodel.
Method:Anobservationalretrospectivestudyin12,327singletonpregnanciestoanalyzetheresultsof thecombined firsttrimesterscreening,thenuchaltranslucency97.5percentile,theircytogenetic resultsandbirthoutcomes.
Results:Atotalof533(4.3%)pregnantwomenhadariskincombinedfirsttrimesterscreeningabove1/
300.Inthisgroup,sixtyninehadanunbalancedkaryotype.Theabnormal/normalkaryotyperatiowas1/
28inpregnantwomenwithintermediaterisk(1/51-1/300)fortrisomy21andtrisomy18,1/58with intermediateriskjustfortrisomy21and1/37withintermediateriskjustfortrisomy18.A19.8%ofthe unbalancedkaryotypeshadchromosomalabnormalitiesotherthantrisomies21,18and13.Twofalse negativescasesatfirsttrimestercombinedscreeningpresentedanuchaltranslucencyp97.5th. Conclusion:Weproposetheintroductionofthecell-freefetalDNAtestwhentheriskoffirsttrimester combinedscreeningisintermediate(1/51–1/300)andwhennuchaltranslucencyisp97.5thwithalow risk in the combined screening. This policy would allow us to continue to detect uncommon chromosomalabnormalities.
©2019TheAuthor(s).PublishedbyElsevierB.V.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
First trimester combined screening (FTCS) has reported detection rates for trisomy 21 (T21) of 85–90% with a false positiverateof3–5%[1,2]anditsinfluenceinwomen’sprenatal choiceshasalready beendemonstrated[3–5]. Pregnantwomen withalowriskatFTCSusuallydeclineaninvasivetestbecauseof theriskofmiscarriagethatisquotedin0.1–1%[6,7].Cell-freefetal DNA(cf-DNA)testinmaternalbloodforT21,trisomy18(T18)and trisomy13(T13)offersanalternativeoptionwithahighspecificity and sensitivity for all pregnant women but especially as a contingentscreeningmodelinwomenatriskforfetal common aneuploidies.
T21,T18andT13representedapproximately70%ofaneuploi- diesprenatallydetected [8,9], butthereareotherchromosomal abnormalitiesthatmustbeevaluatebeforetheimplementationof thecf-DNAtestinordertoavoidtheirundiagnosis[8,10–12].
TheaimofthisstudyistoassesstheresultsoftheFTCStodesign aprenatalprotocolinourhospital,withtheintroductionofthecf- DNA test as a contingent screening model to achieve a better selectionofpregnantwomenatriskforfetalaneuploidiesandto avoidtheinvasivetest.Wepresenttheanalysisofapopulationof pregnantwomenwiththeirresultsatbirthandproposeacut-off riskfortheintroductionofthecf-DNAtestforT21,T18andT13as wellastheinclusionofothercriteriaforthecf-DNAtest.
Methods
Weperformedanobservationalretrospectivecohortstudy,to evaluate theresults oftheFTCS andtheprenatalandpostnatal cytogeneticstudies,during2009–2014,onpregnantwomenwho came to our hospital. The inclusion criteria were all singleton
* Correspondingauthorat:ClinicalGeneticsUnit.HospitalUniversitarioClínico SanCarlos,C/ProfMartínLagoss/n.,28040Madrid,Spain.
E-mailaddress:[email protected](C.Cotarelo-Pérez).
http://dx.doi.org/10.1016/j.eurox.2019.100002
2590-1613/©2019TheAuthor(s).PublishedbyElsevierB.V.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/
).
ContentslistsavailableatScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology: X
j o u r n al h o m e p a g e : w w w . el s e v i e r . c o m / l o c a t e / e u r o x
pregnancies who were undergone to FTCS and the exclusion criteriathosewithnoFTCS,twinpregnanciesormiscarriages.
Allpregnantwomenunderwentanultrasoundscanbetween10 and14weeks’gestationalformeasuringcrown-rumplengthand nuchaltranslucency(NT)followingbyabiochemical analysisof the pregnancy-associated plasma protein-A (PAPP-A) and β fraction of free human chorionic gonadotrophin at the same day.NTpercentilewasestimatedwiththescaleofBorrelletal[13].
