7about Maternal Serum Screening MSS is offered as a program with access to pre & post test information, genetic counselling and diagnostic services – cvs, amnio & ultrasound.Information forHealth Professionalsabout Maternal Serum Screening
11Screening“the systematic application of a test procedure to identify individuals at sufficient risk to warrant diagnostic investigations”CVS 12 wksAmniocentesis 15+wksMorphology Ultrasound 18+wksAim is to maximise detection of affected pregnancies and minimise false +ves
14Fetus must occupy 3/4 of the image Fetus must be in a Neutral positionHyperextension of fetal neck can increase the NT by 0.6 mmFlexion of the neck can decrease the NT by 0.4 mmUmbilical cord round the fetal neck ( 5 -10% of cases) can increase the NT by 0.8 mmAmniotic membrane and Nuchal membrane must be separateMeasure the max thickness of the subcutaneous translucency
15Increased nuchal translucency and exomphalos in a trisomy 18 fetus at 12 weeks of gestation
17Severe asymmetrical growth restriction in a 13-week fetus with triploidy.
18- NT is an ultrasonographic feature visible in 1st Tr of NUCHAL TRANSLUCENCY- NT is an ultrasonographic feature visible in 1st Tr ofpregnancy- NT results from an accumulation of fluid at the base offetal neckNT thickness increases with GA (0.8 to 1.6 mm)Non specific marker,thickness >2.5(3.0) mm associated with an increased risk of aneuploidy, cardiovascular & pulmonary defects, skeletal dysplasia, renal, metabolic defects & congenital infections & fetal demise.
19Variables Population Medians / MoM Gestational Age Maternal Age Recurrence RiskSingleton vs TwinsMaternal WeightEthnicityDiabetesSmokingAnalytical ImprecisionRisk Calculation ~ NT ~ Biochemistry ~ Combined ~ IntegratedOUTCOME
21Effectiveness of different methods of screening Screening for trisomy 21Effectiveness of different methods of screening100,000 pregnanciesMethod of screeningNumber detectedDetection rateScreen positive* 5%N=5,000Trisomy 21N=200* 2.5% Screen positiveIntegrated TestMaternal age6030%Serum biochemistry at 16 wks13065%Nuchal translucency (NT) at 12 wks75%150Fetal NT & ß-hCG & PAPP- A at 12 wks180*90%Nicolaides KH. Fetal nuchal translucency. Am J Obstet Gynecol 2004
23Background Risk Gestational age 20 40 60 80 100 10 15 25 30 35 65% Trisomy 2120406080100101525303515% Trisomy 1312% Trisomy 18<1% Triploidy95% 47xxx/xxy/xyy20% 45x%Nicolaides et al., The week scan, London 1999Snijders et al 1995
24Background Risk Maternal age 0.0001 0.001 0.01 0.1 1 10 20 25 30 35 40 44YearsRisk %Trisomy 21Trisomy 18Trisomy 13xxx/xxy/xyy45xTriploidyNicolaides et al., The week scan, London 1999Snijders et al 1995
26Marker Levels Change Significantly with Gestation Measured levels are converted to Multiples Of the Population Median or MoM values.1 MoM = Reference for all markersbeta hCG at 10 wks GAPatient IU/L = 2 multiplesMedian IU/LMoM values are independent of gestational age and concentration UnitsLogMoM values are used in calculations as they exhibit a Gaussian distribution ( Mean +/- SD)
31Twins Management Screening and Chorionicity Nuchal discordance (mono and dichorionic)Diagnostic tests (CVS and Amniocentesis)Selective feticideTwin to twin transfusionLaser ablation of vesselsDelivery
38Other Not NTD & Not DS: AFP < 2 MoM & DS risk is < 1 in 300 RISKSOpen Neural Tube Defects (NTD)Down syndrome / AneuploidyOtherNTD Down syndrome / Aneuploidy2nd Trimester 1st & 2nd Trimester↑ AFP ≥ 2 MoM ↑ Risk ≥ 1 in 300Independent of Maternal Age Age DependentMorphology scan CVS / Amnio~ 1/30 will have a NTD ~ 1/20 or 1/40 will have DSOther Not NTD & Not DS: AFP < 2 MoM & DS risk is < 1 in 300ButBiochemical results fall outside the Normal expected.
39Not NTD & Not Downs Profiles SAMSAS screened pregnancies N=62,5631st Trimester N= 26,9142nd Trimester N= 35,649ProfileNon DownsN= 206 (0.77%)ProfileNot NTD Not DownsN= 123 (0.35%)Total N = 329 (0.53%)OUTCOMESNOT KNOWNN = 25 (7.6%)NORMALN = 103 (31.3%)FETAL DEATHN = 171 (52%)ABNORMALN = 30 ( 9.1%)9 x Triploidy, 9 x T183 x T15, 3 x Anenceph.1st Tr2 x Turners, 2 x Mult. Abn.2 x Metabolic
40Not viable at time of screen. No NT measured Not Known= 4Normal= 2 (Obese~no NT)Fetal Death= 137Abnormal= 6 (1xTriploidy,2xXO,2xT15,1xAnencephaly)Anomalies Found 143/145Odds 1/1 ( 98.6%)N= 24Not Known= 2Normal= 0Fetal Death= 18Abnormal= 4 (2xT18,1xAnencephaly,1xMultiple Con. Abn.)Anomalies Found 22/22Odds 1/1 (100%)
41Viable at time of screen. Viable at time of screen. Not Known= 12Normal= 62Fetal Death= 13Abnormal= 12 (4xTrip.,6xT18,1xMultiple Con. Abn.,1xMetabolic)Anomalies Found 25/87Odds 1/3.5 ( 28.6%)N= 57Not Known= 7Normal= 39Fetal Death= 3Abnormal= 8 (4xTriploidy,1xT18,1xOther,1xAnencephaly,1xRenal)Anomalies Found 11/50Odds 1/4.5 ( 22%)
52Advantages of 1st trimester screening benefits of an early scanless false +ves & -vesless normal fetuses losthigher detectionpersonal benefits to patients from earlier diagnosisDisadvantagescost of the nuchal translucency scanlogistically more difficult to manage
53Logistical considerations? 1TR & 2TR screening will coexist.Management of reports & requests.How many risks, by whom and when?Audits and ongoing programme evaluation.