FTCSwasperformedandprovidedariskassessmentforT21and T18(SsdwLabV.5.0.©SBPSoftwareCB.Spain).Pregnancieswitha FTCSriskgreaterthan1/300forT21orT18wereconsideredatrisk forfetalaneuploidies.Pregnantwomenwithadvancedmaternal age(AMA, 35 years old), abnormal ultrasound, FTCS at risk, family or personal history of aneuploidies or maternal anxiety werereferredforprenatalcounselling.Aninvasiveprenataltesting bychorionicvillussamplingoramniocentesiswasofferedtothem and a rapidtest by quantitative fluorescence-polymerasechain reaction (QF-PCR, Devyser Compact v3) for themost common aneuploidiesandakaryotypestudywereperformed.Pregnancies withriskatFTCS1/50forT21orT18wereconsideredathighrisk, with a FTCS risk between 1/51–1/300 for T21 or T18 were consideredatintermediateriskandwithaFTCSrisk<1/300forT21 andT18wereconsideredatlowrisk.Inpregnancieswithhighrisk oranabnormalultrasoundscan,subtelomericandmicrodeletion syndromeswereruledoutbymultiplexligationdependentprobe amplification techniques (MLPA, Salsa P036, P070, P245, MRC Holland)orarraycomparativegenomichybridization(array-CGH, KaryoNIM60K1prenatal),aslong astheresultsofQF-PCRand karyotypeswerenormal.Birthoutcomedatawerecompiledand postnatal karyotypes were performed if newborns physical examinationsuggestedachromosomalsyndrome.
In order todecide the FTCS risk cut-offin which pregnant womencouldbenefitfromcf-DNAtestforT21,T18andT13asan alternative option to an invasive procedure, we analyzed the prenatalandpostnatalunbalancedkaryotypesclassifyingthemin threegroups:high,intermediateandlowriskjustforT21,justfor T18andforbothtrisomies(T21-T18)atFTCS.Otherriskcut-offsfor T21andT18atFTCShavealsobeenevaluated.Falsenegativecases forT21andNTpercentileinourriskgroupswereevaluated.Other chromosomal abnormalities with relevant clinical significance whichcouldnotbedetectedbycf-DNAtestwereincludedintothe analysis.
Thisstudywasapprovedbytheresearchethicscommitteeof ourhospital.
Results
During the period 2009–2014 a total of 12,327 singleton pregnanciescametoourhospitalforfetalscreeningofcommon aneuploidiesbyFTCS.Table1showsdemographicandclinicaldata ofourpopulation.
Fig.1showsaschematicdistributionofpregnantwomen.In 954 cases an invasive prenatal test was performed for fetal karyotype,whichwasnormalorbalancedin878cases(92%).There were 76 unbalanced prenatal karyotypes and 5 unbalanced postnatalkaryotypes.Theprevalenceofchromosomalabnormali- tiesinourcohortwas0.7%.
FTCSandunbalancedkaryotypes
Therewere533(4.3%of12,327)ofallpregnantwomenwith FTCSriskabove1/300.Only12.9%ofthesepregnancieswithFTCS at risk had an unbalanced karyotype. The results of FTCS and karyotypesstudiesin ourriskgroupsareshowninTable2.The detectionrateofFTCSforT21andT18was88.5%witha4%offalse positives.ThedetectionrateonlyforT21was83.3%witha2.3%of falsepositives.Thepositivepredictivevalueswere10.1%and10.9%
forbothT21-T18andonlyforT21,respectively.
T21,T18andT13represented80.2%ofunbalancedkaryotypesin ourcohort.AllT18andT13hadaFTCSatrisk.Therewere39cases ofT21prenatallydetected,35byaFTCSatrisk(R1/300),3by abnormalultrasoundand1byAMA.Intheremainingabnormal group, 8.65% of the cases weresex chromosomal aneuploidies (SCAs),8.65%otheruncommonchromosomalabnormalitiesand 2.5%weretriploidy.Inpregnancieswithhighrisk(1/50)inthe FTCS were detected 43% of the uncommon chromosomal abnormalities, and 57%weredetected in thelow risk groupin the FTCS, all of them by karyotype. There were no cases in pregnancieswithintermediateriskintheFTCS.
All the complementary studies by MLPA or array-CGH in pregnancieswithhighrisk(R1/50)intheFTCSorwithabnormal ultrasound scan, as long as they had normal QF-PCR and karyotypes,werenormal.
FTCSriskcut-offs
TheTable3 showsthedistributionofseveralrisk cut-offsat FTCSaccordingtoT21,T18andothersunbalancedkaryotypes.Of the81unbalancedchromosomalabnormalities,60%(49/81)were
Table1
Demographicandclinicaldatain12,327pregnantwomen.
Populationdatan=12,327 Risk1/50n=147 Risk1/51–1/300n=386 Risk<1/300n=11,794
Maternalage 36.34.7 36.94.4 31.15.4
Weight 65.912.2 71.615.2 62.811.1
Size 161.66.6 163.36.5 1626.8
Smoker 24(16.3) 71(18.4) 1,432(12.2)
Origin
Caucasian 108(73.5) 275(71.2) 7,587(64.3)
Afro-Caribbean 2(1.4) 5(1.3) 516(4.4)
Asian 1(0.7) 9(2.3) 410(3.5)
Arabs 4(2.7) 9(2.3) 304(2.6)
South-American 30(20.4) 79(20.5) 2,769(23.5)
Others 2(1.4) 9(2.3) 208(1.8)
Nuchaltranslucency(mm) 3.52 1.50.6 1.30.3
Crown-rumplength(mm) 57.68.8 61.68.3 60.48.1
aFree-βHCG(MoM) 1.41.3 1.31.2 1.20.9
bPAPP-A(MoM) 0.690.5 0.630.5 1.30.7
aFree-βHCG:βfractionoffreehumanchorionicgonadotrophin.
b PAPP-A:Pregnancy-associatedplasmaprotein-A.Dataaregivenasfrequenciesandpercentages(%)forqualitativevariablesandasmeanandstandarddeviationfor quantitativevariableswithsymmetricdistribution.
Fig.1.Distributionofpregnantwomenreferredforprenatalcounselling.
Table2
ResultsofFTCSandkaryotypestudiesperformedinpregnantwomenbyriskgroupduring2009–2014.
†FTCS
RiskforT21-T18 Riskjustfor T21
Riskjustfor T18
Low risk
FTCSRiskgroups zHR-T21 xIR-T21 HR-
T21 IR- T21
{LR-T21 LR-T21
††HR-T18 zzIR- T18
HR- T18
IR- T18
xxLR-T18 HR- T18
IR- T18
LR-T18 Total
Pregnantwomenoneachriskgroup 6 20 2 28 92 173 27 185 11,794 12,327
Invasivetest 6 20 1 19 81 108 18 103 598 954
Normalorbalancedkaryotype 0 5 1 18 49 105 12 99 589 878
Unbalancedkaryotype 6 15 0 1 33 3 6 5 12 81
Trisomy21 6 1 a26 2 g7 42
Trisomy18 6 6 6 e1 19
Trisomy13 3 1 4
MonosomyX 2 2
Triploidy 1 1 2
SexualChromosomalAbnormalities b1 d1 f2 h1 5
UncommonChromosomalAbnormalities c3 i4 7
Ratiobetweenunbalancedkaryotypeandpregnantwomenoneachrisk group
1:1 1:1.2 0:2 1:28 1:3 1:58 1:4.5 1:37 1:983 1:152
†FTCS:FirstTrimesterCombinedScreening.
z HR-T21:HighRiskforT21(1/2-1/50).
x IR-T21:IntermediateRiskforT21(1/51-1/300).
{LR-T21:LowRiskforT21(<1/300).
†† HR-T18:HighRiskforT18(1/2-1/50).
zzIR-T18:IntermediateRiskforT18(1/51-1/300).
xxLR-T18:LowRiskforT18(<1/300).
a25Prenataland1postnatalkaryotypes.
b 1mosaicXXY/XYTrisomy.
c1MosaicTrisomy22,1PartialDuplication5qand1PartialTrisomy14qwithPartialMonosomy17q.
d XXXTrisomy.
e1PostnatalKaryotype.
f 1XYYTrisomyand1MosaicMonosomyX.
g 4Prenataland3postnatalkaryotype.
hXXYTrisomy.
i 1MosaicTetraploidy,1MosaicTrisomy20,1Mosaic13qDeletionand1Supernumerarymarkerchromosome15.
detectedwhen the riskwas greater than1/10 and 74% (60/81) whenitwasgreaterthan1/50.The97.7%ofthepregnanciesinthe intermediateriskgroup(1/51-1/300)had anormal outcome.In thisintermediateriskgrouptherewere9unbalancedkaryotypes (9/386):threeT21,oneT18,oneT13,onetriploidyandthreeSCAs cases.Inthelowriskgroup(<1/300)therewere25%(5/20)ofthe chromosomal abnormalities others than T21 and T18. These 5 unbalancedkaryotypesareshowninTable2,andonlythepartial deletion of 13q chromosome mosaicism detected by a Dandy- Walkermalformationonsecondtrimesterultrasoundhadclinical relevance.