54How can these be addressed? Centralised service & database for,- all patient demographics- biochemical results- NT measurements & providers- reporting- recalculation of risks- retrievable data for analysisLogical software - risks linked to gestation (1TR & 2TR algorithms)
55Trends in state/based Down syndrome screening and invasive prenatal testing with the introduction of first trimester combined Down syndrome, South AustraliaMuller PR, Cocciolone R, Haan EA, et alAm J Obstet Gynecol 2007;196:315.e1-315.e7.
56Utilization of maternal serum Down syndrome screening % of all confinements 69-79%NS
57Utilization of second trimester maternal serum (∆) and first trimester combined Down syndrome screening (□), % of all confinements* P < 0.00175%49%**25%0.8%
58% confinements ≥ 35 years (•) of age vs % of confinements undergoing invasive prenatal tests (∆) 9.3%*7.6%
59Confinements ≥ 35 years of age undergoing invasive prenatal tests 43%* 24.8%* P < 0.001
60Number of invasive prenatal tests to detect one DS fetus YearDown syndrome casesRate of DS per invasive procedure*1995321/8619961/941997411/831998461/611999421/712000371/792001361/902002441/6620031/462004341/492005471/40** p < 0.001
61Number of invasive prenatal tests to detect one aneuploid fetus YearAneuploidy casesRate of aneuploidy per invasive procedure*1995511/351996461/471997501/381998651/311999601/332000561/322001551/3020022003641/2420041/212005911/15** p < 0.001
62Overall Prenatal Detected Down Syndrome cases (%) YearDown syndrome casesPrenatal detected DS cases(%)**19953271.9199681.319974170.719984673.919994271.420003770.320013658.320024465.9200381.020043488.220054783.0** p = 0.21
63Demonstrated an improved efficiency in the utilization of invasive prenatal tests Despite the increase in gravid women ≥ 35 years of age the number of invasive prenatal tests in this age group has significantly declinedDespite the significant decrease in invasive prenatal tests the overall antenatal detection of Down syndrome did not decrease, and appears to increase once the utilization of first trimester combined Down syndrome screening reaches > 30% of confinements
64To review changes in the utilization and effectiveness of state/population-based antenatal screening for NTDs in South Australia from 1986 to 2004
66Overall antenatal detection of NTD(%) YearAverage births/Yr(#)Average NTDs/YrOverall antenatal detection of NTD(%)19,714418619,43732*88.817,8672494.5 ***State-wide educational drive on the benefits of Folic Acidsupplementation for the reduction of NTDs 1994** p<0.001
67Despite a significant decrease in the utilization of MSAFP screening, the population-based detection of NTDs has increased significantly in South Australia.The decreased utilization of second trimester MSAFP represents improve clinician confidence in second trimester ultrasound for the detection of NTDs
69ADAM12, a disintegrin and metalloprotease The superfamily of zinc peptidases – MetzincinsReprolysins/AdamalysinsSVMPs (snake venom proteases)ADAMs (a disintegrin and metalloprotease)ADAMTS (with thrombospondin motifs)Matrix metalloproteases (MMPs)AstacinsSerralysinsADAM12 is a multidomain protein with protease, cell adhesion, fusion and signaling activities. ADAM12 is a member of the large family of ADAM12 proteins, of which more than 30 have been identified. 19 ADAM genes are currently known in humans. Human ADAM12 is encoded by a single gene located on chomosome 10q26.3, where ADAM8 also resides. ADAM12 gene has 2 distinct splice variants, producing the long ADAM12-L form and the shorter ADAM12-S form: ADAM12-S consists of 718 amino acids (secreted form), ADAM12-L consists of 881 amino acids (prototype transmembrane form)ADAM12 is one of only a few ADAMs that exist in two formsNote that ADAM12 cannot be measuredfrom EDTA plasma!
70ADAMs are focus in asthma, alzheimer and cancer research In humans ADAM mRNA is present at low levels in most adult tissueshuman placenta expresses very high levels of ADAM12A large proportion of human carcinomas express ADAM12breast carcinoma tissue and urine of breast cancer patients, liver metastases of colon carcinomaOverall, it appears that ADAMs are mainly expressed during growth and developmentNote that our license covers Maternal Health applications
72ADAMs are of high research focus pro-metalloproteasedisintegrintransmembranecytoplasmiccysteine-richEGF-likeSeveral studies has shown tha ADAMS are mainly located inside cellsTranslocation from intracellular storage to the cell surface might be regulatedADAM12 metalloprotease is activated inside the cell unlike matrixmetalloproteases which are secreted as proforms and become activatedoutside the cellADAM12-S cleaves IGFBP-3 and IGFBP-5 via its cysteine-rich domain, whichmay regulate bioavailability of IGF (PAPP-A is a protease for IGFBP-4)ADAM12 releases soluble HB-EGF acivating epidermal growth factor and thuspromotes cardiac hypertrophyADAM12 interacts with integrin and syndecan adhesion receptorsADAM12 has one of the longest cytoplasmic domains compared to other ADAMs;the tail is at least involved in the regulation of ADAM12 localization (inside the cell orat the cell surface)19 genes in the human