FalsenegativecasesforT21
ThesevenfalsenegativescasesoftheFTCSforT21areshownin Table4.Twoofthem(numbers1and5)hadaFTCSriskbetween1/
301-1/1000andbothhadaNTin97.5percentile(p97.5th).
NTandunbalancedkaryotypes
Therewerea total amountof 38 caseswithNThigher than p97.5thandlowriskforT21atFTCS(21cases,GroupA+17cases, GroupB,Table5),and33ofthesepregnantwomenwereunder35 yearsold.Therewere35caseswithaNTbetweenp97.5th-p99th andonlyT21caseshavebeendetected.Thetwofalsenegativesof theFTCSforT21wereinthisgroup(GroupA,Table5).Ofthe142 fetuseswithaNTp99th(GroupB,Table5), 17casespresentedlow riskforT21andnormaloutcome.
cf-DNAascontingentscreeningmodel
Theintroductionofthecf-DNAtestforT21,T18andT13willbe recommendedinourhospitalasfirstchoiceinpregnantwomen withanintermediateriskatFTCS(1/51-1/300)andinthosewitha NTp97.5thandlowriskatFTCS(<1/300).Aninvasivetestwill
berecommendedinpregnantwomenwithariskatcombinedtest 1/50.
Discussion
In our series, 74% (60/81) of chromosomal unbalanced abnormalitieswithserious effectonfetusphenotype, including uncommonaneuploidies,hadahighrisk(R1/50)attheFTCS.At thisriskcut-offwecandetectthehighestpercentageofT21(32/
42) and T18 (18/19) cases as well as 50% (10/20) of others unbalanced karyotypes: monosomy X, T13, triploidy and the uncommonchromosomalabnormalitiesassociatedwithadverse outcome.Ourresultsareaccordingwithpreviousreports[11,14].
Also,itseemsthattheratiobetweenunbalancedkaryotypeand pregnanciesoneachriskgroupssupporttherecommendationof aninvasivetest(between1/1and1/4.5,Table2).
Wehaveconsideredasintermediateriskthepregnancieswhich haveaFTCSbetween1/51-1/300becauseunbalancedkaryotypes representonly2.3%(9/386)ofthecases.Inthisintermediaterisk grouptheratio betweenchromosomalabnormalities and preg- nanciesoneachriskgroupssuggestsacf-DNAtest(between1/28 and1/58,Table2).Otherauthorsraisethepossibilityofofferingcf- DNAtestatariskcut-offof1/11to1/500or1/1000[15].Inour seriesthereare11.9%ofT21and26.3%ofT18betweentheriskcut- off 1/11-1/50 which makesus consideran invasive test in this group.
Therearereportswhichanalyzethedistributionofriskfrom FTCS according to T21, T18, T13 and others chromosomal abnormalities outcome. The authors propose different policies fortheintroductionofcf-DNAtest.Withacut-offriskat1/1000, their detectionrate for T21 was 98% [15,16]. In our series the detectionrateatthiscut-offwouldbe88%butbetween1/301– 1000therewere1048pregnantwomenandonlytwocasesofT21.
Sothisoptionwouldincreasethecostofcf-DNAtestimplementa- tion.BesideswecoulddetectthistwoT21casesthroughtheNT Table3
DistributionoftheFTCSriskcut-offsaccordingtoT21,T18andothersunbalancedkaryotypes.
Riskcuttoffsat†FTCS Trisomy21cases(%)n=42 Trisomy18cases(%)n=19 Othersunbalancedkaryotypescases(%)n=20 Unbalanced/totalcases
R1/10 27(64.3) 13(68.4) 9(45) 49/86
R1/50 32(76.2) 18(94.7) 10(50) 60/147
R1/11-1/50 5(11.9) 5(26.3) 1(5) 11/150
R1/11-1/300 8(19) 6(31.6) 6(30) 20/447
R1/51-1/300 3(7.1) 1(5.3) 5(25) 9/386
R1/301-1/1000 2(4.8) _ 2(10) 4/1048
R1/1001-1/2000 3(7.1) _ 1(5) 4/1215
R1/2001-1/3000 1(2.4) _ _ 1/926
R1/3001-1/6000 1(2.4) _ 1(5) 2/2130
R<1/6001 _ _ 1(5) 1/6475
†FTCS:FirstTrimesterCombinedScreening.WhentherewerehighorintermediaterisksforbothT21-T18,thehighestriskofthetwowasconsideredtostratifytheresults ofthekaryotypes.Datesaregivenasfrequenciesandpercentages.
Table4
FalsenegativescasesatFTCSforT21.
Casenumber Trisomy21riskat{FTCS Maternalageatterm †NuchalTranslucencymm(Percentile) Indicationforprenatalcounselling
1 1/445 28 3.1(p97.5th) NT>3mm
2 1/1167 39 1.5(p5th) xFHD
3 1/1273 28 1.8(p75th) xFHD
4 1/1626 38 1(p10th) zAMA
5 1/882 30 2.9(p97.5th)
6 1/2687 24 1.9(p75th)
7 1/5116 30 1(p10th)
{FTCS:Firsttrimestercombinedscreening.
†NTmillimeters(percentile)dependingonCRL[13].
x FHD:Fetalheartdefect.
z AMA:Advancedmaternalage.
percentilebecausethesetwocaseshadaNTpercentilebetween p97.5th–p99thandlowriskatFTCSina<35yearsoldwomen.The scopeofmaternalageonthecalculationofrisksinFTCSisprobably modifyingtheriskdespitetheNTmeasurement.Wecoulddetect moreT21casesifweofferedacf-DNAtesttoallpregnancieswith NTp97.5thwhenFTCSriskislowanditsupposeasmallincrease in costbecause there are21 pregnantwomen that meet these criteria(GroupA,Table5).
AnincreasedNT(p99thor3.5mm)isassociatedwithahigh riskofchromosomalabnormalities[11],beingmonosomyX,T21 andT18casesthemorefrequentunbalancedkaryotypesfoundin thesecases[14,17,18].NTinp99thisanindicationforinvasivetest butwethinkthatitisnecessarytogettheresultofFTCSinthese pregnanciesbecauseitprovidesinformationthatcanhelpwomen tomakeadecisionaboutalltheiroptions,mainlywhentheNTis
<3.5mm.Inourseries,therewasonlyoneabnormalkaryotype (T21)withintermediateriskforT21andnonewithlowriskforT21 despiteoftheNTinp99th.Althoughotherauthorsreportdifferent percentagesofuncommonchromosomal abnormalitiesin preg- nancieswithaNTinp99thdependingonthetechniqueusedforits detection[19,20]inourseriesallthecomplementarymolecular studieswerenormalandhadanormaloutcome.Sowecouldoffer cf-DNAtesttoallpregnancieswithNTinp99thandlowriskfor T21.
Evidencedataabouttheperformanceofcf-DNAtestinageneral populationshowa positivepredictive valuerangefor T21from 45.5%[21]to94.4%[22]andshowhighsensitivityandspecificityin lowriskpopulation[23].Becausethepositivepredictivevalueof FTCSislessthanincf-DNAtestandtheFTCSfalsenegativecasesfor T21aremorefrequentinwomenundertheageof35,itwouldbe necessary to perform the cf-DNA test into general obstetric population[24].Currentlythisisnotpossibleinourpublichealth serviceduetothecostofthetest.
There are several studies that have shown that contingent modelcanbecost-effectivebecauseitimpliesareductioninthe rateoftheinvasivetestsandalowerprocedure-relatedlossrate [25,26].Although thecost effectivenessstudiesshouldbedone with caution due to the largenumber of topics that must be evaluated,inourcohortwehave7falsenegativescasesforT21that wouldmeananadditionalcostbetween594,000–790,000sfor thehealth and social careper case [27,28], and therefore that would imply an additional cost between 337–448 s for each pregnantwoman.Withthistheoreticalsavingwecouldintroduce thecf-DNAtoallpregnantwomen,butmaintainingtheFTCSthat allowsustohaveadditionalinformationonPAPP-Alevelstoassess theriskofpreeclampsiaorpretermdelivery.Besides,bothFTCS and TN allow us to identify otherchromosomal abnormalities
otherthanT21whicharenotestimatedbythecf-DNA.Inaddition, cf-DNAalsohasfalsenegativeandpositiveresults,althoughthere areveryfew.Detectingpathologicalcasesdoesnotalwaysimply costreductionsinceweoughtalwaystorespecttheautonomyof thepregnantwomen. Inthenearfuture amoreaccurate study abouteconomicfeasibilityshouldbedone.
Availabledataindicatethatcf-DNAtesthaslessaccuracyfor SCAsthanforT21andT18,mainlyduetoaconfinedplacentalor maternalmosaicismthatcanincreasethefalsepositiverates[29– 31].WeassumethatwewillnotdiagnoseSCAsdifferentthannon mosaicmonosomyXifwedonotanalyzethefetalsexbycf-DNA test. These SCAs have a mild phenotype and theirdiagnosis is usuallyfortuitouswhen invasivetest areperformedbyAMAor FTCSatrisktoruleoutaT21fetus[32].Inaddition,Xchromosome aneuploidies have been associated to AMA and these cases probably remain undiagnosed at this moment because in our cohort,88%(3,022/3,423)ofpregnantwomenwithAMAandlow riskatFTCSdeclinedaninvasivetest.
Itisnecessarytoremindtheimportantroleofultrasoundscan screening that could detect fetus at risk for any chromosomal abnormalities,includinguncommonabnormalities,triploidiesand falsenegativecasesofcf-DNAtestorFTCS.Inourseries,threeof theFTCSfalsenegatives,onetriploidyandapartialdeletionof13q chromosomemosaicismweredetectedbyanabnormalultrasound scanandtheycouldbemissedbycf-DNAtestorFTCS.
Regardlessofourrecommendations,allpregnantwomenmust beinformedaboutthechromosomalabnormalitiesthatcouldntbe detectedbycf-DNAtestorbysecondtrimesterultrasoundaswell asaboutallprenataldiagnosisoptions.
Oneofthelimitationsofthisstudyisthatthecohortbelongs onlytoourcenter sothis proposedpolicycannotbeappliedto anotherpopulation.AnotherlimitationcouldbethelackofMLPA orarray-CGHresultsthatdetectunusualcrypticanomaliesinall invasive testsofpregnantwomenatintermediate riskand that couldhaveafutureclinicalimpactonnewborn,althoughthedata at birth were normal. The low prevalence of uncommon chromosome abnormalities could affect the validation of our newpolicy.
Here we present a contingent screening model for the introduction of cf-DNA test in ourhospital in two pregnancies group:i)thosewithanintermediateriskatFTCSandii)thosewith alowriskatFTCSandNTp97.5th.Weconsiderthatthosetwo assumptions could allow us to detect the most common aneuploidies, and todecrease the number of invasive test and consequently,the fetal losses.Our datasuggest thatthe others uncommonchromosomalabnormalitieswithsevereeffectinthe fetal phenotypewouldnotbeunderdiagnosed sinceallof them Table5
KaryotypeandNuchalTraslucency97.5thpercentile[13].
GroupA:p97.5th†NT<p99th(35cases) GroupB:NTp99th(142cases)
zFTCS xHR-T21 {IR-T21 ††LR-T21 HR-T21 IR-T21 LR-T21
Age(years) <35 35 <35 35 <35 35 <35 35 <35 35 <35 35 Total
Trisomy21 – 1 – – a2 – 8 21 1 – – – 33
OtherUnbalancedFetalKaryotype – – – – – – 4 17 – – – – 21
NormalKaryotype – – 5 8 14 5 27 25 12 10 b17 – 123
Total 1 13 21 102 23 17 177
†NT:Nuchaltranslucency.
z FTCS:CombinedFirstTrimesterScreeningtest.
x HR-T21:HighRiskforT21(1/2-1/50).
{IR-T21:IntermediateRiskforT21(1/51-1/300).
†† LR-T21:LowRiskforT21(<1/300).
afalsenegativescasesforT21.
b 14caseswithNT<3,5mm.
hadahighriskatFTCSoranabnormalultrasoundscaninwhichit wasrecommendedtoperformaninvasivetest.Thenewproposed policyhasbeenimplementedinourhospitalsinceOctober2015 andfuture analysesof those datawiththepreviouspolicywill allowustoverifyandtoimproveourprenatalprotocol.
Contributiontoauthorship
Carmen Cotarelo-Pérez, Raluca Oancea-Ionescu and María Fenollar-Cortéscontributedequallytothiswork.
Disclosurestatement
Theauthorsdeclarenoconflictofinterest.
Fundingsources None.
Acknowledgements
Weappreciatethecollaborationfortheanalysisofthedatato predoctoralstudentMissIreneSerranoGarcía,Mathematicsofthe ResearchUnit,DepartmentofEpidemiology.
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